# documents

url: http://arxiv.org/abs/1411.5360v1
scrape_date: 2025-02-28T11:50:23.986410
content_type: markdown
hash: 3b42b7af8d8c73914a0aa9c671e92223b020a39b9ca57b9bd237ded3453e9929
title:
[1411.5360v1] Communication over the network of binary switches regulates the activation of A$_{2A}$ adenosine receptor

content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [q-bio](/list/q-bio/recent) > arXiv:1411.5360v1 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Quantitative Biology > Biomolecules

**arXiv:1411.5360v1** (q-bio) 

[Submitted on 19 Nov 2014]

# Title:Communication over the network of binary switches regulates the activation of A$_{2A}$ adenosine receptor

Authors:[Yoonji Lee](https://arxiv.org/search/q-bio?searchtype=author&query=Lee,+Y), [Sun Choi](https://arxiv.org/search/q-bio?searchtype=author&query=Choi,+S), [Changbong Hyeon](https://arxiv.org/search/q-bio?searchtype=author&query=Hyeon,+C)

View a PDF of the paper titled Communication over the network of binary switches regulates the activation of A$_{2A}$ adenosine receptor, by Yoonji Lee and Sun Choi and Changbong Hyeon

[View PDF](/pdf/1411.5360v1)

> Abstract:Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total $\sim$ 5 $\mu$sec molecular dynamics simulations of A$_{2A}$ adenosine receptor (A$_{2A}$AR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield $2^{10}$ microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor [this http URL](http://activation.Finally), our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif. 

Comments: | 28 pages, 17 figures  
---|---  
Subjects: |  Biomolecules (q-bio.BM); Molecular Networks (q-bio.MN)  
Cite as: | [arXiv:1411.5360](https://arxiv.org/abs/1411.5360) [q-bio.BM]  
  | (or  [arXiv:1411.5360v1](https://arxiv.org/abs/1411.5360v1) [q-bio.BM] for this version)   
  |  <https://doi.org/10.48550/arXiv.1411.5360> Focus to learn more arXiv-issued DOI via DataCite  
Journal reference: | PLoS Comp. Biol. (2015) 11(2): e1004044  
Related DOI:  | <https://doi.org/10.1371/journal.pcbi.1004044> Focus to learn more DOI(s) linking to related resources   
  
## Submission history

From: Changbong Hyeon [[view email](/show-email/19ae62aa/1411.5360)]   
**[v1]** Wed, 19 Nov 2014 19:05:32 UTC (4,878 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled Communication over the network of binary switches regulates the activation of A$_{2A}$ adenosine receptor, by Yoonji Lee and Sun Choi and Changbong Hyeon

  * [View PDF](/pdf/1411.5360v1)
  * [TeX Source](/src/1411.5360v1)
  * [Other Formats](/format/1411.5360v1)



[view license](http://arxiv.org/licenses/nonexclusive-distrib/1.0/ "Rights to this article")

Current browse context: 

q-bio.BM

[< prev](/prevnext?id=1411.5360&function=prev&context=q-bio.BM "previous in q-bio.BM \(accesskey p\)")   |   [next >](/prevnext?id=1411.5360&function=next&context=q-bio.BM "next in q-bio.BM \(accesskey n\)")   


[new](/list/q-bio.BM/new) |  [recent](/list/q-bio.BM/recent) | [2014-11](/list/q-bio.BM/2014-11)

Change to browse by: 

[q-bio](/abs/1411.5360?context=q-bio)  
[q-bio.MN](/abs/1411.5360?context=q-bio.MN)  


### References & Citations

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:1411.5360)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=1411.5360)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:1411.5360)



[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/1411.5360&description=Communication over the network of binary switches regulates the activation of A$_{2A}$ adenosine receptor "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/1411.5360&title=Communication over the network of binary switches regulates the activation of A$_{2A}$ adenosine receptor "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/1411.5360) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)



  *[Related DOI]: Digital Object Identifier


url: http://arxiv.org/abs/2412.17780v3
scrape_date: 2025-02-28T11:50:23.988411
content_type: markdown
hash: c47a4f0190cd385436baf908971194655b23eb928fbac9421d0eb66fe809921d
title:
[2412.17780v3] PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion

content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [q-bio](/list/q-bio/recent) > arXiv:2412.17780v3 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Quantitative Biology > Biomolecules

**arXiv:2412.17780v3** (q-bio) 

[Submitted on 23 Dec 2024 ([v1](https://arxiv.org/abs/2412.17780v1)), last revised 1 Jan 2025 (this version, v3)]

# Title:PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion

Authors:[Sophia Tang](https://arxiv.org/search/q-bio?searchtype=author&query=Tang,+S), [Yinuo Zhang](https://arxiv.org/search/q-bio?searchtype=author&query=Zhang,+Y), [Pranam Chatterjee](https://arxiv.org/search/q-bio?searchtype=author&query=Chatterjee,+P)

View a PDF of the paper titled PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion, by Sophia Tang and 2 other authors

[View PDF](/pdf/2412.17780v3) [HTML (experimental)](https://arxiv.org/html/2412.17780v3)

> Abstract:Peptide therapeutics, a major class of medicines, have achieved remarkable success across diseases such as diabetes and cancer, with landmark examples such as GLP-1 receptor agonists revolutionizing the treatment of type-2 diabetes and obesity. Despite their success, designing peptides that satisfy multiple conflicting objectives, such as target binding affinity, solubility, and membrane permeability, remains a major challenge. Classical drug development and structure-based design are ineffective for such tasks, as they fail to optimize global functional properties critical for therapeutic efficacy. Existing generative frameworks are largely limited to continuous spaces, unconditioned outputs, or single-objective guidance, making them unsuitable for discrete sequence optimization across multiple properties. To address this, we present PepTune, a multi-objective discrete diffusion model for the simultaneous generation and optimization of therapeutic peptide SMILES. Built on the Masked Discrete Language Model (MDLM) framework, PepTune ensures valid peptide structures with state-dependent masking schedules and penalty-based objectives. To guide the diffusion process, we propose a Monte Carlo Tree Search (MCTS)-based strategy that balances exploration and exploitation to iteratively refine Pareto-optimal sequences. MCTS integrates classifier-based rewards with search-tree expansion, overcoming gradient estimation challenges and data sparsity inherent to discrete spaces. Using PepTune, we generate diverse, chemically-modified peptides optimized for multiple therapeutic properties, including target binding affinity, membrane permeability, solubility, hemolysis, and non-fouling characteristics on various disease-relevant targets. In total, our results demonstrate that MCTS-guided discrete diffusion is a powerful and modular approach for multi-objective sequence design in discrete state spaces. 

Subjects: |  Biomolecules (q-bio.BM); Artificial Intelligence (cs.AI)  
---|---  
Cite as: | [arXiv:2412.17780](https://arxiv.org/abs/2412.17780) [q-bio.BM]  
  | (or  [arXiv:2412.17780v3](https://arxiv.org/abs/2412.17780v3) [q-bio.BM] for this version)   
  |  <https://doi.org/10.48550/arXiv.2412.17780> Focus to learn more arXiv-issued DOI via DataCite  
  
## Submission history

From: Pranam Chatterjee [[view email](/show-email/2d8ce335/2412.17780)]   
**[[v1]](/abs/2412.17780v1)** Mon, 23 Dec 2024 18:38:49 UTC (42,470 KB)  
**[[v2]](/abs/2412.17780v2)** Mon, 30 Dec 2024 16:41:00 UTC (42,439 KB)  
**[v3]** Wed, 1 Jan 2025 15:34:56 UTC (42,440 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion, by Sophia Tang and 2 other authors

  * [View PDF](/pdf/2412.17780v3)
  * [HTML (experimental)](https://arxiv.org/html/2412.17780v3)
  * [TeX Source](/src/2412.17780v3)
  * [Other Formats](/format/2412.17780v3)



[ ![license icon](https://arxiv.org/icons/licenses/by-nc-nd-4.0.png) view license ](http://creativecommons.org/licenses/by-nc-nd/4.0/ "Rights to this article")

Current browse context: 

q-bio.BM

[< prev](/prevnext?id=2412.17780&function=prev&context=q-bio.BM "previous in q-bio.BM \(accesskey p\)")   |   [next >](/prevnext?id=2412.17780&function=next&context=q-bio.BM "next in q-bio.BM \(accesskey n\)")   


[new](/list/q-bio.BM/new) |  [recent](/list/q-bio.BM/recent) | [2024-12](/list/q-bio.BM/2024-12)

Change to browse by: 

[cs](/abs/2412.17780?context=cs)  
[cs.AI](/abs/2412.17780?context=cs.AI)  
[q-bio](/abs/2412.17780?context=q-bio)  


### References & Citations

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:2412.17780)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=2412.17780)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:2412.17780)



[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/2412.17780&description=PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/2412.17780&title=PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/2412.17780) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)


url: http://arxiv.org/abs/0809.1717v1
scrape_date: 2025-02-28T11:50:23.988415
content_type: markdown
hash: a2d37c86c830d711b65433fc280c868c9f9972108ab2417bcaad956ea5df0637
title:
[0809.1717v1] Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit

content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [q-bio](/list/q-bio/recent) > arXiv:0809.1717v1 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Quantitative Biology > Biomolecules

**arXiv:0809.1717v1** (q-bio) 

[Submitted on 10 Sep 2008]

# Title:Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit

Authors:[Jianfeng Liu](https://arxiv.org/search/q-bio?searchtype=author&query=Liu,+J) (IGF), [Damien Maurel](https://arxiv.org/search/q-bio?searchtype=author&query=Maurel,+D) (IGF), [Sébastien Etzol](https://arxiv.org/search/q-bio?searchtype=author&query=Etzol,+S) (IGF), [Isabelle Brabet](https://arxiv.org/search/q-bio?searchtype=author&query=Brabet,+I) (IGF), [Hervé Ansanay](https://arxiv.org/search/q-bio?searchtype=author&query=Ansanay,+H), [Jean-Philippe Pin](https://arxiv.org/search/q-bio?searchtype=author&query=Pin,+J) (IGF), [Philippe Rondard](https://arxiv.org/search/q-bio?searchtype=author&query=Rondard,+P) (IGF)

View a PDF of the paper titled Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit, by Jianfeng Liu (IGF) and 6 other authors

[View PDF](/pdf/0809.1717v1)

> Abstract: The gamma-aminobutyric acid type B (GABAB) receptor is an allosteric complex made of two subunits, GABAB1 (GB1) and GABAB2 (GB2). Both subunits are composed of an extracellular Venus flytrap domain (VFT) and a heptahelical domain (HD). GB1 binds GABA, and GB2 plays a major role in G-protein activation as well as in the high agonist affinity state of GB1. How agonist affinity in GB1 is regulated in the receptor remains unknown. Here, we demonstrate that GB2 VFT is a major molecular determinant involved in this control. We show that isolated versions of GB1 and GB2 VFTs in the absence of the HD and C-terminal tail can form hetero-oligomers as shown by time-resolved fluorescence resonance energy transfer (based on HTRF technology). GB2 VFT and its association with GB1 VFT controlled agonist affinity in GB1 in two ways. First, GB2 VFT exerted a direct action on GB1 VFT, as it slightly increased agonist affinity in isolated GB1 VFT. Second and most importantly, GB2 VFT prevented inhibitory interaction between the two main domains (VFT and HD) of GB1. According to this model, we propose that GB1 HD prevents the possible natural closure of GB1 VFT. In contrast, GB2 VFT facilitates this closure. Finally, such inhibitory contacts between HD and VFT in GB1 could be similar to those important to maintain the inactive state of the receptor. 

Subjects: |  Biomolecules (q-bio.BM); Neurons and Cognition (q-bio.NC)  
---|---  
Cite as: | [arXiv:0809.1717](https://arxiv.org/abs/0809.1717) [q-bio.BM]  
  | (or  [arXiv:0809.1717v1](https://arxiv.org/abs/0809.1717v1) [q-bio.BM] for this version)   
  |  <https://doi.org/10.48550/arXiv.0809.1717> Focus to learn more arXiv-issued DOI via DataCite  
Journal reference: | The Journal of Biological Chemistry 279, 16 (2004) 15824-30  
Related DOI:  | <https://doi.org/10.1074/jbc.M313639200> Focus to learn more DOI(s) linking to related resources   
  
## Submission history

From: Philippe Rondard [[view email](/show-email/e81b9966/0809.1717)] [via CCSD proxy]   
**[v1]** Wed, 10 Sep 2008 07:04:48 UTC (388 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit, by Jianfeng Liu (IGF) and 6 other authors

  * [View PDF](/pdf/0809.1717v1)
  * [Other Formats](/format/0809.1717v1)



[view license](http://arxiv.org/licenses/nonexclusive-distrib/1.0/ "Rights to this article")

Current browse context: 

q-bio.BM

[< prev](/prevnext?id=0809.1717&function=prev&context=q-bio.BM "previous in q-bio.BM \(accesskey p\)")   |   [next >](/prevnext?id=0809.1717&function=next&context=q-bio.BM "next in q-bio.BM \(accesskey n\)")   


[new](/list/q-bio.BM/new) |  [recent](/list/q-bio.BM/recent) | [2008-09](/list/q-bio.BM/2008-09)

Change to browse by: 

[q-bio](/abs/0809.1717?context=q-bio)  
[q-bio.NC](/abs/0809.1717?context=q-bio.NC)  


### References & Citations

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:0809.1717)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=0809.1717)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:0809.1717)



[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/0809.1717&description=Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/0809.1717&title=Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/0809.1717) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)



  *[Related DOI]: Digital Object Identifier


url: http://arxiv.org/abs/2411.17967v1
scrape_date: 2025-02-28T11:50:23.988638
content_type: markdown
hash: b66cf9d4594213f3996d20ac94b0cf4c209d8886cec0a3526d77abb356578320
title:
[2411.17967v1] QuaLLM-Health: An Adaptation of an LLM-Based Framework for Quantitative Data Extraction from Online Health Discussions

content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [cs](/list/cs/recent) > arXiv:2411.17967v1 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Computer Science > Computation and Language

**arXiv:2411.17967v1** (cs) 

[Submitted on 27 Nov 2024]

# Title:QuaLLM-Health: An Adaptation of an LLM-Based Framework for Quantitative Data Extraction from Online Health Discussions

Authors:[Ramez Kouzy](https://arxiv.org/search/cs?searchtype=author&query=Kouzy,+R), [Roxanna Attar-Olyaee](https://arxiv.org/search/cs?searchtype=author&query=Attar-Olyaee,+R), [Michael K. Rooney](https://arxiv.org/search/cs?searchtype=author&query=Rooney,+M+K), [Comron J. Hassanzadeh](https://arxiv.org/search/cs?searchtype=author&query=Hassanzadeh,+C+J), [Junyi Jessy Li](https://arxiv.org/search/cs?searchtype=author&query=Li,+J+J), [Osama Mohamad](https://arxiv.org/search/cs?searchtype=author&query=Mohamad,+O)

View a PDF of the paper titled QuaLLM-Health: An Adaptation of an LLM-Based Framework for Quantitative Data Extraction from Online Health Discussions, by Ramez Kouzy and 5 other authors

[View PDF](/pdf/2411.17967v1) [HTML (experimental)](https://arxiv.org/html/2411.17967v1)

> Abstract:Health-related discussions on social media like Reddit offer valuable insights, but extracting quantitative data from unstructured text is challenging. In this work, we present an adapted framework from QuaLLM into QuaLLM-Health for extracting clinically relevant quantitative data from Reddit discussions about glucagon-like peptide-1 (GLP-1) receptor agonists using large language models (LLMs). We collected 410k posts and comments from five GLP-1-related communities using the Reddit API in July 2024. After filtering for cancer-related discussions, 2,059 unique entries remained. We developed annotation guidelines to manually extract variables such as cancer survivorship, family cancer history, cancer types mentioned, risk perceptions, and discussions with physicians. Two domain-experts independently annotated a random sample of 100 entries to create a gold-standard dataset. We then employed iterative prompt engineering with OpenAI's "GPT-4o-mini" on the gold-standard dataset to build an optimized pipeline that allowed us to extract variables from the large dataset. The optimized LLM achieved accuracies above 0.85 for all variables, with precision, recall and F1 score macro averaged > 0.90, indicating balanced performance. Stability testing showed a 95% match rate across runs, confirming consistency. Applying the framework to the full dataset enabled efficient extraction of variables necessary for downstream analysis, costing under $3 and completing in approximately one hour. QuaLLM-Health demonstrates that LLMs can effectively and efficiently extract clinically relevant quantitative data from unstructured social media content. Incorporating human expertise and iterative prompt refinement ensures accuracy and reliability. This methodology can be adapted for large-scale analysis of patient-generated data across various health domains, facilitating valuable insights for healthcare research. 

Subjects: |  Computation and Language (cs.CL)  
---|---  
Cite as: | [arXiv:2411.17967](https://arxiv.org/abs/2411.17967) [cs.CL]  
  | (or  [arXiv:2411.17967v1](https://arxiv.org/abs/2411.17967v1) [cs.CL] for this version)   
  |  <https://doi.org/10.48550/arXiv.2411.17967> Focus to learn more arXiv-issued DOI via DataCite  
  
## Submission history

From: Ramez Kouzy [[view email](/show-email/67db7a59/2411.17967)]   
**[v1]** Wed, 27 Nov 2024 00:52:21 UTC (145 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled QuaLLM-Health: An Adaptation of an LLM-Based Framework for Quantitative Data Extraction from Online Health Discussions, by Ramez Kouzy and 5 other authors

  * [View PDF](/pdf/2411.17967v1)
  * [HTML (experimental)](https://arxiv.org/html/2411.17967v1)
  * [TeX Source](/src/2411.17967v1)
  * [Other Formats](/format/2411.17967v1)



[ ![license icon](https://arxiv.org/icons/licenses/by-nc-sa-4.0.png) view license ](http://creativecommons.org/licenses/by-nc-sa/4.0/ "Rights to this article")

Current browse context: 

cs.CL

[< prev](/prevnext?id=2411.17967&function=prev&context=cs.CL "previous in cs.CL \(accesskey p\)")   |   [next >](/prevnext?id=2411.17967&function=next&context=cs.CL "next in cs.CL \(accesskey n\)")   


[new](/list/cs.CL/new) |  [recent](/list/cs.CL/recent) | [2024-11](/list/cs.CL/2024-11)

Change to browse by: 

[cs](/abs/2411.17967?context=cs)  


### References & Citations

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:2411.17967)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=2411.17967)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:2411.17967)



[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/2411.17967&description=QuaLLM-Health: An Adaptation of an LLM-Based Framework for Quantitative Data Extraction from Online Health Discussions "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/2411.17967&title=QuaLLM-Health: An Adaptation of an LLM-Based Framework for Quantitative Data Extraction from Online Health Discussions "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/2411.17967) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)


url: http://arxiv.org/abs/2112.07890v1
scrape_date: 2025-02-28T11:50:23.988396
content_type: markdown
hash: 502076d3bda9a6b7223130b0d6d30aa7769cb5922c60c92551988ee8f2886051
title:
[2112.07890v1] Investigating myocardial infarction and its effects in patients with urgent medical problems using advanced data mining tools

content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [cs](/list/cs/recent) > arXiv:2112.07890v1 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Computer Science > Machine Learning

**arXiv:2112.07890v1** (cs) 

[Submitted on 15 Dec 2021]

# Title:Investigating myocardial infarction and its effects in patients with urgent medical problems using advanced data mining tools

Authors:[Tanya Aghazadeh](https://arxiv.org/search/cs?searchtype=author&query=Aghazadeh,+T), [Mostafa Bagheri](https://arxiv.org/search/cs?searchtype=author&query=Bagheri,+M)

View a PDF of the paper titled Investigating myocardial infarction and its effects in patients with urgent medical problems using advanced data mining tools, by Tanya Aghazadeh and Mostafa Bagheri

[View PDF](/pdf/2112.07890v1)

> Abstract:In medical science, it is very important to gather multiple data on different diseases and one of the most important objectives of the data is to investigate the diseases. Myocardial infarction is a serious risk factor in mortality and in previous studies, the main emphasis has been on people with heart disease and measuring the likelihood of myocardial infarction in them through demographic features, echocardiography, and electrocardiogram. In contrast, the purpose of the present study is to utilize data analysis algorithms and compare their accuracy in patients with a heart attack in order to identify the heart muscle strength during myocardial infarction by taking into account emergency operations and consequently predict myocardial infarction. For this purpose, 105 medical records of myocardial infarction patients with fourteen features including age, the time of emergency operation, Creatine Phosphokinase (CPK) test, heart rate, blood sugar, and vein are gathered and investigated through classification techniques of data analysis including random decision forests, decision tree, support vector machine (SVM), k-nearest neighbor, and ordinal logistic regression. Finally, the model of random decision forests with an accuracy of 76% is selected as the best model in terms of the mean evaluation indicator. Also, seven features of the creatine Phosphokinase test, urea, white and red blood cell count, blood sugar, time, and hemoglobin are identified as the most effective features of the ejection fraction variable. 

Subjects: |  Machine Learning (cs.LG)  
---|---  
Cite as: | [arXiv:2112.07890](https://arxiv.org/abs/2112.07890) [cs.LG]  
  | (or  [arXiv:2112.07890v1](https://arxiv.org/abs/2112.07890v1) [cs.LG] for this version)   
  |  <https://doi.org/10.48550/arXiv.2112.07890> Focus to learn more arXiv-issued DOI via DataCite  
  
## Submission history

From: Mostafa Bagheri [[view email](/show-email/4f1e7459/2112.07890)]   
**[v1]** Wed, 15 Dec 2021 05:10:55 UTC (410 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled Investigating myocardial infarction and its effects in patients with urgent medical problems using advanced data mining tools, by Tanya Aghazadeh and Mostafa Bagheri

  * [View PDF](/pdf/2112.07890v1)
  * [TeX Source](/src/2112.07890v1)
  * [Other Formats](/format/2112.07890v1)



[ ![license icon](https://arxiv.org/icons/licenses/by-4.0.png) view license ](http://creativecommons.org/licenses/by/4.0/ "Rights to this article")

Current browse context: 

cs.LG

[< prev](/prevnext?id=2112.07890&function=prev&context=cs.LG "previous in cs.LG \(accesskey p\)")   |   [next >](/prevnext?id=2112.07890&function=next&context=cs.LG "next in cs.LG \(accesskey n\)")   


[new](/list/cs.LG/new) |  [recent](/list/cs.LG/recent) | [2021-12](/list/cs.LG/2021-12)

Change to browse by: 

[cs](/abs/2112.07890?context=cs)  


### References & Citations

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:2112.07890)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=2112.07890)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:2112.07890)



### [DBLP](https://dblp.uni-trier.de) \- CS Bibliography

[listing](https://dblp.uni-trier.de/db/journals/corr/corr2112.html#abs-2112-07890 "listing on DBLP") | [bibtex](https://dblp.uni-trier.de/rec/bibtex/journals/corr/abs-2112-07890 "DBLP bibtex record")

[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/2112.07890&description=Investigating myocardial infarction and its effects in patients with urgent medical problems using advanced data mining tools "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/2112.07890&title=Investigating myocardial infarction and its effects in patients with urgent medical problems using advanced data mining tools "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

IArxiv recommender toggle

IArxiv Recommender _([What is IArxiv?](https://iarxiv.org/about))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/2112.07890) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)


url: http://arxiv.org/abs/1808.08375v1
scrape_date: 2025-02-28T11:50:24.023935
content_type: markdown
hash: cb22dfce3607b257a0d97373c603486275eb8ba93bfd78c3970528f89c98c75c
title:
[1808.08375v1] Molecular dynamics simulations reveal the role of ceramicine B as novel PPARγ partial agonist against type 2 diabetes

content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [q-bio](/list/q-bio/recent) > arXiv:1808.08375v1 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Quantitative Biology > Biomolecules

**arXiv:1808.08375v1** (q-bio) 

[Submitted on 25 Aug 2018]

# Title:Molecular dynamics simulations reveal the role of ceramicine B as novel PPARγ partial agonist against type 2 diabetes

Authors:[Bidyut Mallick](https://arxiv.org/search/q-bio?searchtype=author&query=Mallick,+B)

View a PDF of the paper titled Molecular dynamics simulations reveal the role of ceramicine B as novel PPAR{\gamma} partial agonist against type 2 diabetes, by Bidyut Mallick

[View PDF](/pdf/1808.08375v1)

> Abstract:Peroxisome proliferator-activated receptors gamma (PPAR{\gamma}) are ligand-activated controllers of various metabolic actions and insulin sensitivity. PPAR{\gamma} is thus considered as an important target to treat type 2 diabetes. Available PPAR{\gamma} drugs (full agonists) have robust insulin-sensitizing properties but are accompanied by severe side effects leading to complicated health problems. Here, we have used molecular docking and a molecular dynamics simulation study to find a novel PPAR{\gamma} ligand from a natural product. Our study suggests that the inhibition of ceramicine B in the PPAR{\gamma} ligand-binding domain (LBD) could act as a partial agonist and block cdk5-mediated phosphorylation. This result may provide an opportunity for the development of new anti-diabetic drugs by targeting PPAR{\gamma} while avoiding the side effects associated with full agonists. 

Subjects: |  Biomolecules (q-bio.BM)  
---|---  
Cite as: | [arXiv:1808.08375](https://arxiv.org/abs/1808.08375) [q-bio.BM]  
  | (or  [arXiv:1808.08375v1](https://arxiv.org/abs/1808.08375v1) [q-bio.BM] for this version)   
  |  <https://doi.org/10.48550/arXiv.1808.08375> Focus to learn more arXiv-issued DOI via DataCite  
  
## Submission history

From: Bidyut Mallick [[view email](/show-email/0940f1ce/1808.08375)]   
**[v1]** Sat, 25 Aug 2018 08:25:21 UTC (1,693 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled Molecular dynamics simulations reveal the role of ceramicine B as novel PPAR{\gamma} partial agonist against type 2 diabetes, by Bidyut Mallick

  * [View PDF](/pdf/1808.08375v1)
  * [Other Formats](/format/1808.08375v1)



[ ![license icon](https://arxiv.org/icons/licenses/zero-1.0.png) view license ](http://creativecommons.org/publicdomain/zero/1.0/ "Rights to this article")

Current browse context: 

q-bio.BM

[< prev](/prevnext?id=1808.08375&function=prev&context=q-bio.BM "previous in q-bio.BM \(accesskey p\)")   |   [next >](/prevnext?id=1808.08375&function=next&context=q-bio.BM "next in q-bio.BM \(accesskey n\)")   


[new](/list/q-bio.BM/new) |  [recent](/list/q-bio.BM/recent) | [2018-08](/list/q-bio.BM/2018-08)

Change to browse by: 

[q-bio](/abs/1808.08375?context=q-bio)  


### References & Citations

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:1808.08375)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=1808.08375)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:1808.08375)



[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/1808.08375&description=Molecular dynamics simulations reveal the role of ceramicine B as novel PPAR{\\gamma} partial agonist against type 2 diabetes "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/1808.08375&title=Molecular dynamics simulations reveal the role of ceramicine B as novel PPAR{\\gamma} partial agonist against type 2 diabetes "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/1808.08375) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)


url: http://arxiv.org/abs/2005.01887v2
scrape_date: 2025-02-28T11:50:23.988419
content_type: markdown
hash: d21cfe0906ef5d0787fb54e8964e52a75eb026235b8047ef7317b904e94105c5
title:
[2005.01887v2] Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog

content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [q-bio](/list/q-bio/recent) > arXiv:2005.01887v2 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Quantitative Biology > Biomolecules

**arXiv:2005.01887v2** (q-bio) 

[Submitted on 4 May 2020 ([v1](https://arxiv.org/abs/2005.01887v1)), last revised 10 Jun 2020 (this version, v2)]

# Title:Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog

Authors:[Pascal Tétreault](https://arxiv.org/search/q-bio?searchtype=author&query=T%C3%A9treault,+P), [Élie Besserer-Offroy](https://arxiv.org/search/q-bio?searchtype=author&query=Besserer-Offroy,+%C3%89), [Rebecca L. Brouillette](https://arxiv.org/search/q-bio?searchtype=author&query=Brouillette,+R+L), [Adeline René](https://arxiv.org/search/q-bio?searchtype=author&query=Ren%C3%A9,+A), [Alexandre Murza](https://arxiv.org/search/q-bio?searchtype=author&query=Murza,+A), [Roberto Fanelli](https://arxiv.org/search/q-bio?searchtype=author&query=Fanelli,+R), [Karyn Kirby](https://arxiv.org/search/q-bio?searchtype=author&query=Kirby,+K), [Alexandre J. Parent](https://arxiv.org/search/q-bio?searchtype=author&query=Parent,+A+J), [Isabelle Dubuc](https://arxiv.org/search/q-bio?searchtype=author&query=Dubuc,+I), [Nicolas Beaudet](https://arxiv.org/search/q-bio?searchtype=author&query=Beaudet,+N), [Jérôme Côté](https://arxiv.org/search/q-bio?searchtype=author&query=C%C3%B4t%C3%A9,+J), [Jean-Michel Longpré](https://arxiv.org/search/q-bio?searchtype=author&query=Longpr%C3%A9,+J), [Jean Martinez](https://arxiv.org/search/q-bio?searchtype=author&query=Martinez,+J), [Florine Cavelier](https://arxiv.org/search/q-bio?searchtype=author&query=Cavelier,+F), [Philippe Sarret](https://arxiv.org/search/q-bio?searchtype=author&query=Sarret,+P)

View a PDF of the paper titled Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog, by Pascal T\'etreault and 14 other authors

[View PDF](/pdf/2005.01887v2)

> Abstract:Neurotensin (NT) exerts naloxone-insensitive antinociceptive action through its binding to both NTS1 and NTS2 receptors and NT analogs provide stronger pain relief than morphine on a molecular basis. Here, we examined the analgesic/adverse effect profile of a new NT(8-13) derivative denoted JMV2009, in which the Pro10 residue was substituted by a silicon-containing unnatural amino acid silaproline. We first report the synthesis and in vitro characterization (receptor-binding affinity, functional activity and stability) of JMV2009. We next examined its analgesic activity in a battery of acute, tonic and chronic pain models. We finally evaluated its ability to induce adverse effects associated with chronic opioid use, such as constipation and analgesic tolerance or related to NTS1 activation, like hypothermia. In in vitro assays, JMV2009 exhibited high binding affinity for both NTS1 and NTS2, improved proteolytic resistance as well as agonistic activities similar to NT, inducing sustained activation of p42/p44 MAPK and receptor internalization. Intrathecal injection of JMV2009 produced dose-dependent antinociceptive responses in the tail-flick test and almost completely abolished the nociceptive-related behaviors induced by chemical somatic and visceral noxious stimuli. Likewise, increasing doses of JMV2009 significantly reduced tactile allodynia and weight bearing deficits in nerve-injured rats. Importantly, chronic agonist treatment did not result in the development of analgesic tolerance. Furthermore, JMV2009 did not cause constipation and was ineffective in inducing hypothermia. These findings suggest that NT drugs can act as an effective opioid-free medication for the management of pain or can serve as adjuvant analgesics to reduce the opioid adverse effects. 

Comments: | This is the post-print (accepted) version of the following article: Tétreault P, et al. (2020), Eur J Pharmacol. doi: <https://doi.org/10.1016/j.ejphar.2020.173174>, which has been accepted and published in final form at [this https URL](https://doi.org/10.1016/j.ejphar.2020.173174)  
---|---  
Subjects: |  Biomolecules (q-bio.BM); Quantitative Methods (q-bio.QM)  
Cite as: | [arXiv:2005.01887](https://arxiv.org/abs/2005.01887) [q-bio.BM]  
  | (or  [arXiv:2005.01887v2](https://arxiv.org/abs/2005.01887v2) [q-bio.BM] for this version)   
  |  <https://doi.org/10.48550/arXiv.2005.01887> Focus to learn more arXiv-issued DOI via DataCite  
Journal reference: | Eur J Pharmacol, 173174 (2020)  
Related DOI:  | <https://doi.org/10.1016/j.ejphar.2020.173174> Focus to learn more DOI(s) linking to related resources   
  
## Submission history

From: Élie Besserer-Offroy Ph.D. [[view email](/show-email/410e183c/2005.01887)]   
**[[v1]](/abs/2005.01887v1)** Mon, 4 May 2020 23:41:54 UTC (924 KB)  
**[v2]** Wed, 10 Jun 2020 19:02:30 UTC (501 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog, by Pascal T\'etreault and 14 other authors

  * [View PDF](/pdf/2005.01887v2)
  * [Other Formats](/format/2005.01887v2)



[ ![license icon](https://arxiv.org/icons/licenses/by-nc-sa-4.0.png) view license ](http://creativecommons.org/licenses/by-nc-sa/4.0/ "Rights to this article")

Current browse context: 

q-bio.BM

[< prev](/prevnext?id=2005.01887&function=prev&context=q-bio.BM "previous in q-bio.BM \(accesskey p\)")   |   [next >](/prevnext?id=2005.01887&function=next&context=q-bio.BM "next in q-bio.BM \(accesskey n\)")   


[new](/list/q-bio.BM/new) |  [recent](/list/q-bio.BM/recent) | [2020-05](/list/q-bio.BM/2020-05)

Change to browse by: 

[q-bio](/abs/2005.01887?context=q-bio)  
[q-bio.QM](/abs/2005.01887?context=q-bio.QM)  


### References & Citations

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:2005.01887)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=2005.01887)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:2005.01887)



[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/2005.01887&description=Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/2005.01887&title=Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/2005.01887) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)



  *[Related DOI]: Digital Object Identifier


url: http://arxiv.org/abs/2310.03235v2
scrape_date: 2025-02-28T11:50:24.068645
content_type: markdown
hash: 0b34a8fd968ade281f60de8d14c2aa9b624bba524d106ca77f3cf3b05c940fd8
title:
[2310.03235v2] Applying the causal roadmap to longitudinal national Danish registry data: a case study of second-line diabetes medication and dementia

content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [stat](/list/stat/recent) > arXiv:2310.03235v2 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Statistics > Applications

**arXiv:2310.03235v2** (stat) 

[Submitted on 5 Oct 2023 ([v1](https://arxiv.org/abs/2310.03235v1)), last revised 24 Oct 2023 (this version, v2)]

# Title:Applying the causal roadmap to longitudinal national Danish registry data: a case study of second-line diabetes medication and dementia

Authors:[Nerissa Nance](https://arxiv.org/search/stat?searchtype=author&query=Nance,+N), [Andrew Mertens](https://arxiv.org/search/stat?searchtype=author&query=Mertens,+A), [Thomas Gerds](https://arxiv.org/search/stat?searchtype=author&query=Gerds,+T), [Zeyi Wang](https://arxiv.org/search/stat?searchtype=author&query=Wang,+Z), [Christian Torp-Pedersen](https://arxiv.org/search/stat?searchtype=author&query=Torp-Pedersen,+C), [Mark van der Laan](https://arxiv.org/search/stat?searchtype=author&query=van+der+Laan,+M), [Kajsa Kvist](https://arxiv.org/search/stat?searchtype=author&query=Kvist,+K), [Theis Lange](https://arxiv.org/search/stat?searchtype=author&query=Lange,+T), [Bochra Zareini](https://arxiv.org/search/stat?searchtype=author&query=Zareini,+B), [Maya Petersen](https://arxiv.org/search/stat?searchtype=author&query=Petersen,+M)

View a PDF of the paper titled Applying the causal roadmap to longitudinal national Danish registry data: a case study of second-line diabetes medication and dementia, by Nerissa Nance and 9 other authors

[View PDF](/pdf/2310.03235v2)

> Abstract:The causal roadmap is a formal framework for causal and statistical inference that supports clear specification of the causal question, interpretable and transparent statement of required causal assumptions, robust inference, and optimal precision. The roadmap is thus particularly well-suited to evaluating longitudinal causal effects using large scale registries; however, application of the roadmap to registry data also introduces particular challenges. In this paper we provide a detailed case study of the longitudinal causal roadmap applied to the Danish National Registry to evaluate the comparative effectiveness of second-line diabetes drugs on dementia risk. Specifically, we evaluate the difference in counterfactual five-year cumulative risk of dementia if a target population of adults with type 2 diabetes had initiated and remained on GLP-1 receptor agonists (a second-line diabetes drug) compared to a range of active comparator protocols. Time-dependent confounding is accounted for through use of the iterated conditional expectation representation of the longitudinal g-formula as a statistical estimand. Statistical estimation uses longitudinal targeted maximum likelihood, incorporating machine learning. We provide practical guidance on the implementation of the roadmap using registry data, and highlight how rare exposures and outcomes over long-term follow up can raise challenges for flexible and robust estimators, even in the context of the large sample sizes provided by the registry. We demonstrate how simulations can be used to help address these challenges by supporting careful estimator pre-specification. We find a protective effect of GLP-1RAs compared to some but not all other second-line treatments. 

Subjects: |  Applications (stat.AP)  
---|---  
Cite as: | [arXiv:2310.03235](https://arxiv.org/abs/2310.03235) [stat.AP]  
  | (or  [arXiv:2310.03235v2](https://arxiv.org/abs/2310.03235v2) [stat.AP] for this version)   
  |  <https://doi.org/10.48550/arXiv.2310.03235> Focus to learn more arXiv-issued DOI via DataCite  
  
## Submission history

From: Nerissa Nance [[view email](/show-email/214b7348/2310.03235)]   
**[[v1]](/abs/2310.03235v1)** Thu, 5 Oct 2023 01:02:40 UTC (5,262 KB)  
**[v2]** Tue, 24 Oct 2023 15:53:21 UTC (5,263 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled Applying the causal roadmap to longitudinal national Danish registry data: a case study of second-line diabetes medication and dementia, by Nerissa Nance and 9 other authors

  * [View PDF](/pdf/2310.03235v2)
  * [TeX Source](/src/2310.03235v2)
  * [Other Formats](/format/2310.03235v2)



[ ![license icon](https://arxiv.org/icons/licenses/by-nc-sa-4.0.png) view license ](http://creativecommons.org/licenses/by-nc-sa/4.0/ "Rights to this article")

Current browse context: 

stat.AP

[< prev](/prevnext?id=2310.03235&function=prev&context=stat.AP "previous in stat.AP \(accesskey p\)")   |   [next >](/prevnext?id=2310.03235&function=next&context=stat.AP "next in stat.AP \(accesskey n\)")   


[new](/list/stat.AP/new) |  [recent](/list/stat.AP/recent) | [2023-10](/list/stat.AP/2023-10)

Change to browse by: 

[stat](/abs/2310.03235?context=stat)  


### References & Citations

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:2310.03235)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=2310.03235)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:2310.03235)



[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/2310.03235&description=Applying the causal roadmap to longitudinal national Danish registry data: a case study of second-line diabetes medication and dementia "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/2310.03235&title=Applying the causal roadmap to longitudinal national Danish registry data: a case study of second-line diabetes medication and dementia "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/2310.03235) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)


url: https://pmc.ncbi.nlm.nih.gov/articles/PMC9945324/
scrape_date: 2025-02-28T11:50:24.205022
content_type: markdown
hash: cf854c941e68aa558bc129d0948840f9d3f9221a56c6704204834e3c6cb407d6
title:
            GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach - PMC
        

content:
Skip to main content 

![](/static/img/us_flag.svg)

An official website of the United States government 

Here's how you know

Here's how you know

![](/static/img/icon-dot-gov.svg)

**Official websites use .gov**   
A **.gov** website belongs to an official government organization in the United States. 

![](/static/img/icon-https.svg)

**Secure .gov websites use HTTPS**   
A **lock** (  Lock Locked padlock icon  ) or **https://** means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. 

[ ![
                                  NCBI home page
                              ](/static/img/ncbi-logos/nih-nlm-ncbi--white.svg) ](https://www.ncbi.nlm.nih.gov/)

Search 

Log in

  * [ Dashboard ](https://www.ncbi.nlm.nih.gov/myncbi/)
  * [ Publications ](https://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/)
  * [ Account settings ](https://www.ncbi.nlm.nih.gov/account/settings/)
  * Log out 



Search…  Search NCBI 

Primary site navigation 


Logged in as: ****

  * [ Dashboard ](https://www.ncbi.nlm.nih.gov/myncbi/)
  * [ Publications ](https://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/)
  * [ Account settings ](https://www.ncbi.nlm.nih.gov/account/settings/)



Log in 

[](/ "Home")

Search PMC Full-Text Archive Search in PMC ![Search](/static/img/usa-icons-bg/search--white.svg)

  * [ Advanced Search ](https://www.ncbi.nlm.nih.gov/pmc/advanced/)
  * [ Journal List ](/journals/)
  * [ User Guide ](/about/userguide/)



  *   * [ ](https://doi.org/10.3389/fendo.2023.1085799 "View on publisher site")
  * [ ](pdf/fendo-14-1085799.pdf "Download PDF")
  *   *   * ## PERMALINK

Copy




As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.  
Learn more: [PMC Disclaimer](/about/disclaimer/) | [ PMC Copyright Notice ](/about/copyright/)

![Frontiers in Endocrinology logo](https://cdn.ncbi.nlm.nih.gov/pmc/banners/logo-frontendo.gif)

Front Endocrinol (Lausanne)

. 2023 Feb 1;14:1085799. doi: [10.3389/fendo.2023.1085799](https://doi.org/10.3389/fendo.2023.1085799)

  * [Search in PMC](https://www.ncbi.nlm.nih.gov/pmc/?term=%22Front%20Endocrinol%20\(Lausanne\)%22%5Bjour%5D)
  * [Search in PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=%22Front%20Endocrinol%20\(Lausanne\)%22%5Bjour%5D)
  * [View in NLM Catalog](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Front%20Endocrinol%20\(Lausanne\)%22%5BTitle%20Abbreviation%5D)
  * [Add to search](?term=%22Front%20Endocrinol%20\(Lausanne\)%22%5Bjour%5D)



# GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach

[Jing-Yue Wang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Wang%20JY%22%5BAuthor%5D)

### Jing-Yue Wang

1 Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China 

Find articles by [Jing-Yue Wang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Wang%20JY%22%5BAuthor%5D)

1,†, [Quan-Wei Wang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Wang%20QW%22%5BAuthor%5D)

### Quan-Wei Wang

1 Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China 

Find articles by [Quan-Wei Wang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Wang%20QW%22%5BAuthor%5D)

1,†, [Xin-Yu Yang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Yang%20XY%22%5BAuthor%5D)

### Xin-Yu Yang

1 Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China 

Find articles by [Xin-Yu Yang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Yang%20XY%22%5BAuthor%5D)

1, [Wei Yang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Yang%20W%22%5BAuthor%5D)

### Wei Yang

1 Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China 

Find articles by [Wei Yang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Yang%20W%22%5BAuthor%5D)

1, [Dong-Rui Li](https://pubmed.ncbi.nlm.nih.gov/?term=%22Li%20DR%22%5BAuthor%5D)

### Dong-Rui Li

1 Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China 

Find articles by [Dong-Rui Li](https://pubmed.ncbi.nlm.nih.gov/?term=%22Li%20DR%22%5BAuthor%5D)

1, [Jing-Yu Jin](https://pubmed.ncbi.nlm.nih.gov/?term=%22Jin%20JY%22%5BAuthor%5D)

### Jing-Yu Jin

1 Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China 

Find articles by [Jing-Yu Jin](https://pubmed.ncbi.nlm.nih.gov/?term=%22Jin%20JY%22%5BAuthor%5D)

1, [Hui-Cong Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20HC%22%5BAuthor%5D)

### Hui-Cong Zhang

1 Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China 

Find articles by [Hui-Cong Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20HC%22%5BAuthor%5D)

1, [Xian-Feng Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20XF%22%5BAuthor%5D)

### Xian-Feng Zhang

2 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China 

Find articles by [Xian-Feng Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=%22Zhang%20XF%22%5BAuthor%5D)

2,*

  * Author information
  * Article notes
  * Copyright and License information



1 Department of Cardiovascular Medicine, The First Hospital of Jilin University, Changchun, China 

2 Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China 

Edited by: Xiaodong Sun, Affiliated Hospital of Weifang Medical University, China

Reviewed by: Kefei Dou, Chinese Academy of Medical Sciences and Peking Union Medical College, China; Finbarr P. M. O’Harte, Ulster University, United Kingdom

✉

*Correspondence: Xian-Feng Zhang, zhangxianf@jlu.edu.cn

†These authors have contributed equally to this work and share first authorship

This article was submitted to Obesity, a section of the journal Frontiers in Endocrinology

Received 2022 Oct 31; Accepted 2023 Jan 2; Collection date 2023.

Copyright © 2023 Wang, Wang, Yang, Yang, Li, Jin, Zhang and Zhang

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

[PMC Copyright notice](/about/copyright/)

PMCID: PMC9945324 PMID: [36843578](https://pubmed.ncbi.nlm.nih.gov/36843578/)

## Abstract

Obesity is a complex disease characterized by excessive fat accumulation which is caused by genetic, environmental and other factors. In recent years, there has been an increase in the morbidity, disability rate,and mortality due to obesity, making it great threat to people’s health and lives, and increasing public health care expenses. Evidence from previous studies show that weight loss can significantly reduce the risk of obesity-related complications and chronic diseases. Diet control, moderate exercise, behavior modification programs, bariatric surgery and prescription drug treatment are the major interventions used to help people lose weight. Among them, anti-obesity drugs have high compliance rates and cause noticeable short-term effects in reducing obese levels. However, given the safety or effectiveness concerns of anti-obesity drugs, many of the currently used drugs have limited clinical use. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a group of drugs that targets incretin hormone action, and its receptors are widely distributed in nerves, islets, heart, lung, skin, and other organs. Several animal experiments and clinical trials have demonstrated that GLP-1R agonists are more effective in treating or preventing obesity. Therefore, GLP-1R agonists are promising agents for the treatment of obese individuals. This review describes evidence from previous research on the effects of GLP-1R agonists on obesity. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop obesity treatments based on GLP-1R agonists.

**Keywords:** GLP-1R agonists, obesity, weight-reducing drugs, metabolic diseases, dual agonism

## 1\. Introduction

In the past decade, obesity and related co-morbidities have become critical public health problems and serious medical conditions worldwide (1). A state of positive energy balance exists in the duration of the energy intake exceeding energy consumption, resulting in the storage of the excess calories in adipose tissue, which first leads to body phenotypic overweight (body mass index, BMI 25-30 kg/m2). It then develops into a weight disorder called obesity, defined as a BMI ≥30 kg/m2 (2). In pathology classification, there is no clear consensus on terminology. The most important sub-groups reviewed include abnormal metabolic obesity, normal metabolic obesity, abnormal metabolic weight, normal metabolic weight, and sarcopenic obesity (3). In Europe, the incidence of obesity is five times higher than it was after World War II, and the number of obese people doubles yearly (4). A study of BRICS (Brazil, Russia, India, China, and South Africa) countries during 2007-2010 found that obesity was associated with hypertension, angina, diabetes, and arthritis (5). Obesity is not just a risk factor for other diseases, such as cardiovascular diseases, type 2 diabetes (T2DM), arthritis, and some cancers (6), but also a complex disease with multiple causes, which has its own disabling ability, pathophysiology, and co-morbidities (7). Obesity dramatically increases the risk of diseases and disables ability. Herein, it is a significant health challenge that leads to a decline in life quality and life expectancy. So far, in the long run, obesity prevention and treatment strategies-whether at the individual or group level, have not been very successful (8). Lifestyle and behavioral interventions aimed at reducing calorie intake and increasing energy expenditure have limited effects because complex and lasting hormonal, metabolic and neurochemical adaptations can prevent weight loss and promote weight recovery (8). A systematic review and meta-analysis proved that weight loss had been shown to prevent and mitigate obesity-related complications (9). Weight-loss surgery effectively reduces weight and complications in patients with severe obesity; however, weight gain is a common complication following surgery (10). An intragastric balloon (IGB) is a usually safe, reversible, and less invasive way to cause weight loss based on occupying stomach space to increase satiety. However, regarding weight loss, the results of using IGBs cannot be compared with bariatric surgery (11). Drug therapy for weight loss has made significant progress. However, many anti-obesity agents that have entered human clinical trials have shown unacceptable adverse events; many of them cannot be used for more than 3 months; the curative effect is moderate and suboptimal in the long term (12). The leptin-melanocortin axis, the opioid system, glucagon-like peptide-1 (GLP-1)/glucagon-like peptide-1 receptor (GLP-1R) system, and fibroblast growth factor 21 (FGF21)/its receptor complex FGFR1c/β-klotho axis are several common pathways confirmed by researches and pharmacological targets that play an essential role in regulating energy balance and feeding behavior (2). GLP-1 analogs and GLP-1R agonists can exert hypoglycemic effects and reduce weight. However, natural GLP-1 can easily be degraded by dipeptidyl peptidase 4 (DPP-4) _in vivo_ and lose its activity. In order to make GLP-1 better used in the clinic, drug developers modified its structure and developed a series of GLP-1R agonists (13). Many clinical trials have proven GLP-1R agonists’ effectiveness and safety in treating or preventing obesity (14).

GLP-1, a 30- or 31-amino-acid-long peptide hormone, is a gastrointestinal peptide secreted by the intestinal tract that potentiates insulin release and reduces glucagon’s concentration in physiological conditions (15, 16). In 1983, it was found to be a cleavage product of proglucagon processing and secreted by intestinal epithelial endocrine L cells (17). It also comes from α-cells in the pancreatic islet and neurons in the nucleus of the solitary tract (18). GLP-1 is necessary for standard glucose tolerance and functions through specific GLP-1Rs, which belong to the G-protein-coupled glucagon receptor family, expressed in islet β-cells and stomach, small intestine, mucosa, heart, and other cell types (18, 19). GLP-1R agonists are a group of drugs based on the entero-insular axis (19). D’Alessio et al. (18) demonstrated that circulating peptides mediate insulinotropic activity with either bariatric surgery or treatment with long-acting GLP-1R agonists. Therefore, GLP-1R agonists may be new and promising treatment alternatives for obese subjects. However, the mechanism of GLP-1R in treating obesity is still uncertain, and more clinical evidence is needed for its long-term safety and efficacy. A schematic overview of GLP-1R agonists is summarized in  **Scheme 1** . The possible mechanisms of weight loss caused by GLP-1R agonists is shown in  **Figure 1** . Comparisons of common weight loss drugs are made in  **Table 1** .

### Scheme 1.

[![Scheme 1](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6348/9945324/e3c58dac1d7f/fendo-14-1085799-g002.jpg)](https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=9945324_fendo-14-1085799-g002.jpg)

[Open in a new tab](figure/sch1/)

A schematic overview of GLP-1 receptor agonists: classification, drug safety, and effectiveness. GI, Gastrointestinal; GLP-1R, Glucagon-like peptide-1 receptor; PEG, Polyethylene glycol. *Liraglutide and Semaglutide have been approved by the United States Food and Drug Administration for weight loss.

### Figure 1.

[![Figure 1](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6348/9945324/6d2077426058/fendo-14-1085799-g001.jpg)](https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=9945324_fendo-14-1085799-g001.jpg)

[Open in a new tab](figure/f1/)

The possible mechanisms of weight loss caused by GLP-1. GI, Gastrointestinal; GLP-1, Glucagon-like peptide-1; GLP-1R, Glucagon-like peptide-1 receptor. Created with BioRender.com.

### Table 1.

Anti-obesity drugs: principal categories, functions, side effects, half-life and usage (20, 21).

Major Categories | Functions | Primary side effects&Limits | Half-life/hours | Usage  
---|---|---|---|---  
Orlistat | •Weight loss  
•Reducing the risk of regaining weight already lost  
•Only in adults that are overweight or obese | •Side effects  
Allergic; Pain in the stomach or lower back; Kidney and liver problems. | 1-2 | 120mg, TID (P.O.)/60mg, TID(P.O.)  
Naltrexone-Bupropion | •Bupropion  
Antidepressant; Decreasing appetite.  
•Naltrexone  
Blocking the effects of opioids/alcohol; Curbing hunger and food cravings.  
• Contrave  
Managing weight in obese/overweight adults. | •Side effects  
Allergic; Seizures; Eating disorder; High blood pressure; Suicidal thoughts or actions.  
•Limits of use  
Effect on cardiovascular morbidity and mortality: unclear; Safety and effectiveness of combined medication: unclear. | 21/5 | 8/90 mg,BID (P.O.)  
Phentermine-Topiramate* | •BMI≥ 30 kg/m2   
•BMI≥ 27 kg/m2 with hyT2DM/dyslipidemia etc | • Side effects  
Allergic; Mood changes; Trouble sleeping; Increases of acid in the blood; Kidney stones.  
•Limits of use  
Effect on cardiovascular morbidity and mortality: unclear; Safety and effectiveness of combined medication: unclear. | 20/65 | •Start treatment with 3.75/23mg, QD (P.O.)  
•Recommended dose of 7.5/46mg, QD (P.O.)  
•Dose escalation to 15/92mg, QD (P.O.)  
Lorcaserin | •BMI≥ 30 kg/m2   
•BMI≥ 27 kg/m2 with hypertension/T2DM/dyslipidemia etc | •Side effects  
Anxiety; Bladder pain; Bloody or cloudy urine; Blurred vision; Body aches or pain; Cancer. | 11 | 10mg, BID(P.O.)  
Semaglutide | • T2DM  
•T2DM and established cardiovascular disease  
•Obesity | •Side effects  
Bladder pain; Bloody or cloudy urine; Chills; Cough; Diarrhea etc.  
•Limits of use  
Patients with a history of pancreatitis: unclear; Patients with T1DM: unclear. | 165 | 2.4 mg,QW(Subcut)  
Liraglutide | •T2DM  
•T2DM and established cardiovascular disease  
•Obesity | •Side effects  
Bladder pain; Bloody or cloudy urine; Chills;  
Cough; Diarrhea etc.  
•Limits of use  
Patients with a history of pancreatitis: unclear; Patients with T1DM: unclear. | 13 | 3mg,QD(Subcut)  
  
[Open in a new tab](table/T1/)

QD, One time a day; QW, One time a week; BID, Two times a day; I.V., Intravenous; TID, Three times a day; P.O., By mouth; BMI, Body mass index; T2DM, Type 2 diabetes mellitus; T1DM, Type 1 diabetes mellitus; Subcut, Subcutaneous injection. *The anti-obesity drugs' estimated percentile ranking of weight loss of 10% in participants who took weight-loss medications for more than a year is Phentermine-Topiramate, 54%; Liraglutide, 34%; Naltrexone-Bupropion, 30%; Lorcaserin, 25%; Orlistat, 20% (20).

## 2\. Relationship between GLP-1 and obesity

The mechanism for the decrease in GLP-1 secretion is incompletely understood in obese people. Ranganath (22) et al. believe that the decrease of GLP-1 in obese subjects may be related to increased plasma non-esterified fatty acids (NEFA). Two clinical studies in simple obesity patients found that higher fasting and postprandial NEFA levels, the insulin-promoting effect of GLP-1 and its postulated role as a satiety factor may inhibit nutrition-mediated secretion (23).

In the central nervous system, proglucagon and proglucagon-derived peptides (GLP-1, glucagon-like peptide-2, GLP-2, and oxyntomodulin, OXM) are only present in a small group of neurons in the nucleus tractus solitarius (24, 25). These constitute the neural pathway that connects the “visceral sensory” brainstem and the hypothalamic nucleus to participate in energy homeostasis. Experiments on mice have shown that intraventricular administration of GLP-1, GLP-2, and OXM could significantly reduce food intake (25, 26). Central GLP-1 activation may be combined with GLP-2 and/or OXM activation to form a potential pharmacological tool to reduce meal intake and possibly increase energy consumption (25, 27). The expression of GLP-1 and/or GLP-1R was found in hypothalamic feeding centers (28, 29), hindbrain matrix (30), the lateral parabrachial nucleus of the posterior nucleus (31), and mesolimbic substrates (32–34), etc. parts which directly effect on appetite and lead to weight loss.

In addition, the GLP-1 can inhibit postprandial gastric emptying and reduce gastric acid secretion, inhibit gastric and duodenal peristalsis by inhibiting vagus nerve, and increase the pressure of pylorus, thus reducing appetite, causing a reduction in body weight and participating in the so-called “ileal braking” effect (19, 35). Beiroa (36) et al. injected GLP-1 analog, liraglutide (LIR), into mice. LIR was found to stimulate the thermogenesis of brown adipose tissue and the browning of adipose cells, independent of the intake of nutrients. It can increase the thermogenesis and utilization of triacylglycerol-derived fatty acids and glucose in brown adipocytes and reduce the lipid content through the central GLP-1R agonists’ signaling pathway, such as central AMP-activated protein kinase or sirtuin-1 (SIRT1), also known as NAD-dependent deacetylase SIRT1 (36–39).

## 3\. Experimental evidence of GLP-1R agonists

GLP-1R agonists can be divided into short-acting and long-acting preparations according to the time-effect and the volume of injections. Short-acting preparations include beinaglutide (BN) and exenatide (EX), which generally need to be injected 2-3 times a day. Long-acting preparations include lixisenatide (LIXI) and LIR, which are injected once a day. Long-acting preparations also include semaglutide (SMG), dulaglutide (DUL), long-acting release formulation of exenatide (EX-LAR), and polyethylene glycol loxenatide (PEX-168), which generally need to be injected once a week. The data in this section is from animal and human trials.

### 3.1. Short−acting GLP−1 receptor agonists

#### 3.1.1. Beinaglutide

BN is a recombinant human GLP-1(7-36) acid, obtained by genetic engineering technology, and the amino acid sequence of its active component is the same as that of GLP-1 in the human body. As the first original research drug in the field of diabetes in China, it has been recommended for meal injection and approved for the hypoglycemic intervention of T2DM (40), especially for patients with poor blood glucose control by metformin alone. BN can also be used for patients with poor blood glucose control alone. The starting dose is 0.1 mg (50 µl) three times daily and is injected subcutaneously 5 minutes before meals. After 2 weeks of treatment, the dose should be increased to 0.2 mg (100 µl) three times daily. This product has a half-life of about 11 minutes and can effectively control blood glucose within 2 hours after the meal. The drug is quickly eliminated in the body without accumulation.

In clinical studies, Wang (41) et al. included 36 patients (T2DM) with BMI ≥ 24 kg/m2. After treatment with BN for 3 months, BMI, fasting blood glucose, glycosylated hemoglobin, visceral and subcutaneous fat, silk protein E1, leptin, C-reactive protein (CRP), and tumor necrosis factor decreased significantly; the level of CRP is related to the weight loss percentage treated with BN. A real-world study from China evaluated the actual efficacy of BN in treating overweight/obese T2DM patients in an actual diagnosis and treatment environment. The study found that the average weight decreased by 10.05 kg after 3 months of treatment (40). In animal studies, Fang (42) et al. studied the pharmacological and pharmacokinetic efficacy of BN in C57BL/6 and ob/ob mice. Results showed that BN could reduce glucose levels, improve insulin secretion in glucose tolerance tests in a dose-dependent manner, and inhibit food intake and gastric emptying. BN inhibited meal intake at higher doses for more than 4 hours, leading to weight loss in ob/ob mice after about two weeks of treatment. In the nonalcoholic steatohepatitis (NASH) model, BN can reduce liver weight and steatosis and improve insulin sensitivity. There were significant changes in fatty acid β-oxidation (Ppara, Acadl, Acox1), mitochondrial function (Mfn1, Mfn2), antioxidation (Sod2), SIRT1. This suggests that BN may be an effective treatment for obesity and NASH (42). A clinical study involving 78 non-diabetic overweight/obese patients found that BN may be a more effective treatment option for overweight/obese Chinese than metformin (43). For example, a patient with a BMI of 17.96 kg/m2 found that BN did not make him lose weight but increased it. The researcher believes that it may be related to the patient’s habit of excessive intake (44). An animal experiment on mice found that the mechanism of BN treating obesity is targeting the composition of major lipid classes and the expression of genes in lipid metabolism in adipose tissue to counteract high-fat diet-induced obesity (45).

BN can reduce body weight, inhibit inflammatory reactions, directly be excreted by the kidney, and have fewer adverse reactions. However, relevant research on it has not been found abroad. In the future, more prospective randomized controlled clinical studies can be conducted for patients with diabetic obesity or simple obesity.

#### 3.1.2. Exenatide

As the first GLP-1R agonist approved for T2DM, EX is a new class of compound and a synthetic product of exendin-4, which is a compound naturally derived from the Gila monster and has multiple hypoglycemic mechanisms: inhibiting of glucagon release from α cells, slowing of gastric emptying, decreasing appetite and increasing glucose-dependent insulin secretion (12, 46, 47). It is similar to human GLP-1 in function (46). Human GLP-1 was rapidly degraded by DPP-4, while EX showed prolonged kinetics because of its resistance to proteolysis of DPP-4 (48). EX has a relatively short half-life of 2.4 hours, which can be detected in plasma within 15 minutes after administration, and can still be detected 15 hours after a single subcutaneous injection > 0.2 µg/kg (12).

Lipotoxicity induced by saturated free fatty acids plays a vital role in renal injury in obese patients (49). It is found that EX can reverse the damage of renal tubular epithelial cells caused by a high-fat diet, and its effect is applied to simvastatin by reversing the down-regulation of SIRT1, preventing the production of reactive oxygen species and inhibiting the apoptosis of mitochondria (50).

There is little research on the weight loss effect of EX on simple obesity patients, and more clinical trials are conducted on patients with T2DM. A randomized, double-blind, placebo-controlled, parallel-group study showed that among the patients with T2DM treated with EX monotherapy, EX could improve glycated hemoglobin, fasting blood glucose, and postprandial blood glucose control, reduce weight, improve β cell function, and adjust blood pressure. EX is well tolerated (51). In a triple-blind, placebo-controlled 30-week clinical study involving patients with T2DM with a BMI of 33 ± 6 kg/m2, it was found that the weight loss in the EX treatment group was significantly higher than that in the control group. The primary adverse reaction to EX is nausea, suggesting that nausea may be the primary mechanism of weight loss (52). A 24-week multicenter, randomized, double-blind, placebo-controlled clinical study conducted by Apovian (53) found that EX combined with lifestyle adjustment could significantly reduce the weight of patients, all of which were 6.16 ± 0.54 kg. However, the incidence of nausea was higher than that of the control group. At present, the studies of EX on non-diabetic obesity mainly include 152 cases of simple obesity (weight loss of 5.1 kg) (54), 60 cases of polycystic ovary syndrome (weight loss of 3.2-6.0 kg) (55), and 10 cases of metabolic syndrome (weight loss of 3.7 kg) (56), among which the most common adverse reaction is still vomiting.

To sum up, EX can reduce the weight of diabetic patients with or without obesity, and it can also reduce the weight of simple obesity and polycystic ovary syndrome/metabolic syndrome with obesity. Clinical trials have shown that it has the potential to cause weight loss in non-diabetic obese individuals (57). The disadvantage is that it can cause vomiting; injection therapy is not convenient. Thus, more prospective clinical studies on non-diabetic obese patients are needed.

### 3.2. Long−acting GLP−1 receptor agonists: once-daily

#### 3.2.1. Lixisenatide

LIXI is a once-daily GLP-1R agonist. As a synthetic analog of its endogenous exendin-4, compared with exendin-4, LIXI deleted one proline and added six lysine residues, which increased its binding affinity with the GLP-1R by four times and increased its circulating half-life (58, 59). Furthermore, the dissociation rate with the receptor is slow, and the high affinity and slow dissociation with the receptor prolongs the time of pharmacological effect (58, 60). The indication is to effectively reduce glycosylated hemoglobin levels in patients with T2DM by reducing fasting and postprandial blood glucose levels (61, 62). LIXI is administered subcutaneously, quickly absorbed into the blood, without biotransformation in the liver, and is degraded by proteolytic enzyme and then eliminated by the kidney (63, 64). Along with its role in lowering blood glucose levels, LIXI has many other functions, such as cardiovascular benefits, delaying gastric emptying, protective effect on pancreatic beta-cells, and increased insulin mRNA expression and hormone secretion (65). Also, LIXI is well tolerated, and nausea and vomiting are the most commonly reported adverse events (66, 67).

A prospective clinical study from Spain found that besides controlling blood glucose (fasting blood glucose and glycosylated hemoglobin), LIXI can also improve blood lipids, especially total cholesterol and triglyceride (68). The exact mechanism may be that LIXI reduces chylomicron triacylglycerol by delaying gastric emptying by increased clearance (69). In iGlarLixi (insulin glargine: LIXI = 1:1) study, adult Japanese patients with T2DM lost more weight compared to the iGlar (insulin glargine U100) study (-0.51 kg vs. +0.55 kg). However, iGlarLixi patients had more gastrointestinal-related adverse, primarily nausea (16.9% vs. 0.8%) in this 26-week, randomized, open-label study (70). At the same time, the research of GetGoal-Duo1 and GetGoal-L also found that when the basic insulin treatment was not effective, the combination of LIXI could not only significantly improve fasting blood glucose and glycosylated hemoglobin but also significantly reduce weight, with the weight dropping by 0.9 kg and 1.3 kg respectively (71). In GetGoal-S, a subanalysis of GetGoal-S and GetGoal-F1 studies, they found that LIXI could significantly reduce subjects’ body weight (− 1.76 ± 0.20 kg;-1.12 kg; -2.6/2.7 kg), respectively (72–74). The main adverse events of LIXI are gastrointestinal adverse reactions, mainly manifested as nausea and vomiting in the initial stage (75, 76). Compared with EX, the frequency of subcutaneous injection of LIXI is less, and the incidence of gastrointestinal adverse reactions and hypoglycemia is lower. Compared with LIXI, LIR is more effective in improving blood glucose and reducing weight, and both treatments are well tolerated (75, 77, 78).

In clinical studies, LIXI has shown the benefits of weight loss, which is well tolerated by patients and can meet the needs of overweight patients for weight control. Given that there are no major, obvious differences in tolerability, efficacy on glycemic parameters, weight loss, or overt advantages regarding administration, it is likely that the use of LIXI in place of other GLP-1 agonists will be based on cost (79).

#### 3.2.2. Liraglutide

LIR was formed by adding a 16-carbon palmitoyl fatty acid to the 26th position of GLP-1 by gene recombination technology and replacing the 34th position of lysine on GLP-1 with arginine. These structural modifications increase aggregation and promote non-covalent binding of the albumin, thus inhibiting the DPP-4, which is injected subcutaneously in the form of isotonic fluid. LIR is suitable to be administered once a day, with a tmax of 9~13 hours and t1/2 of 13 hours (80–82). Clinically, it is mainly used to treat T2DM and causes weight reduction when used in large doses (3mg/day) (83). The United States Food and Drug Administration (FDA) approved it to treat obesity. Its main principles include that it can inhibit the feeding center, thus reducing appetite; it can delay gastric emptying, resulting in slow digestion and absorption of food, to achieve the role of diet control (84–86).

Compared with the treatment of short-acting GLP-1R agonists, LIR has a greater improvement in lowering glycated hemoglobin and fasting blood glucose. It has fewer side effects than EX twice a day (87). A clinical study involving 564 adults (BMI 30-40 kg/m2, without T2DM) found that compared with orlistat (3×120 mg, weight loss of 4.1 kg), LIR (subcutaneous administration of 1.2 mg/d, 1.8 mg/d, 2.4 mg/d or 3 mg/d) had an average weight loss of 4.8-7.2 kg, the two-year extended experiment of which also showed similar results (88, 89). The relevant study also found that the 1-year average weight loss of participants (LIR 3.0 mg) was 9.2 kg reporting nausea/vomiting episodes, while that of participants without nausea/vomiting was 6.3 kg. Researchers believe that nausea/vomiting is related to greater weight loss (90). A three-year obesity and prediabetes trial found that LIR 3 mg can improve health benefits in reducing the diabetes risk of patients with obesity and prediabetes (91). Pi-Sunyer (92) et al. enrolled 3731 patients without T2DM (BMI ≥ 27 kg/m2 or 30 kg/m2) and gave LIR 3mg daily subcutaneous injection. After 56 weeks of treatment, the average weight loss of the patients was 8.40 ± 7.3 kg, and the most common adverse reactions were mild or moderate nausea and diarrhea. A 56-week trial included 422 patients with BMI≥30 kg/m2 or BMI≥27 kg/m2 with dyslipidemia and/or hypertension (non-diabetic). These patients reduced their initial weight by ≥5% through a low-calorie diet during the 4-12 weeks pre-trial induction period. It was found that more patients in the LIR group than the placebo group maintained their weight loss by ≥5%, which indicated that LIR 3.0 mg/d is expected to improve the maintenance of weight loss (93).

GLP-1 analog has 97% homology with human GLP-1 and has been approved for the clinical treatment of diabetes and obesity. However, it should be noted that combined with insulin may lead to hypoglycemia (94). It is worth mentioning that China's FDA said that the application for a marketing license for LIR injection for obesity or overweight indications had been accepted, which was the first time that the weight control indications of GLP-1R agonists have been accepted in China.

### 3.3. Long-acting GLP−1 receptor agonists: Once-weekly

#### 3.3.1. Semaglutide

SMG is an analog of long-acting GLP-1, mainly used to control T2DM, and is also suitable for promoting weight loss in people with mild obesity (95, 96). The usage for treating obesity is subcutaneous injection once a week. For both diabetic and non-diabetic patients, the drug can reduce weight (97, 98). Here, we mainly summarize the relevant experiments on the SMG treatment effect in people with obesity (STEP) programs.

More than 1,200 patients with T2DM complicated with obesity were randomly divided into 1mg SMG group, 2.4mg SMG group, or placebo group and given once a week in STEP2 research. The weight loss ranges of the two treatment groups were -6.9 kg (-7%) and -9.7 kg (-9.6%), respectively. The 2.4 mg group lost the most weight, which means that among adults suffering from overweight or obesity and T2DM, SMG 2.4 mg once a week has achieved significant clinically significant weight loss (99). In the STEP1 trial (100), Wilding et al. recruited 1961 non-diabetic adults with a BMI of 30 kg/m2 (or ≥27 kg/m2 with more than 1 body weight-related coexisting disease). The SMG group (once 2.4 mg, once a week) was treated for 68 weeks, and the average weight loss in the SMG group was 15.3 kg. More patients in the SMG group achieved a weight loss of ≥ 5% (86.4% vs. 31.5%), ≥ 10% (69.1% vs. 12.0%), and ≥ 15% (50.5% vs. 4.9%), compared with the placebo group. STEP 8 and STEP 3 showed similar results (101, 102).

In the United States, oral and injectable forms of SMG are approved for treating T2DM, while only injectable forms are approved for treating obesity (103). Like other GLP-1R agonists, SMG often causes adverse reactions. The main adverse reactions were gastrointestinal side effects, including nausea, diarrhea, and vomiting. These adverse reactions are generally mild to moderate and gradually alleviated in most patients (100, 104). Like LIR, the race of patients involved in related clinical studies is relatively small. More clinical trials aimed at obese people in Asia and Africa are expected to prove its effectiveness and safety. Regarding the treatment of obesity, we expect SMG to be approved by more countries’ FDA in the future.

#### 3.3.2. Dulaglutide

DUL is a long-acting GLP-1R agonist which can promote insulin secretion, inhibit gastric emptying, and reduce appetite. It is approved for treating hyperglycemia in patients with T2DM in many countries (105, 106). Like other GLP-1R agonists, when used alone or treated with non-insulin secretagogues, DUL treatment is associated with weight loss or decreased weight gain (107). It has a long half-life period and is injected once a week. The average peak time of subcutaneous injection is 48 hours. The most common adverse reactions were nausea, headache, vomiting, and diarrhea (108). Among them, gastrointestinal adverse reactions mainly occurred in the early stage of the first drug use, with mild to moderate degrees (109). Here, we mainly summarize the relevant research on assessing the weekly administration of DUL (AWARD).

AWARD-6 is a randomized, open, parallel-grouped, multicenter, phase 3, non-inferiority study comparing the safety and efficacy of weekly DUL and daily LIR in patients with uncontrolled T2DM treated with metformin. Compared with LIR once a day, once weekly subcutaneous injection of DUL similarly lowers body weight: –2.90 kg (-3.61 kg for LIR) after 26 weeks of treatment (109). At 26 weeks after treatment, the weight loss was -2.29 ± 0.24 kg for 1.5 mg DUL, -1.36 ± 0.24 kg for 0.75 mg DUL, and -2.22 ± 0.24 kg for metformin (110). In patients with T2DM who are poorly controlled by metformin, increasing DUL from 1.5mg to 3.0mg or 4.5mg can provide glycosylated hemoglobin and weight loss related to clinically relevant doses and has similar safety (111). It is worth mentioning that in the AWARD-2 study, there were several cases of pancreatitis caused by DUL (112). Therefore, during DUL treatment, we should pay close attention to the related signs of pancreatitis, and if pancreatitis occurs, we need to stop the drug immediately (113).

In summary, the recommended clinical treatment for diabetes is 0.75 mg or 1.5 mg. Studies have found that higher doses can further reduce glycosylated hemoglobin and body weight, and the safety is similar to low doses. However, DUL’s long-term efficacy and safety need to be further studied.

#### 3.3.3. Long-acting release formulation of exenatide (Microspheres)

Polymer materials commonly used in microsphere preparation are polylactic-co-glycolic acid (PLGA), which is approved by FDA and has good safety and biodegradability. It is often used as a drug carrier and biological scaffold. EX microspheres are a long-acting release of EX. After weekly subcutaneous injection, EX was slowly released from the microspheres by diffusion and microsphere rupture and reached a stable plasma concentration about 6-8 weeks after treatment (114). Nausea and vomiting are less frequent in patients receiving EX-LAR than in patients taking EX (114).

A 30-week randomized non-inferiority study comparing 2 mg once-weekly EX-LAR with 10 µg twice-daily EX in 295 patients with T2DM. In terms of weight loss, there was no significant difference between weight loss with EX (-3.6 kg) and with EX-LAR (-3.7 kg) (115). A study involving treatment up to 104 or 117 weeks in 134 patients with T2DM showed EX microspheres-naïve patients experienced weight reductions of -2.7 kg (116). Hirsch et al. (117) found that after 24 weeks of drug treatment of once-weekly EX-LAR or dapagliflozin or co-administered, nondiabetic women with a BMI (≥30 kg/m2 and ≤ 45 kg/m2) and polycystic ovary syndrome all lost weight. Among them, weight loss was the most in the double treatment.

Once-weekly treatment with EX-LAR (considering the potential beneficial effects of GLP-1R activation on β cells and weight loss associated with many patients) is a promising potential strategy for diabetes prevention. Similarly, once-weekly EX-LAR preparation can be used as an anti-obesity treatment in patients without T2DM or impaired glucose tolerance (118). EX long-acting preparation can reduce weight, but there are few related clinical studies, and most focus on patients with T2DM.

#### 3.3.4. Polyethylene glycol loxenatide

The early GLP-1R agonist has many defects, such as multiple injections and a high incidence of adverse reactions in the digestive tract, which limits its clinical application. PEX-168 is a new agent of long-acting GLP-1R agonist, which is molecularly modified from EX _via_ amino acid modification and PEGylation (119), the first GLP-1R agonist modified by PEG to achieve long-term pharmacological action (120, 121). It has the advantages of a prolonged administration interval (once a week), few adverse reactions in the digestive tract (122), and adverse effects reported ranging from ‘mild’ to ‘moderate’ (122, 123).

Guo (120) et al. found that PEX-168 significantly reduced the body weight of simple obese mice. The weight loss of the low dose (0.03 mg/kg) group, medium dose (0.1 mg/kg) group, and high dose (0.33 mg/kg) group were about 2g, 4g, and 1g (8 weeks). A multicenter, randomized, double-blind, multiple dose-escalation study showed that after 4 weeks of treatment of PEX-168 with different doses, the weight decreased by -0.8-1.8kg. After 8 weeks of treatment, the weight decreased by -1.4-3.3kg (122).

PEX-168 is a China-domestic long-acting GLP-1R agonist approved by the China's FDA for marketing and used for blood glucose control of adult patients with T2DM.

## 4\. Others: GIPR/GLP-1R dual agonists and GIPR/GLP-1R/GCGR triagonists

Intestinal endocrine K cells produce gastric inhibitory polypeptide (GIP). Like GLP-1, GIP stimulates insulin secretion from pancreatic β cells in a glucose-dependent manner (124). Glucagon (GCG) is a 29 amino acid peptide secreted by pancreatic α cells when blood glucose levels are low. Its ability to increase energy expenditure has been known for over 60 years (125). Recently, several multi-targeting agonists of GIPR, GLP-1R, or GCGR for treating T2DM and obesity have been in clinical trials. These agonists are developed to maximize metabolic benefits and reduce side effects (126). Therefore, the research and development of the relevant drugs and the replacement therapy of double GIP-GLP-1R agonists (e.g., tirzepatide) and triple GIP-GCG-GLP-1R (e.g., peptide 20) agonist are key research fields.

Research on obese mice suggests that unimolecular poly-pharmacology is an effective means to deal with various mechanisms leading to obesity and further indicates that GCGR activation is the distinguishing factor between single or double agonists and triple agonists of incretin receptors (127). Studies in knock-out mice confirms the significant potential for novel triple-acting hybrid peptides as therapeutic options for obesity (128). Five clinical trials (SURPASS 1-5 trials) conducted in patients with T2DM showed that tirzepatide at 5-15 mg per week could reduce body weight (5.4-11.7kg), which was never seen with a single drug (129). Karagiannis et al. found that tezepatide had a significant dose-dependent advantage in weight loss compared with placebo, GLP-1R agonists, and basal insulin (130). Zhao et al. provide valuable insights into the structural basis of the functional versatility of tirzepatide and peptide 20 by cryo-electron microscopy (126). Researchers interested in this direction can see more details on the efficacy of GLP-1R/GCGR agonists in the treatment of obesity in Sanchez-Garrido’s review (131).

GLP-1R agonists improve glucose homeostasis in patients with T2DM, cause weight loss, and benefit cardiovascular health over time. However, dose-dependent gastrointestinal effects limit efficacy, so drugs with GLP-1 and GCG pharmacology can also target alternative pathways and may expand the therapeutic index (132).

## 5\. Future research outlook

Over a relatively short period, obesity is a significant public health problem rising. Despite numerous studies, the causes of the obesity epidemic are still not fully understood, and traditional calorie-restricted diets still lack long-term effects (133). It needs effective prevention and treatment. Weight loss surgery may be the most effective treatment for morbid obesity, but we need less radical choices, such as drugs (134). However, obesity is a global health challenge with few drug options (100). The long-term weight-loss agents approved by the FDA of the United States are orlistat, lorcaserin, naltrexone-bupropion, topiramate phenylacetate, LIR, SMG etc. (20). Orlistat is the only weight-reducing drug approved for marketing in China so far. However, these diet pills are controversial because of their safety and long-term efficacy (135, 136). In 2005, a new treatment of T2DM based on the action of GLP-1 was introduced (137). Two GLP-1R agonists have been approved in the United States to treat obesity: semaglutide and LIR, both of which are injected subcutaneously. Whether the patient has diabetes or not, these drugs should be the first-line drugs for obesity (138). For patients with diabetes, the side effects, injection demand, and cost of these drugs should be weighed against the effects of improving blood glucose and losing weight. Currently, GLP-1R agonists are mainly targeted on the endogenous GLP-1R signaling system, which causes GLP-1R agonists to have many pharmacodynamic characteristics like GLP-1. These drugs vary, like changing pharmacokinetics, and different drugs have different dose plans for daily or weekly injections (139).

Besides lowering blood glucose and reducing weight (incredibly visceral fat), GLP-1R agonists can also lower blood pressure, improve blood lipid disorder, and reduce fatty liver (16, 140). The inhibitory effect of GLP-1 on gastric emptying is dose-dependent, and the use of lower doses of GLP-1 in patients with T2DM may also be suitable for blood glucose control (141). Also, GLP-1R agonists can protect the heart and kidneys, reduce the risk of cardiovascular events, and delay the progress of diabetic nephropathy, which is especially important for people with diabetes. The common adverse reactions of GLP-1R agonists include gastrointestinal reactions, mainly loss of appetite, nausea, vomiting, diarrhea, abdominal pain, etc., primarily mild or moderate. To alleviate the gastrointestinal reaction of patients, at the beginning of the application of these drugs, clinical workers should know that the dosage should be gradually increased from a small dosage to enhance patients’ tolerance. Generally, single use will not lead to hypoglycemia, but if combined with sulfonylureas or insulin, attention should be paid to prevent hypoglycemia (142). Other adverse reactions are rare, such as pancreatitis and rash.

Given that GLP-1R agonists have superior weight loss effects and good safety, some of its products have been officially approved by FDA for chronic weight management of obese or overweight adults. The GLP-1R agonists are promising candidates for the treatment of obesity. Currently, except for LIR and SMG, the numbers of related clinical studies of other GLP-1R agonists are few, especially in obese or overweight people without diabetes. Meanwhile, research on the mechanism and efficacy of GLP-1R/GIPR dual agonists and GLP-1R/GIPR/GCGR triple agonists paves the way to a ground-breaking therapy specific for obesity, which suggests multi-target drugs may have more advantages than a single target. Together, GLP-1R, GIPR, and GCGR agonists are expected to see more clinical trial evidence to prove their efficacy and safety in treating obese patients.

Pedrosa et al. (143) summed up GLP-1R agonists to treat obesity and prevent cardiovascular disease. Liu et al. (144) expounded on the modified GLP-1R agonists from the perspective of the patent. Jensterle et al. (145) presented the primary outcomes of clinical trial programs called SCALE and STEP and studies on the efficacy of GLP-1R agonists in pediatric obesity. In this review, we will mainly focus on introducing GLP-1R agonists and trials, and briefly describe the latest research progress of double or triple-target drugs. We anticipate that this study will help biomedical researchers or clinical workers to treat obesity by providing ideas for developing novel drug strategies or scientific research ideas.

## Author contributions

J-YW and Q-WW wrote the first draft of the manuscript. D-RL, J-YJ, and H-CZ revised the manuscript. WY and X-YY made the figures and table. X-FZ critically revised the manuscript. All authors contributed to the article and approved the submitted version.

## Funding Statement

This study was supported by the National Science Foundation of China (No. 82070362).

## Abbreviations

BMI, Body mass index; BN, Beinaglutide; CRP, C-reactive protein; DPP-4, Dipeptidyl peptidase 4; DUL, Dulaglutide; EX, Exenatide EX-LAR, Long-acting release formulation of exenatide; FDA, Food and Drug Administration; FGF, Fibroblast growth factor; IGB, Intragastric balloon; GCG, Glucagon; GLP-1, Glucagon-like peptide-1; GLP-2, Glucagon-like peptide-2; GIP, Gastric inhibitory polypeptide; GI, Gastrointestinal; GLP-1R, Glucagon-like peptide-1 receptor; LIR, Liraglutide; LIXI, Lixisenatide; NEFA, Non-esterified fatty acids; NASH, Nonalcoholic steatohepatitis; OXM, Oxyntomodulin; PEX-168, Polyethylene glycol loxenatide; SMG, Semaglutide; SIRT1, Sirtuin-1; T2DM, Type 2 diabetes.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

  * 1. Malik VS, Willet WC, Hu FB. Nearly a decade on — trends, risk factors and policy implications in global obesity. Nat Rev Endocrinol (2020) 16:615–6. doi: 10.1038/s41574-020-00411-y  [[DOI](https://doi.org/10.1038/s41574-020-00411-y)] [[PMC free article](/articles/PMC7461756/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/32873971/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Rev%20Endocrinol&title=Nearly%20a%20decade%20on%20%E2%80%94%20trends,%20risk%20factors%20and%20policy%20implications%20in%20global%20obesity&author=VS%20Malik&author=WC%20Willet&author=FB%20Hu&volume=16&publication_year=2020&pmid=32873971&doi=10.1038/s41574-020-00411-y&)]
  * 2. Jackson VM, Breen DM, Fortin J-P, Liou A, Kuzmiski JB, Loomis AK, et al. Latest approaches for the treatment of obesity. Expert Opin Drug Discovery (2015) 10:825–39. doi: 10.1517/17460441.2015.1044966  [[DOI](https://doi.org/10.1517/17460441.2015.1044966)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/25967138/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Drug%20Discovery&title=Latest%20approaches%20for%20the%20treatment%20of%20obesity&author=VM%20Jackson&author=DM%20Breen&author=J-P%20Fortin&author=A%20Liou&author=JB%20Kuzmiski&volume=10&publication_year=2015&pmid=25967138&doi=10.1517/17460441.2015.1044966&)]
  * 3. Perez-Campos E, Mayoral L-C, Andrade G, Mayoral E-C, Huerta T, Canseco S, et al. Obesity subtypes, related biomarkers & heterogeneity. Indian J Med Res (2020) 151:11. doi: 10.4103/ijmr.IJMR_1768_17  [[DOI](https://doi.org/10.4103/ijmr.IJMR_1768_17)] [[PMC free article](/articles/PMC7055173/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/32134010/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Indian%20J%20Med%20Res&title=Obesity%20subtypes,%20related%20biomarkers%20&%20heterogeneity&author=E%20Perez-Campos&author=L-C%20Mayoral&author=G%20Andrade&author=E-C%20Mayoral&author=T%20Huerta&volume=151&publication_year=2020&pages=11&pmid=32134010&doi=10.4103/ijmr.IJMR_1768_17&)]
  * 4. Condon C. The fat bomb exploded but no one heard the bang. Eur J Cardiovasc Nurs (2006) 5:99–101. doi: 10.1016/j.ejcnurse.2005.12.003  [[DOI](https://doi.org/10.1016/j.ejcnurse.2005.12.003)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/16480926/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Eur%20J%20Cardiovasc%20Nurs&title=The%20fat%20bomb%20exploded%20but%20no%20one%20heard%20the%20bang&author=C%20Condon&volume=5&publication_year=2006&pages=99-101&pmid=16480926&doi=10.1016/j.ejcnurse.2005.12.003&)]
  * 5. Shukla A, Kumar K, Singh A. Association between obesity and selected morbidities: A study of BRICS countries. PloS One (2014) 9:e94433. doi: 10.1371/journal.pone.0094433  [[DOI](https://doi.org/10.1371/journal.pone.0094433)] [[PMC free article](/articles/PMC3981786/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24718033/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=PloS%20One&title=Association%20between%20obesity%20and%20selected%20morbidities:%20A%20study%20of%20BRICS%20countries&author=A%20Shukla&author=K%20Kumar&author=A%20Singh&volume=9&publication_year=2014&pages=e94433&pmid=24718033&doi=10.1371/journal.pone.0094433&)]
  * 6. Hainer V, Toplak H, Mitrakou A. Treatment modalities of obesity. Diabetes Care (2008) 31:S269–77. doi: 10.2337/dc08-s265  [[DOI](https://doi.org/10.2337/dc08-s265)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/18227496/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Treatment%20modalities%20of%20obesity&author=V%20Hainer&author=H%20Toplak&author=A%20Mitrakou&volume=31&publication_year=2008&pmid=18227496&doi=10.2337/dc08-s265&)]
  * 7. Conway B, Rene A. Obesity as a disease: no lightweight matter. Obes Rev (2004) 5:145–51. doi: 10.1111/j.1467-789X.2004.00144.x  [[DOI](https://doi.org/10.1111/j.1467-789X.2004.00144.x)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/15245383/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Obes%20Rev&title=Obesity%20as%20a%20disease:%20no%20lightweight%20matter&author=B%20Conway&author=A%20Rene&volume=5&publication_year=2004&pmid=15245383&doi=10.1111/j.1467-789X.2004.00144.x&)]
  * 8. Blüher M. Obesity: global epidemiology and pathogenesis. Nat Rev Endocrinol (2019) 15:288–98. doi: 10.1038/s41574-019-0176-8  [[DOI](https://doi.org/10.1038/s41574-019-0176-8)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/30814686/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Rev%20Endocrinol&title=Obesity:%20global%20epidemiology%20and%20pathogenesis&author=M%20Bl%C3%BCher&volume=15&publication_year=2019&pmid=30814686&doi=10.1038/s41574-019-0176-8&)]
  * 9. Ma C, Avenell A, Bolland M, Hudson J, Stewart F, Robertson C, et al. Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis. BMJ (2017) 359:j4849. doi: 10.1136/bmj.j4849  [[DOI](https://doi.org/10.1136/bmj.j4849)] [[PMC free article](/articles/PMC5682593/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/29138133/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=BMJ&title=Effects%20of%20weight%20loss%20interventions%20for%20adults%20who%20are%20obese%20on%20mortality,%20cardiovascular%20disease,%20and%20cancer:%20systematic%20review%20and%20meta-analysis&author=C%20Ma&author=A%20Avenell&author=M%20Bolland&author=J%20Hudson&author=F%20Stewart&volume=359&publication_year=2017&pages=j4849&pmid=29138133&doi=10.1136/bmj.j4849&)]
  * 10. Cooper TC, Simmons EB, Webb K, Burns JL, Kushner RF. Trends in weight regain following roux-en-Y gastric bypass (RYGB) bariatric surgery. Obes Surg (2015) 25:1474–81. doi: 10.1007/s11695-014-1560-z  [[DOI](https://doi.org/10.1007/s11695-014-1560-z)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/25595383/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Obes%20Surg&title=Trends%20in%20weight%20regain%20following%20roux-en-Y%20gastric%20bypass%20\(RYGB\)%20bariatric%20surgery&author=TC%20Cooper&author=EB%20Simmons&author=K%20Webb&author=JL%20Burns&author=RF%20Kushner&volume=25&publication_year=2015&pmid=25595383&doi=10.1007/s11695-014-1560-z&)]
  * 11. Tsesmeli N, Coumaros D. Review of endoscopic devices for weight reduction: old and new balloons and implantable prostheses. Endoscopy (2009) 41:1082–9. doi: 10.1055/s-0029-1215269  [[DOI](https://doi.org/10.1055/s-0029-1215269)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/19899029/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Endoscopy&title=Review%20of%20endoscopic%20devices%20for%20weight%20reduction:%20old%20and%20new%20balloons%20and%20implantable%20prostheses&author=N%20Tsesmeli&author=D%20Coumaros&volume=41&publication_year=2009&pmid=19899029&doi=10.1055/s-0029-1215269&)]
  * 12. Folli F, Guardado Mendoza R. Potential use of exenatide for the treatment of obesity. Expert Opin Investig Drugs (2011) 20:1717–22. doi: 10.1517/13543784.2011.630660  [[DOI](https://doi.org/10.1517/13543784.2011.630660)] [[PMC free article](/articles/PMC3495586/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/22017240/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Investig%20Drugs&title=Potential%20use%20of%20exenatide%20for%20the%20treatment%20of%20obesity&author=F%20Folli&author=R%20Guardado%20Mendoza&volume=20&publication_year=2011&pmid=22017240&doi=10.1517/13543784.2011.630660&)]
  * 13. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art - PubMed. Available at: <https://pubmed.ncbi.nlm.nih.gov/33068776/> (Accessed November 14, 2022).
  * 14. Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet (2021) 398:262–76. doi: 10.1016/S0140-6736(21)00536-5  [[DOI](https://doi.org/10.1016/S0140-6736\(21\)00536-5)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34216571/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Lancet&title=SGLT2%20inhibitors%20and%20GLP-1%20receptor%20agonists:%20established%20and%20emerging%20indications&author=E%20Brown&author=HJL%20Heerspink&author=DJ%20Cuthbertson&author=JPH%20Wilding&volume=398&publication_year=2021&pmid=34216571&doi=10.1016/S0140-6736\(21\)00536-5&)]
  * 15. Gutniak M, Ørkov C, Holst JJ, Ahrén B, Efendić S. Antidiabetogenic effect of glucagon-like peptide-1 (7–36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med (1992) 326:1316–22. doi: 10.1056/NEJM199205143262003  [[DOI](https://doi.org/10.1056/NEJM199205143262003)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/1348845/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=N%20Engl%20J%20Med&title=Antidiabetogenic%20effect%20of%20glucagon-like%20peptide-1%20\(7%E2%80%9336\)amide%20in%20normal%20subjects%20and%20patients%20with%20diabetes%20mellitus&author=M%20Gutniak&author=C%20%C3%98rkov&author=JJ%20Holst&author=B%20Ahr%C3%A9n&author=S%20Efendi%C4%87&volume=326&publication_year=1992&pmid=1348845&doi=10.1056/NEJM199205143262003&)]
  * 16. Nauck MA. Glucagon-like peptide 1 (GLP-1): a potent gut hormone with a possible therapeutic perspective. Acta Diabetol (1998) 35:117–29. doi: 10.1007/s005920050116  [[DOI](https://doi.org/10.1007/s005920050116)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/9840447/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Acta%20Diabetol&title=Glucagon-like%20peptide%201%20\(GLP-1\):%20a%20potent%20gut%20hormone%20with%20a%20possible%20therapeutic%20perspective&author=MA%20Nauck&volume=35&publication_year=1998&pmid=9840447&doi=10.1007/s005920050116&)]
  * 17. Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC. Exon duplication and divergence in the human preproglucagon gene. Nature (1983) 304:368–71. doi: 10.1038/304368a0  [[DOI](https://doi.org/10.1038/304368a0)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/6877358/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nature&title=Exon%20duplication%20and%20divergence%20in%20the%20human%20preproglucagon%20gene&author=GI%20Bell&author=R%20Sanchez-Pescador&author=PJ%20Laybourn&author=RC%20Najarian&volume=304&publication_year=1983&pmid=6877358&doi=10.1038/304368a0&)]
  * 18. D’Alessio D. IsGLP-1 a hormone: Whether and when? J Diabetes Investig (2016) 7:50–5. doi: 10.1111/jdi.12466  [[DOI](https://doi.org/10.1111/jdi.12466)] [[PMC free article](/articles/PMC4854505/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27186356/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Diabetes%20Investig&title=IsGLP-1%20a%20hormone:%20Whether%20and%20when&author=D%20D%E2%80%99Alessio&volume=7&publication_year=2016&pmid=27186356&doi=10.1111/jdi.12466&)]
  * 19. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab (2018) 27:740–56. doi: 10.1016/j.cmet.2018.03.001  [[DOI](https://doi.org/10.1016/j.cmet.2018.03.001)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/29617641/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Cell%20Metab&title=Mechanisms%20of%20action%20and%20therapeutic%20application%20of%20glucagon-like%20peptide-1&author=DJ%20Drucker&volume=27&publication_year=2018&pmid=29617641&doi=10.1016/j.cmet.2018.03.001&)]
  * 20. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Association of pharmacological treatments for obesity with weight loss and adverse events. JAMA (2016) 315:2424. doi: 10.1001/jama.2016.7602  [[DOI](https://doi.org/10.1001/jama.2016.7602)] [[PMC free article](/articles/PMC5617638/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27299618/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=JAMA&title=Association%20of%20pharmacological%20treatments%20for%20obesity%20with%20weight%20loss%20and%20adverse%20events&author=R%20Khera&author=MH%20Murad&author=AK%20Chandar&author=PS%20Dulai&author=Z%20Wang&volume=315&publication_year=2016&pages=2424&pmid=27299618&doi=10.1001/jama.2016.7602&)]
  * 21. Uptodate . Available at: <https://www.uptodate.cn/contents/search>.
  * 22. Ranganath LR, Beety JM, Morgan LM, Wright JW, Howland R, Marks V. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut (1996) 38:916–9. doi: 10.1136/gut.38.6.916  [[DOI](https://doi.org/10.1136/gut.38.6.916)] [[PMC free article](/articles/PMC1383202/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/8984033/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Gut&title=Attenuated%20GLP-1%20secretion%20in%20obesity:%20cause%20or%20consequence&author=LR%20Ranganath&author=JM%20Beety&author=LM%20Morgan&author=JW%20Wright&author=R%20Howland&volume=38&publication_year=1996&pmid=8984033&doi=10.1136/gut.38.6.916&)]
  * 23. Ranganath L, Norris F, Morgan L, Wright J, Marks V. Inhibition of carbohydrate-mediated glucagon-like peptide-I (7–36)amide secretion by circulating non-esterified fatty acids. Clin Sci (1999) 96:335–42. doi: 10.1042/cs0960335  [[DOI](https://doi.org/10.1042/cs0960335)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/10087239/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Clin%20Sci&title=Inhibition%20of%20carbohydrate-mediated%20glucagon-like%20peptide-I%20\(7%E2%80%9336\)amide%20secretion%20by%20circulating%20non-esterified%20fatty%20acids&author=L%20Ranganath&author=F%20Norris&author=L%20Morgan&author=J%20Wright&author=V%20Marks&volume=96&publication_year=1999&pmid=10087239&doi=10.1042/cs0960335&)]
  * 24. Vrang N, Larsen PJ. Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: Role of peripherally secreted and centrally produced peptides. Prog Neurobiol (2010) 92:442–62. doi: 10.1016/j.pneurobio.2010.07.003  [[DOI](https://doi.org/10.1016/j.pneurobio.2010.07.003)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/20638440/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Prog%20Neurobiol&title=Preproglucagon%20derived%20peptides%20GLP-1,%20GLP-2%20and%20oxyntomodulin%20in%20the%20CNS:%20Role%20of%20peripherally%20secreted%20and%20centrally%20produced%20peptides&author=N%20Vrang&author=PJ%20Larsen&volume=92&publication_year=2010&pmid=20638440&doi=10.1016/j.pneurobio.2010.07.003&)]
  * 25. Larsen P, Vrang N, Tang-Christensen M. Central pre-proglucagon derived peptides: Opportunities for treatment of obesity. Curr Pharm Des (2003) 9:1373–82. doi: 10.2174/1381612033454775  [[DOI](https://doi.org/10.2174/1381612033454775)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/12769729/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Curr%20Pharm%20Des&title=Central%20pre-proglucagon%20derived%20peptides:%20Opportunities%20for%20treatment%20of%20obesity&author=P%20Larsen&author=N%20Vrang&author=M%20Tang-Christensen&volume=9&publication_year=2003&pmid=12769729&doi=10.2174/1381612033454775&)]
  * 26. Baggio LL, Huang Q, Brown TJ, Drucker DJ, Baggio LL, Huang Q, et al. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology (2004) 127:546–58. doi: 10.1053/j.gastro.2004.04.063  [[DOI](https://doi.org/10.1053/j.gastro.2004.04.063)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/15300587/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Gastroenterology&title=Oxyntomodulin%20and%20glucagon-like%20peptide-1%20differentially%20regulate%20murine%20food%20intake%20and%20energy%20expenditure&author=LL%20Baggio&author=Q%20Huang&author=TJ%20Brown&author=DJ%20Drucker&author=LL%20Baggio&volume=127&publication_year=2004&pmid=15300587&doi=10.1053/j.gastro.2004.04.063&)]
  * 27. Smits MM, Tonneijck L, Muskiet MHA, Kramer MHH, Cahen DL, van Raalte DH. Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas. Diabetes Obes Metab (2016) 18:224–35. doi: 10.1111/dom.12593  [[DOI](https://doi.org/10.1111/dom.12593)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26500045/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Obes%20Metab&title=Gastrointestinal%20actions%20of%20glucagon-like%20peptide-1-based%20therapies:%20glycaemic%20control%20beyond%20the%20pancreas&author=MM%20Smits&author=L%20Tonneijck&author=MHA%20Muskiet&author=MHH%20Kramer&author=DL%20Cahen&volume=18&publication_year=2016&pmid=26500045&doi=10.1111/dom.12593&)]
  * 28. Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol-Regul Integr Comp Physiol (2016) 310:R885–95. doi: 10.1152/ajpregu.00520.2015  [[DOI](https://doi.org/10.1152/ajpregu.00520.2015)] [[PMC free article](/articles/PMC4888559/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27030669/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Physiol-Regul%20Integr%20Comp%20Physiol&title=GLP-1%20and%20weight%20loss:%20unraveling%20the%20diverse%20neural%20circuitry&author=SE%20Kanoski&author=MR%20Hayes&author=KP%20Skibicka&volume=310&publication_year=2016&pmid=27030669&doi=10.1152/ajpregu.00520.2015&)]
  * 29. Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, LIR and exendin-4 . Available at: <https://pubmed.ncbi.nlm.nih.gov/21693680/> (Accessed August 9, 2022). [[DOI](https://doi.org/10.1210/en.2011-0174)] [[PMC free article](/articles/PMC3138234/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/21693680/)]
  * 30. Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab (2012) 16:296–309. doi: 10.1016/j.cmet.2012.06.015  [[DOI](https://doi.org/10.1016/j.cmet.2012.06.015)] [[PMC free article](/articles/PMC4862653/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/22902836/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Cell%20Metab&title=Hindbrain%20neurons%20as%20an%20essential%20hub%20in%20the%20neuroanatomically%20distributed%20control%20of%20energy%20balance&author=HJ%20Grill&author=MR%20Hayes&volume=16&publication_year=2012&pages=296-309&pmid=22902836&doi=10.1016/j.cmet.2012.06.015&)]
  * 31. Alhadeff AL, Baird J-P, Swick JC, Hayes MR, Grill HJ. Glucagon-like peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed. Neuropsychopharmacology (2014) 39:2233–43. doi: 10.1038/npp.2014.74  [[DOI](https://doi.org/10.1038/npp.2014.74)] [[PMC free article](/articles/PMC4104342/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24681814/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Neuropsychopharmacology&title=Glucagon-like%20peptide-1%20receptor%20signaling%20in%20the%20lateral%20parabrachial%20nucleus%20contributes%20to%20the%20control%20of%20food%20intake%20and%20motivation%20to%20feed&author=AL%20Alhadeff&author=J-P%20Baird&author=JC%20Swick&author=MR%20Hayes&author=HJ%20Grill&volume=39&publication_year=2014&pmid=24681814&doi=10.1038/npp.2014.74&)]
  * 32. Alhadeff AL, Rupprecht LE, Hayes MR. GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology (2012) 153:647–58. doi: 10.1210/en.2011-1443  [[DOI](https://doi.org/10.1210/en.2011-1443)] [[PMC free article](/articles/PMC3275387/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/22128031/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Endocrinology&title=GLP-1%20neurons%20in%20the%20nucleus%20of%20the%20solitary%20tract%20project%20directly%20to%20the%20ventral%20tegmental%20area%20and%20nucleus%20accumbens%20to%20control%20for%20food%20intake&author=AL%20Alhadeff&author=LE%20Rupprecht&author=MR%20Hayes&volume=153&publication_year=2012&pmid=22128031&doi=10.1210/en.2011-1443&)]
  * 33. Dickson SL, Shirazi RH, Hansson C, Bergquist F, Nissbrandt H, Skibicka KP. The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: A new role for mesolimbic GLP-1 receptors. J Neurosci (2012) 32:4812–20. doi: 10.1523/JNEUROSCI.6326-11.2012  [[DOI](https://doi.org/10.1523/JNEUROSCI.6326-11.2012)] [[PMC free article](/articles/PMC6620919/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/22492036/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Neurosci&title=The%20glucagon-like%20peptide%201%20\(GLP-1\)%20analogue,%20exendin-4,%20decreases%20the%20rewarding%20value%20of%20food:%20A%20new%20role%20for%20mesolimbic%20GLP-1%20receptors&author=SL%20Dickson&author=RH%20Shirazi&author=C%20Hansson&author=F%20Bergquist&author=H%20Nissbrandt&volume=32&publication_year=2012&pmid=22492036&doi=10.1523/JNEUROSCI.6326-11.2012&)]
  * 34. Merchenthaler I, Lane M, Shughrue P. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol (1999) 403:261–80. doi:  [[DOI](https://doi.org/10.1002/\(sici\)1096-9861\(19990111\)403:2&#x0003c;261::aid-cne8&#x0003e;3.0.co;2-5)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/9886047/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%C2%A0Comp%20Neurol&title=Distribution%20of%20pre-pro-glucagon%20and%20glucagon-like%20peptide-1%20receptor%20messenger%20RNAs%20in%20the%20rat%20central%20nervous%20system&author=I%20Merchenthaler&author=M%20Lane&author=P%20Shughrue&volume=403&publication_year=1999&pmid=9886047&doi=10.1002/\(sici\)1096-9861\(19990111\)403:2&#x0003c;261::aid-cne8&#x0003e;3.0.co;2-5&)]
  * 35. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev (2007) 87:1409–39. doi: 10.1152/physrev.00034.2006  [[DOI](https://doi.org/10.1152/physrev.00034.2006)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/17928588/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Physiol%20Rev&title=The%20physiology%20of%20glucagon-like%20peptide%201&author=JJ%20Holst&volume=87&publication_year=2007&pmid=17928588&doi=10.1152/physrev.00034.2006&)]
  * 36. Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes (2014) 63:3346–58. doi: 10.2337/db14-0302  [[DOI](https://doi.org/10.2337/db14-0302)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24917578/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes&title=GLP-1%20agonism%20stimulates%20brown%20adipose%20tissue%20thermogenesis%20and%20browning%20through%20hypothalamic%20AMPK&author=D%20Beiroa&author=M%20Imbernon&author=R%20Gallego&author=A%20Senra&author=D%20Herranz&volume=63&publication_year=2014&pmid=24917578&doi=10.2337/db14-0302&)]
  * 37. Burmeister MA, Ayala J, Drucker DJ, Ayala JE. Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose. Am J Physiol-Endocrinol Metab (2013) 304:E677–85. doi: 10.1152/ajpendo.00446.2012  [[DOI](https://doi.org/10.1152/ajpendo.00446.2012)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/23341495/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Physiol-Endocrinol%20Metab&title=Central%20glucagon-like%20peptide%201%20receptor-induced%20anorexia%20requires%20glucose%20metabolism-mediated%20suppression%20of%20AMPK%20and%20is%20impaired%20by%20central%20fructose&author=MA%20Burmeister&author=J%20Ayala&author=DJ%20Drucker&author=JE%20Ayala&volume=304&publication_year=2013&pmid=23341495&doi=10.1152/ajpendo.00446.2012&)]
  * 38. Kooijman S, Wang Y, Parlevliet ET, Boon MR, Edelschaap D, Snaterse G, et al. Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice. Diabetologia (2015) 58:2637–46. doi: 10.1007/s00125-015-3727-0  [[DOI](https://doi.org/10.1007/s00125-015-3727-0)] [[PMC free article](/articles/PMC4589565/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26254578/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetologia&title=Central%20GLP-1%20receptor%20signalling%20accelerates%20plasma%20clearance%20of%20triacylglycerol%20and%20glucose%20by%20activating%20brown%20adipose%20tissue%20in%20mice&author=S%20Kooijman&author=Y%20Wang&author=ET%20Parlevliet&author=MR%20Boon&author=D%20Edelschaap&volume=58&publication_year=2015&pmid=26254578&doi=10.1007/s00125-015-3727-0&)]
  * 39. Xu F, Lin B, Zheng X, Chen Z, Cao H, Xu H, et al. GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia (2016) 59:1059–69. doi: 10.1007/s00125-016-3896-5  [[DOI](https://doi.org/10.1007/s00125-016-3896-5)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26924394/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetologia&title=GLP-1%20receptor%20agonist%20promotes%20brown%20remodelling%20in%20mouse%20white%20adipose%20tissue%20through%20SIRT1&author=F%20Xu&author=B%20Lin&author=X%20Zheng&author=Z%20Chen&author=H%20Cao&volume=59&publication_year=2016&pmid=26924394&doi=10.1007/s00125-016-3896-5&)]
  * 40. Zhang YL, Zhou C, Li XF, Yang MN, Tao L, Zheng XY, et al. Beinaglutide showed significant weight-loss benefit and effective glycaemic control for the treatment of type 2 diabetes in a real-world setting: a 3-month, multicentre, observational, retrospective, open-label study. Obes Sci Amp Pract (2019) 5:366–75. doi: 10.1002/osp4.342  [[DOI](https://doi.org/10.1002/osp4.342)] [[PMC free article](/articles/PMC6700512/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/31452921/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Obes%20Sci%20Amp%20Pract&title=Beinaglutide%20showed%20significant%20weight-loss%20benefit%20and%20effective%20glycaemic%20control%20for%20the%20treatment%20of%20type%202%20diabetes%20in%20a%20real-world%20setting:%20a%203-month,%20multicentre,%20observational,%20retrospective,%20open-label%20study&author=YL%20Zhang&author=C%20Zhou&author=XF%20Li&author=MN%20Yang&author=L%20Tao&volume=5&publication_year=2019&pmid=31452921&doi=10.1002/osp4.342&)]
  * 41. Wang G, Wu P, Qiu Y, Dong X, Wang Y, Chi Y, et al. Effect of beinaglutide treatment on weight loss in Chinese patients with type 2 diabetes mellitus and overweight/obesity. Arch Endocrinol Metab (2021) 65:421–7. doi: 10.20945/2359-3997000000388  [[DOI](https://doi.org/10.20945/2359-3997000000388)] [[PMC free article](/articles/PMC10522179/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34283904/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Arch%20Endocrinol%20Metab&title=Effect%20of%20beinaglutide%20treatment%20on%20weight%20loss%20in%20Chinese%20patients%20with%20type%202%20diabetes%20mellitus%20and%20overweight/obesity&author=G%20Wang&author=P%20Wu&author=Y%20Qiu&author=X%20Dong&author=Y%20Wang&volume=65&publication_year=2021&pmid=34283904&doi=10.20945/2359-3997000000388&)]
  * 42. Fang X, Du Z, Duan C, Zhan S, Wang T, Zhu M, et al. Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model. Life Sci (2021) 270:118966. doi: 10.1016/j.lfs.2020.118966  [[DOI](https://doi.org/10.1016/j.lfs.2020.118966)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/33482185/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Life%20Sci&title=Beinaglutide%20shows%20significantly%20beneficial%20effects%20in%20diabetes/obesity-induced%20nonalcoholic%20steatohepatitis%20in%20ob/ob%20mouse%20model&author=X%20Fang&author=Z%20Du&author=C%20Duan&author=S%20Zhan&author=T%20Wang&volume=270&publication_year=2021&pages=118966&pmid=33482185&doi=10.1016/j.lfs.2020.118966&)]
  * 43. Gao L, Huang H, Zhang L, Zhang N, Fu Y, Zhu D, et al. Comparison of beinaglutide versus metformin for weight loss in overweight and obese non-diabetic patients. Exp Clin Endocrinol Amp Diabetes (2022) 130:358–67. doi: 10.1055/a-1608-0345  [[DOI](https://doi.org/10.1055/a-1608-0345)] [[PMC free article](/articles/PMC9286864/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34856624/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Exp%20Clin%20Endocrinol%20Amp%20Diabetes&title=Comparison%20of%20beinaglutide%20versus%20metformin%20for%20weight%20loss%20in%20overweight%20and%20obese%20non-diabetic%20patients&author=L%20Gao&author=H%20Huang&author=L%20Zhang&author=N%20Zhang&author=Y%20Fu&volume=130&publication_year=2022&pmid=34856624&doi=10.1055/a-1608-0345&)]
  * 44. Ding B, Hu Y, Yuan L, Yan R-N, Ma J-H. Effectiveness of beinaglutide in a patient with late dumping syndrome after gastrectomy. Med (Baltimore) (2021) 100:e26086. doi: 10.1097/MD.0000000000026086  [[DOI](https://doi.org/10.1097/MD.0000000000026086)] [[PMC free article](/articles/PMC8154494/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34032745/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Med%20\(Baltimore\)&title=Effectiveness%20of%20beinaglutide%20in%20a%20patient%20with%20late%20dumping%20syndrome%20after%20gastrectomy&author=B%20Ding&author=Y%20Hu&author=L%20Yuan&author=R-N%20Yan&author=J-H%20Ma&volume=100&publication_year=2021&pages=e26086&pmid=34032745&doi=10.1097/MD.0000000000026086&)]
  * 45. Zhang F, Chen Z, Wu D, Tian L, Chen Q, Ye Y, et al. Recombinant human GLP-1 beinaglutide regulates lipid metabolism of adipose tissues in diet-induced obese mice. iScience (2021) 24:103382. doi: 10.1016/j.isci.2021.103382  [[DOI](https://doi.org/10.1016/j.isci.2021.103382)] [[PMC free article](/articles/PMC8605346/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34841227/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=iScience&title=Recombinant%20human%20GLP-1%20beinaglutide%20regulates%20lipid%20metabolism%20of%20adipose%20tissues%20in%20diet-induced%20obese%20mice&author=F%20Zhang&author=Z%20Chen&author=D%20Wu&author=L%20Tian&author=Q%20Chen&volume=24&publication_year=2021&pages=103382&pmid=34841227&doi=10.1016/j.isci.2021.103382&)]
  * 46. Barnett A. Exenatide. Expert Opin Pharmacother (2007) 8:2593–608. doi: 10.1517/14656566.8.15.2593  [[DOI](https://doi.org/10.1517/14656566.8.15.2593)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/17931093/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Pharmacother&title=Exenatide&author=A%20Barnett&volume=8&publication_year=2007&pmid=17931093&doi=10.1517/14656566.8.15.2593&)]
  * 47. Bray GM. Exenatide. Am J Health Syst Pharm (2006) 63:411–8. doi: 10.2146/ajhp050459  [[DOI](https://doi.org/10.2146/ajhp050459)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/16484515/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Health%20Syst%20Pharm&title=Exenatide&author=GM%20Bray&volume=63&publication_year=2006&pmid=16484515&doi=10.2146/ajhp050459&)]
  * 48. Simonsen L, Holst JJ, Deacon CF. Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia (2006) 49:706–12. doi: 10.1007/s00125-005-0128-9  [[DOI](https://doi.org/10.1007/s00125-005-0128-9)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/16447056/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetologia&title=Exendin-4,%20but%20not%20glucagon-like%20peptide-1,%20is%20cleared%20exclusively%20by%20glomerular%20filtration%20in%20anaesthetised%20pigs&author=L%20Simonsen&author=JJ%20Holst&author=CF%20Deacon&volume=49&publication_year=2006&pmid=16447056&doi=10.1007/s00125-005-0128-9&)]
  * 49. Nishi H, Higashihara T, Inagi R. Lipotoxicity in kidney, heart, and skeletal muscle dysfunction. Nutrients (2019) 11:1664. doi: 10.3390/nu11071664  [[DOI](https://doi.org/10.3390/nu11071664)] [[PMC free article](/articles/PMC6682887/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/31330812/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nutrients&title=Lipotoxicity%20in%20kidney,%20heart,%20and%20skeletal%20muscle%20dysfunction&author=H%20Nishi&author=T%20Higashihara&author=R%20Inagi&volume=11&publication_year=2019&pages=1664&pmid=31330812&doi=10.3390/nu11071664&)]
  * 50. Wang Y, He W, Wei W, Mei X, Yang M, Wang Y. Exenatide attenuates obesity-induced mitochondrial dysfunction by activating SIRT1 in renal tubular cells. Front Endocrinol (2021) 12:622737. doi: 10.3389/fendo.2021.622737  [[DOI](https://doi.org/10.3389/fendo.2021.622737)] [[PMC free article](/articles/PMC8380782/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34434166/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Front%20Endocrinol&title=Exenatide%20attenuates%20obesity-induced%20mitochondrial%20dysfunction%20by%20activating%20SIRT1%20in%20renal%20tubular%20cells&author=Y%20Wang&author=W%20He&author=W%20Wei&author=X%20Mei&author=M%20Yang&volume=12&publication_year=2021&pages=622737&pmid=34434166&doi=10.3389/fendo.2021.622737&)]
  * 51. Moretto T, Milton D, Ridge T, Macconell L, Okerson T, Wolka A, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug–naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther (2008) 30:1448–60. doi: 10.1016/j.clinthera.2008.08.006  [[DOI](https://doi.org/10.1016/j.clinthera.2008.08.006)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/18803987/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Clin%20Ther&title=Efficacy%20and%20tolerability%20of%20exenatide%20monotherapy%20over%2024%20weeks%20in%20antidiabetic%20drug%E2%80%93naive%20patients%20with%20type%202%20diabetes:%20A%20randomized,%20double-blind,%20placebo-controlled,%20parallel-group%20study&author=T%20Moretto&author=D%20Milton&author=T%20Ridge&author=L%20Macconell&author=T%20Okerson&volume=30&publication_year=2008&pmid=18803987&doi=10.1016/j.clinthera.2008.08.006&)]
  * 52. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, et al. Effects of exenatide (Exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care (2004) 27:2628–35. doi: 10.2337/diacare.27.11.2628  [[DOI](https://doi.org/10.2337/diacare.27.11.2628)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/15504997/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Effects%20of%20exenatide%20\(Exendin-4\)%20on%20glycemic%20control%20over%2030%20weeks%20in%20sulfonylurea-treated%20patients%20with%20type%202%20diabetes&author=JB%20Buse&author=RR%20Henry&author=J%20Han&author=DD%20Kim&author=MS%20Fineman&volume=27&publication_year=2004&pmid=15504997&doi=10.2337/diacare.27.11.2628&)]
  * 53. Apovian CM, Bergenstal RM, Cuddihy RM, Qu Y, Lenox S, Lewis MS, et al. Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. Am J Med (2010) 123:468. doi: 10.1016/j.amjmed.2009.11.019  [[DOI](https://doi.org/10.1016/j.amjmed.2009.11.019)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/20399326/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Med&title=Effects%20of%20exenatide%20combined%20with%20lifestyle%20modification%20in%20patients%20with%20type%202%20diabetes&author=CM%20Apovian&author=RM%20Bergenstal&author=RM%20Cuddihy&author=Y%20Qu&author=S%20Lenox&volume=123&publication_year=2010&pages=468&pmid=20399326&doi=10.1016/j.amjmed.2009.11.019&)]
  * 54. Rosenstock J, Klaff LJ, Schwartz S, Northrup J, Holcombe JH, Wilhelm K, et al. Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care (2010) 33:1173–5. doi: 10.2337/dc09-1203  [[DOI](https://doi.org/10.2337/dc09-1203)] [[PMC free article](/articles/PMC2875418/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/20332357/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Effects%20of%20exenatide%20and%20lifestyle%20modification%20on%20body%20weight%20and%20glucose%20tolerance%20in%20obese%20subjects%20with%20and%20without%20pre-diabetes&author=J%20Rosenstock&author=LJ%20Klaff&author=S%20Schwartz&author=J%20Northrup&author=JH%20Holcombe&volume=33&publication_year=2010&pmid=20332357&doi=10.2337/dc09-1203&)]
  * 55. Elkind-Hirsch K, Marrioneaux O, Bhushan M, Vernor D, Bhushan R. Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab (2008) 93:2670–8. doi: 10.1210/jc.2008-0115  [[DOI](https://doi.org/10.1210/jc.2008-0115)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/18460557/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Endocrinol%20Metab&title=Comparison%20of%20single%20and%20combined%20treatment%20with%20exenatide%20and%20metformin%20on%20menstrual%20cyclicity%20in%20overweight%20women%20with%20polycystic%20ovary%20syndrome&author=K%20Elkind-Hirsch&author=O%20Marrioneaux&author=M%20Bhushan&author=D%20Vernor&author=R%20Bhushan&volume=93&publication_year=2008&pmid=18460557&doi=10.1210/jc.2008-0115&)]
  * 56. González-Ortiz M, Martínez-Abundis E, Robles-Cervantes JA, Ramos-Zavala MG. Effect of exenatide on fat deposition and a metabolic profile in patients with metabolic syndrome. Metab Syndr Relat Disord (2011) 9:31–4. doi: 10.1089/met.2010.0025  [[DOI](https://doi.org/10.1089/met.2010.0025)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/20874425/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Metab%20Syndr%20Relat%20Disord&title=Effect%20of%20exenatide%20on%20fat%20deposition%20and%20a%20metabolic%20profile%20in%20patients%20with%20metabolic%20syndrome&author=M%20Gonz%C3%A1lez-Ortiz&author=E%20Mart%C3%ADnez-Abundis&author=JA%20Robles-Cervantes&author=MG%20Ramos-Zavala&volume=9&publication_year=2011&pmid=20874425&doi=10.1089/met.2010.0025&)]
  * 57. Iepsen EW, Torekov SS, Holst JJ. Therapies for inter-relating diabetes and obesity – GLP-1 and obesity. Expert Opin Pharmacother (2014) 15:2487–500. doi: 10.1517/14656566.2014.965678  [[DOI](https://doi.org/10.1517/14656566.2014.965678)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/25260877/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Pharmacother&title=Therapies%20for%20inter-relating%20diabetes%20and%20obesity%20%E2%80%93%20GLP-1%20and%20obesity&author=EW%20Iepsen&author=SS%20Torekov&author=JJ%20Holst&volume=15&publication_year=2014&pmid=25260877&doi=10.1517/14656566.2014.965678&)]
  * 58. Anderson SL, Trujillo JM. Lixisenatide in type 2 diabetes: latest evidence and clinical usefulness. Ther Adv Chronic Dis (2016) 7:4–17. doi: 10.1177/2040622315609312  [[DOI](https://doi.org/10.1177/2040622315609312)] [[PMC free article](/articles/PMC4707429/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26770666/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Ther%20Adv%20Chronic%20Dis&title=Lixisenatide%20in%20type%202%20diabetes:%20latest%20evidence%20and%20clinical%20usefulness&author=SL%20Anderson&author=JM%20Trujillo&volume=7&publication_year=2016&pages=4-17&pmid=26770666&doi=10.1177/2040622315609312&)]
  * 59. Christensen M, Knop FK, Holst JJ, Vilsboll T. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus. IDrugs Investig Drugs J (2009) 12:503–13. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/19629885/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=IDrugs%20Investig%20Drugs%20J&title=Lixisenatide,%20a%20novel%20GLP-1%20receptor%20agonist%20for%20the%20treatment%20of%20type%202%20diabetes%20mellitus&author=M%20Christensen&author=FK%20Knop&author=JJ%20Holst&author=T%20Vilsboll&volume=12&publication_year=2009&pmid=19629885&)]
  * 60. Petersen AB, Knop FK, Christensen M. Lixisenatide for the treatment of type 2 diabetes. Drugs Today (Barc) (2013) 49(9):537–53. doi: 10.1358/dot.2013.49.9.2020940  [[DOI](https://doi.org/10.1358/dot.2013.49.9.2020940)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24086950/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Drugs%20Today%20\(Barc\)&title=Lixisenatide%20for%20the%20treatment%20of%20type%202%20diabetes&author=AB%20Petersen&author=FK%20Knop&author=M%20Christensen&volume=49&issue=9&publication_year=2013&pmid=24086950&doi=10.1358/dot.2013.49.9.2020940&)]
  * 61. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med (2015) 373:2247–57. doi: 10.1056/NEJMoa1509225  [[DOI](https://doi.org/10.1056/NEJMoa1509225)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26630143/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=N%20Engl%20J%20Med&title=Lixisenatide%20in%20patients%20with%20type%202%20diabetes%20and%20acute%20coronary%20syndrome&author=MA%20Pfeffer&author=B%20Claggett&author=R%20Diaz&author=K%20Dickstein&author=HC%20Gerstein&volume=373&publication_year=2015&pmid=26630143&doi=10.1056/NEJMoa1509225&)]
  * 62. Fonseca VA, Alvarado-Ruiz R, Raccah D, Boka G, Miossec P, Gerich JE, et al. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy. Diabetes Care (2012) 35:1225–31. doi: 10.2337/dc11-1935  [[DOI](https://doi.org/10.2337/dc11-1935)] [[PMC free article](/articles/PMC3357248/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/22432104/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Efficacy%20and%20safety%20of%20the%20once-daily%20GLP-1%20receptor%20agonist%20lixisenatide%20in%20monotherapy&author=VA%20Fonseca&author=R%20Alvarado-Ruiz&author=D%20Raccah&author=G%20Boka&author=P%20Miossec&volume=35&publication_year=2012&pmid=22432104&doi=10.2337/dc11-1935&)]
  * 63. McCarty D, Coleman M, Boland CL. Lixisenatide: A new daily GLP-1 agonist for type 2 diabetes management. Ann Pharmacother (2017) 51:401–9. doi: 10.1177/1060028017689878  [[DOI](https://doi.org/10.1177/1060028017689878)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/28133970/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Ann%20Pharmacother&title=Lixisenatide:%20A%20new%20daily%20GLP-1%20agonist%20for%20type%202%20diabetes%20management&author=D%20McCarty&author=M%20Coleman&author=CL%20Boland&volume=51&publication_year=2017&pmid=28133970&doi=10.1177/1060028017689878&)]
  * 64. Pharmacological profile, efficacy and safety of lixisenatide in type 2 diabetes mellitus. Available at: <https://pubmed.ncbi.nlm.nih.gov/24087882/> (Accessed August 10, 2022). [[DOI](https://doi.org/10.1517/14656566.2013.838559)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24087882/)]
  * 65. Forst T, Pfützner A. Pharmacological profile, efficacy and safety of lixisenatide in type 2 diabetes mellitus. Expert Opin Pharmacother (2013) 14:2281–96. doi: 10.1517/14656566.2013.838559  [[DOI](https://doi.org/10.1517/14656566.2013.838559)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24087882/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Pharmacother&title=Pharmacological%20profile,%20efficacy%20and%20safety%20of%20lixisenatide%20in%20type%202%20diabetes%20mellitus&author=T%20Forst&author=A%20Pf%C3%BCtzner&volume=14&publication_year=2013&pmid=24087882&doi=10.1517/14656566.2013.838559&)]
  * 66. Christensen M, Miossec P, Larsen BD, Werner U, Knop FK. The design and discovery of lixisenatide for the treatment of type 2 diabetes mellitus. Expert Opin Drug Discovery (2014) 9:1223–51. doi: 10.1517/17460441.2014.942638  [[DOI](https://doi.org/10.1517/17460441.2014.942638)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/25119443/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Drug%20Discovery&title=The%20design%20and%20discovery%20of%20lixisenatide%20for%20the%20treatment%20of%20type%202%20diabetes%20mellitus&author=M%20Christensen&author=P%20Miossec&author=BD%20Larsen&author=U%20Werner&author=FK%20Knop&volume=9&publication_year=2014&pmid=25119443&doi=10.1517/17460441.2014.942638&)]
  * 67. Horowitz M, Rayner CK, Jones KL. Mechanisms and clinical efficacy of lixisenatide for the management of type 2 diabetes. Adv Ther (2013) 30:81–101. doi: 10.1007/s12325-013-0009-4  [[DOI](https://doi.org/10.1007/s12325-013-0009-4)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/23423907/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Adv%20Ther&title=Mechanisms%20and%20clinical%20efficacy%20of%20lixisenatide%20for%20the%20management%20of%20type%202%20diabetes&author=M%20Horowitz&author=CK%20Rayner&author=KL%20Jones&volume=30&publication_year=2013&pages=81-101&pmid=23423907&doi=10.1007/s12325-013-0009-4&)]
  * 68. Roca-Rodríguez MM, Muros de Fuentes MT, Piédrola-Maroto G, Quesada-Charneco M, Maraver-Selfa S, Tinahones FJ, et al. Lixisenatida en pacientes con diabetes tipo 2 y obesidad: más allá del control glucémico. Aten Primaria (2017) 49:294–9. doi: 10.1016/j.aprim.2016.06.009  [[DOI](https://doi.org/10.1016/j.aprim.2016.06.009)] [[PMC free article](/articles/PMC6875984/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27667144/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Aten%20Primaria&title=Lixisenatida%20en%20pacientes%20con%20diabetes%20tipo%202%20y%20obesidad:%20m%C3%A1s%20all%C3%A1%20del%20control%20gluc%C3%A9mico&author=MM%20Roca-Rodr%C3%ADguez&author=MT%20Muros%20de%20Fuentes&author=G%20Pi%C3%A9drola-Maroto&author=M%20Quesada-Charneco&author=S%20Maraver-Selfa&volume=49&publication_year=2017&pmid=27667144&doi=10.1016/j.aprim.2016.06.009&)]
  * 69. Whyte MB, Shojaee-Moradie F, Sharaf SE, Jackson NC, Fielding B, Hovorka R, et al. Lixisenatide reduces chylomicron triacylglycerol by increased clearance. J Clin Endocrinol Metab (2019) 104:359–68. doi: 10.1210/jc.2018-01176  [[DOI](https://doi.org/10.1210/jc.2018-01176)] [[PMC free article](/articles/PMC6300412/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/30215735/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Endocrinol%20Metab&title=Lixisenatide%20reduces%20chylomicron%20triacylglycerol%20by%20increased%20clearance&author=MB%20Whyte&author=F%20Shojaee-Moradie&author=SE%20Sharaf&author=NC%20Jackson&author=B%20Fielding&volume=104&publication_year=2019&pmid=30215735&doi=10.1210/jc.2018-01176&)]
  * 70. Kaneto H, Takami A, Spranger R, Amano A, Watanabe D, Niemoeller E. Efficacy and safety of insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) in Japanese patients with type 2 diabetes mellitus inadequately controlled on basal insulin and oral antidiabetic drugs: The LixiLan JP-l randomized clinical trial. Diabetes Obes Metab (2020) 22:3–13. doi: 10.1111/dom.14005  [[DOI](https://doi.org/10.1111/dom.14005)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/32072742/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Obes%20Metab&title=Efficacy%20and%20safety%20of%20insulin%20glargine/lixisenatide%20fixed-ratio%20combination%20\(iGlarLixi\)%20in%20Japanese%20patients%20with%20type%202%20diabetes%20mellitus%20inadequately%20controlled%20on%20basal%20insulin%20and%20oral%20antidiabetic%20drugs:%20The%20LixiLan%20JP-l%20randomized%20clinical%20trial&author=H%20Kaneto&author=A%20Takami&author=R%20Spranger&author=A%20Amano&author=D%20Watanabe&volume=22&publication_year=2020&pages=3-13&pmid=32072742&doi=10.1111/dom.14005&)]
  * 71. Riddle MC, Aronson R, Home P, Marre M, Niemoeller E, Miossec P, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin. Diabetes Care (2013) 36:2489–96. doi: 10.2337/dc12-2454  [[DOI](https://doi.org/10.2337/dc12-2454)] [[PMC free article](/articles/PMC3747925/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/23628617/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Adding%20once-daily%20lixisenatide%20for%20type%202%20diabetes%20inadequately%20controlled%20by%20established%20basal%20insulin&author=MC%20Riddle&author=R%20Aronson&author=P%20Home&author=M%20Marre&author=E%20Niemoeller&volume=36&publication_year=2013&pmid=23628617&doi=10.2337/dc12-2454&)]
  * 72. Rosenstock J, Hanefeld M, Shamanna P, Min KW, Boka G, Miossec P, et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-s). J Diabetes Complications (2014) 28:386–92. doi: 10.1016/j.jdiacomp.2014.01.012  [[DOI](https://doi.org/10.1016/j.jdiacomp.2014.01.012)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24650952/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Diabetes%20Complications&title=Beneficial%20effects%20of%20once-daily%20lixisenatide%20on%20overall%20and%20postprandial%20glycemic%20levels%20without%20significant%20excess%20of%20hypoglycemia%20in%20type%202%20diabetes%20inadequately%20controlled%20on%20a%20sulfonylurea%20with%20or%20without%20metformin%20\(GetGoal-s\)&author=J%20Rosenstock&author=M%20Hanefeld&author=P%20Shamanna&author=KW%20Min&author=G%20Boka&volume=28&publication_year=2014&pmid=24650952&doi=10.1016/j.jdiacomp.2014.01.012&)]
  * 73. Bolli GB, Munteanu M, Dotsenko S, Niemoeller E, Boka G, Wu Y, et al. Efficacy and safety of lixisenatide once daily vs. placebo in people with type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabetes Med (2014) 31:176–84. doi: 10.1111/dme.12328  [[DOI](https://doi.org/10.1111/dme.12328)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24117597/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Med&title=Efficacy%20and%20safety%20of%20lixisenatide%20once%20daily%20vs.%20placebo%20in%20people%20with%20type%202%20diabetes%20insufficiently%20controlled%20on%20metformin%20\(GetGoal-F1\)&author=GB%20Bolli&author=M%20Munteanu&author=S%20Dotsenko&author=E%20Niemoeller&author=G%20Boka&volume=31&publication_year=2014&pmid=24117597&doi=10.1111/dme.12328&)]
  * 74. Onishi Y, Niemoeller E, Ikeda Y, Takagi H, Yabe D, Seino Y. Efficacy and safety of lixisenatide in Japanese patients with type 2 diabetes mellitus inadequately controlled by sulfonylurea with or without metformin: Subanalysis of G et G oal- s. J Diabetes Investig (2015) 6:201–9. doi: 10.1111/jdi.12275  [[DOI](https://doi.org/10.1111/jdi.12275)] [[PMC free article](/articles/PMC4364855/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/25802728/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Diabetes%20Investig&title=Efficacy%20and%20safety%20of%20lixisenatide%20in%20Japanese%20patients%20with%20type%202%20diabetes%20mellitus%20inadequately%20controlled%20by%20sulfonylurea%20with%20or%20without%20metformin:%20Subanalysis%20of%20G%20et%20G%20oal-%20s&author=Y%20Onishi&author=E%20Niemoeller&author=Y%20Ikeda&author=H%20Takagi&author=D%20Yabe&volume=6&publication_year=2015&pmid=25802728&doi=10.1111/jdi.12275&)]
  * 75. Nauck M, Rizzo M, Johnson A, Bosch-Traberg H, Madsen J, Cariou B. Once-daily liraglutide versus lixisenatide as add-on to metformin in type 2 diabetes: A 26-week randomized controlled clinical trial. Diabetes Care (2016) 39:1501–9. doi: 10.2337/dc15-2479  [[DOI](https://doi.org/10.2337/dc15-2479)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27311491/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Once-daily%20liraglutide%20versus%20lixisenatide%20as%20add-on%20to%20metformin%20in%20type%202%20diabetes:%20A%2026-week%20randomized%20controlled%20clinical%20trial&author=M%20Nauck&author=M%20Rizzo&author=A%20Johnson&author=H%20Bosch-Traberg&author=J%20Madsen&volume=39&publication_year=2016&pmid=27311491&doi=10.2337/dc15-2479&)]
  * 76. Ahrén B, Leguizamo Dimas A, Miossec P, Saubadu S, Aronson R. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-m). Diabetes Care (2013) 36:2543–50. doi: 10.2337/dc12-2006  [[DOI](https://doi.org/10.2337/dc12-2006)] [[PMC free article](/articles/PMC3747937/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/23536584/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Efficacy%20and%20safety%20of%20lixisenatide%20once-daily%20morning%20or%20evening%20injections%20in%20type%202%20diabetes%20inadequately%20controlled%20on%20metformin%20\(GetGoal-m\)&author=B%20Ahr%C3%A9n&author=A%20Leguizamo%20Dimas&author=P%20Miossec&author=S%20Saubadu&author=R%20Aronson&volume=36&publication_year=2013&pmid=23536584&doi=10.2337/dc12-2006&)]
  * 77. Rosenstock J, Raccah D, Korányi L, Maffei L, Boka G, Miossec P, et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin. Diabetes Care (2013) 36:2945–51. doi: 10.2337/dc12-2709  [[DOI](https://doi.org/10.2337/dc12-2709)] [[PMC free article](/articles/PMC3781502/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/23698396/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Efficacy%20and%20safety%20of%20lixisenatide%20once%20daily%20versus%20exenatide%20twice%20daily%20in%20type%202%20diabetes%20inadequately%20controlled%20on%20metformin&author=J%20Rosenstock&author=D%20Raccah&author=L%20Kor%C3%A1nyi&author=L%20Maffei&author=G%20Boka&volume=36&publication_year=2013&pmid=23698396&doi=10.2337/dc12-2709&)]
  * 78. Hunt B, Kragh N, McConnachie CC, Valentine WJ, Rossi MC, Montagnoli R. Long-term cost-effectiveness of two GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus in the Italian setting: Liraglutide versus lixisenatide. Clin Ther (2017) 39:1347–59. doi: 10.1016/j.clinthera.2017.05.354  [[DOI](https://doi.org/10.1016/j.clinthera.2017.05.354)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/28625506/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Clin%20Ther&title=Long-term%20cost-effectiveness%20of%20two%20GLP-1%20receptor%20agonists%20for%20the%20treatment%20of%20type%202%20diabetes%20mellitus%20in%20the%20Italian%20setting:%20Liraglutide%20versus%20lixisenatide&author=B%20Hunt&author=N%20Kragh&author=CC%20McConnachie&author=WJ%20Valentine&author=MC%20Rossi&volume=39&publication_year=2017&pmid=28625506&doi=10.1016/j.clinthera.2017.05.354&)]
  * 79. Leon N, LaCoursiere R, Yarosh D, Patel RS. Lixisenatide (Adlyxin). Pharm Ther (2017) 42:676–711. [[PMC free article](/articles/PMC5642155/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/29089722/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Pharm%20Ther&title=Lixisenatide%20\(Adlyxin\)&author=N%20Leon&author=R%20LaCoursiere&author=D%20Yarosh&author=RS%20Patel&volume=42&publication_year=2017&pages=676-711&pmid=29089722&)]
  * 80. Russell-Jones D. Molecular, pharmacological and clinical aspects of liraglutide, a once-daily human GLP-1 analogue. Mol Cell Endocrinol (2009) 297:137–40. doi: 10.1016/j.mce.2008.11.018  [[DOI](https://doi.org/10.1016/j.mce.2008.11.018)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/19041364/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Mol%20Cell%20Endocrinol&title=Molecular,%20pharmacological%20and%20clinical%20aspects%20of%20liraglutide,%20a%20once-daily%20human%20GLP-1%20analogue&author=D%20Russell-Jones&volume=297&publication_year=2009&pmid=19041364&doi=10.1016/j.mce.2008.11.018&)]
  * 81. Knudsen LB, Agersoe H, Huusfeldt PO, Nielsen PF, Wilken M. Derivatives of glucagon-like peptide-1 suitable for once daily administration. Diabetes (1999) 48:SA202–2. [[DOI](https://doi.org/10.1021/jm9909645)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/10794683/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes&title=Derivatives%20of%20glucagon-like%20peptide-1%20suitable%20for%20once%20daily%20administration&author=LB%20Knudsen&author=H%20Agersoe&author=PO%20Huusfeldt&author=PF%20Nielsen&author=M%20Wilken&volume=48&publication_year=1999&pmid=10794683&doi=10.1021/jm9909645&)]
  * 82. Madsen K, Knudsen LB, Agersoe H, Nielsen PF, Thøgersen H, Wilken M, et al. Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness. J Med Chem (2007) 50:6126–32. doi: 10.1021/jm070861j  [[DOI](https://doi.org/10.1021/jm070861j)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/17975905/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Med%20Chem&title=Structure-activity%20and%20protraction%20relationship%20of%20long-acting%20glucagon-like%20peptide-1%20derivatives:%20importance%20of%20fatty%20acid%20length,%20polarity,%20and%20bulkiness&author=K%20Madsen&author=LB%20Knudsen&author=H%20Agersoe&author=PF%20Nielsen&author=H%20Th%C3%B8gersen&volume=50&publication_year=2007&pmid=17975905&doi=10.1021/jm070861j&)]
  * 83. Wilding JPH, Overgaard RV, Jacobsen LV, Jensen CB, le Roux CW. Exposure-response analyses of liraglutide 3.0 mg for weight management. Diabetes Obes Metab (2016) 18:491–9. doi: 10.1111/dom.12639  [[DOI](https://doi.org/10.1111/dom.12639)] [[PMC free article](/articles/PMC5069568/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26833744/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Obes%20Metab&title=Exposure-response%20analyses%20of%20liraglutide%203.0%E2%80%89mg%20for%20weight%20management&author=JPH%20Wilding&author=RV%20Overgaard&author=LV%20Jacobsen&author=CB%20Jensen&author=CW%20le%20Roux&volume=18&publication_year=2016&pmid=26833744&doi=10.1111/dom.12639&)]
  * 84. Manigault KR, Thurston MM. Liraglutide: A glucagon-like peptide-1 agonist for chronic weight management. Consult Pharm (2016) 31:685–97. doi: 10.4140/TCP.n.2016.685  [[DOI](https://doi.org/10.4140/TCP.n.2016.685)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/28074747/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Consult%20Pharm&title=Liraglutide:%20A%20glucagon-like%20peptide-1%20agonist%20for%20chronic%20weight%20management&author=KR%20Manigault&author=MM%20Thurston&volume=31&publication_year=2016&pmid=28074747&doi=10.4140/TCP.n.2016.685&)]
  * 85. Liraglutide: A new option for the treatment of obesity . Available at: <https://pubmed.ncbi.nlm.nih.gov/26497479/> (Accessed August 10, 2022).
  * 86. Zhu E, Yang Y, Zhang J, Li Y, Li C, Chen L, et al. Liraglutide suppresses obesity and induces brown fat-like phenotype _via_ soluble guanylyl cyclase mediated pathway _in vivo_ andin vitro. Oncotarget (2016) 7:81077–89. doi: 10.18632/oncotarget.13189  [[DOI](https://doi.org/10.18632/oncotarget.13189)] [[PMC free article](/articles/PMC5348377/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27835589/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Oncotarget&title=Liraglutide%20suppresses%20obesity%20and%20induces%20brown%20fat-like%20phenotype%20via%20soluble%20guanylyl%20cyclase%20mediated%20pathwayin%20vivoandin%20vitro&author=E%20Zhu&author=Y%20Yang&author=J%20Zhang&author=Y%20Li&author=C%20Li&volume=7&publication_year=2016&pmid=27835589&doi=10.18632/oncotarget.13189&)]
  * 87. Pinelli NR, Hurren KM. Efficacy and safety of long-acting glucagon-like peptide-1 receptor agonists compared with exenatide twice daily and sitagliptin in type 2 diabetes mellitus: A systematic review and meta-analysis. Ann Pharmacother (2011) 45:850–60. doi: 10.1345/aph.1Q024  [[DOI](https://doi.org/10.1345/aph.1Q024)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/21730278/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Ann%20Pharmacother&title=Efficacy%20and%20safety%20of%20long-acting%20glucagon-like%20peptide-1%20receptor%20agonists%20compared%20with%20exenatide%20twice%20daily%20and%20sitagliptin%20in%20type%202%20diabetes%20mellitus:%20A%20systematic%20review%20and%20meta-analysis&author=NR%20Pinelli&author=KM%20Hurren&volume=45&publication_year=2011&pmid=21730278&doi=10.1345/aph.1Q024&)]
  * 88. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean MEJ, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (2012) 36:843–54. doi: 10.1038/ijo.2011.158  [[DOI](https://doi.org/10.1038/ijo.2011.158)] [[PMC free article](/articles/PMC3374073/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/21844879/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Int%20J%20Obes&title=Safety,%20tolerability%20and%20sustained%20weight%20loss%20over%202%20years%20with%20the%20once-daily%20human%20GLP-1%20analog,%20liraglutide&author=A%20Astrup&author=R%20Carraro&author=N%20Finer&author=A%20Harper&author=M%20Kunesova&volume=36&publication_year=2012&pmid=21844879&doi=10.1038/ijo.2011.158&)]
  * 89. Astrup A, Rössner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet (2009) 374:1606–16. doi: 10.1016/S0140-6736(09)61375-1  [[DOI](https://doi.org/10.1016/S0140-6736\(09\)61375-1)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/19853906/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Lancet&title=Effects%20of%20liraglutide%20in%20the%20treatment%20of%20obesity:%20a%20randomised,%20double-blind,%20placebo-controlled%20study&author=A%20Astrup&author=S%20R%C3%B6ssner&author=L%20Van%20Gaal&author=A%20Rissanen&author=L%20Niskanen&volume=374&publication_year=2009&pmid=19853906&doi=10.1016/S0140-6736\(09\)61375-1&)]
  * 90. Lean MEJ, Carraro R, Finer N, Hartvig H, Lindegaard ML, Rössner S, et al. Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int J Obes (2014) 38:689–97. doi: 10.1038/ijo.2013.149  [[DOI](https://doi.org/10.1038/ijo.2013.149)] [[PMC free article](/articles/PMC4010971/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/23942319/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Int%20J%20Obes&title=Tolerability%20of%20nausea%20and%20vomiting%20and%20associations%20with%20weight%20loss%20in%20a%20randomized%20trial%20of%20liraglutide%20in%20obese,%20non-diabetic%20adults&author=MEJ%20Lean&author=R%20Carraro&author=N%20Finer&author=H%20Hartvig&author=ML%20Lindegaard&volume=38&publication_year=2014&pmid=23942319&doi=10.1038/ijo.2013.149&)]
  * 91. le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet (2017) 389:1399–409. doi: 10.1016/S0140-6736(17)30069-7  [[DOI](https://doi.org/10.1016/S0140-6736\(17\)30069-7)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/28237263/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Lancet&title=3%20years%20of%20liraglutide%20versus%20placebo%20for%20type%202%20diabetes%20risk%20reduction%20and%20weight%20management%20in%20individuals%20with%20prediabetes:%20a%20randomised,%20double-blind%20trial&author=CW%20le%20Roux&author=A%20Astrup&author=K%20Fujioka&author=F%20Greenway&author=DCW%20Lau&volume=389&publication_year=2017&pmid=28237263&doi=10.1016/S0140-6736\(17\)30069-7&)]
  * 92. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med (2015) 373:11–22. doi: 10.1056/NEJMoa1411892  [[DOI](https://doi.org/10.1056/NEJMoa1411892)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26132939/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=N%20Engl%20J%20Med&title=A%20randomized,%20controlled%20trial%20of%203.0%20mg%20of%20liraglutide%20in%20weight%20management&author=X%20Pi-Sunyer&author=A%20Astrup&author=K%20Fujioka&author=F%20Greenway&author=A%20Halpern&volume=373&publication_year=2015&pages=11-22&pmid=26132939&doi=10.1056/NEJMoa1411892&)]
  * 93. Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE maintenance randomized study. Int J Obes (2013) 37:1443–51. doi: 10.1038/ijo.2013.120  [[DOI](https://doi.org/10.1038/ijo.2013.120)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/23812094/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Int%20J%20Obes&title=Weight%20maintenance%20and%20additional%20weight%20loss%20with%20liraglutide%20after%20low-calorie-diet-induced%20weight%20loss:%20The%20SCALE%20maintenance%20randomized%20study&author=TA%20Wadden&author=P%20Hollander&author=S%20Klein&author=K%20Niswender&author=V%20Woo&volume=37&publication_year=2013&pmid=23812094&doi=10.1038/ijo.2013.120&)]
  * 94. Bode B. Liraglutide: A review of the first once-daily GLP-1 receptor agonist. Am J Manag Care (2011) 17(2 Suppl):s59–70. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/21517658/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Am%20J%20Manag%20Care&title=Liraglutide:%20A%20review%20of%20the%20first%20once-daily%20GLP-1%20receptor%20agonist&author=B%20Bode&volume=17&issue=2%20Suppl&publication_year=2011&pmid=21517658&)]
  * 95. Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide. Front Endocrinol (2019) 10:155. doi: 10.3389/fendo.2019.00155  [[DOI](https://doi.org/10.3389/fendo.2019.00155)] [[PMC free article](/articles/PMC6474072/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/31031702/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Front%20Endocrinol&title=The%20discovery%20and%20development%20of%20liraglutide%20and%20semaglutide&author=LB%20Knudsen&author=J%20Lau&volume=10&publication_year=2019&pages=155&pmid=31031702&doi=10.3389/fendo.2019.00155&)]
  * 96. Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN. Semaglutide as a promising antiobesity drug. Obes Rev (2019) 20:805–15. doi: 10.1111/obr.12839  [[DOI](https://doi.org/10.1111/obr.12839)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/30768766/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Obes%20Rev&title=Semaglutide%20as%20a%20promising%20antiobesity%20drug&author=GA%20Christou&author=N%20Katsiki&author=J%20Blundell&author=G%20Fruhbeck&author=DN%20Kiortsis&volume=20&publication_year=2019&pmid=30768766&doi=10.1111/obr.12839&)]
  * 97. STEP 1 for effective weight control - another first step? Available at: <https://pubmed.ncbi.nlm.nih.gov/33567184/> (Accessed August 10, 2022).
  * 98. Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea. JAMA (2019) 321:1466. doi: 10.1001/jama.2019.2942  [[DOI](https://doi.org/10.1001/jama.2019.2942)] [[PMC free article](/articles/PMC6484814/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/30903796/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=JAMA&title=Effect%20of%20additional%20oral%20semaglutide%20vs%20sitagliptin%20on%20glycated%20hemoglobin%20in%20adults%20with%20type%202%20diabetes%20uncontrolled%20with%20metformin%20alone%20or%20with%20sulfonylurea&author=J%20Rosenstock&author=D%20Allison&author=AL%20Birkenfeld&author=TM%20Blicher&author=S%20Deenadayalan&volume=321&publication_year=2019&pages=1466&pmid=30903796&doi=10.1001/jama.2019.2942&)]
  * 99. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet (2021) 397:971–84. doi: 10.1016/S0140-6736(21)00213-0  [[DOI](https://doi.org/10.1016/S0140-6736\(21\)00213-0)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/33667417/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Lancet&title=Semaglutide%202%C2%B74%20mg%20once%20a%20week%20in%20adults%20with%20overweight%20or%20obesity,%20and%20type%202%20diabetes%20\(STEP%202\):%20a%20randomised,%20double-blind,%20double-dummy,%20placebo-controlled,%20phase%203%20trial&author=M%20Davies&author=L%20F%C3%A6rch&author=OK%20Jeppesen&author=A%20Pakseresht&author=SD%20Pedersen&volume=397&publication_year=2021&pmid=33667417&doi=10.1016/S0140-6736\(21\)00213-0&)]
  * 100. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med (2021) 384:989–1002. doi: 10.1056/NEJMoa2032183  [[DOI](https://doi.org/10.1056/NEJMoa2032183)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/33567185/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=N%20Engl%20J%20Med&title=Once-weekly%20semaglutide%20in%20adults%20with%20overweight%20or%20obesity&author=JPH%20Wilding&author=RL%20Batterham&author=S%20Calanna&author=M%20Davies&author=LF%20Van%20Gaal&volume=384&publication_year=2021&pages=989-1002&pmid=33567185&doi=10.1056/NEJMoa2032183&)]
  * 101. Rubino DM, Greenway FL, Khalid U, O’Neil PM, Rosenstock J, Sørrig R, et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes. JAMA (2022) 327:138. doi: 10.1001/jama.2021.23619  [[DOI](https://doi.org/10.1001/jama.2021.23619)] [[PMC free article](/articles/PMC8753508/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/35015037/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=JAMA&title=Effect%20of%20weekly%20subcutaneous%20semaglutide%20vs%20daily%20liraglutide%20on%20body%20weight%20in%20adults%20with%20overweight%20or%20obesity%20without%20diabetes&author=DM%20Rubino&author=FL%20Greenway&author=U%20Khalid&author=PM%20O%E2%80%99Neil&author=J%20Rosenstock&volume=327&publication_year=2022&pages=138&pmid=35015037&doi=10.1001/jama.2021.23619&)]
  * 102. Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity. JAMA (2021) 325:1403. doi: 10.1001/jama.2021.1831  [[DOI](https://doi.org/10.1001/jama.2021.1831)] [[PMC free article](/articles/PMC7905697/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/33625476/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=JAMA&title=Effect%20of%20subcutaneous%20semaglutide%20vs%20placebo%20as%20an%20adjunct%20to%20intensive%20behavioral%20therapy%20on%20body%20weight%20in%20adults%20with%20overweight%20or%20obesity&author=TA%20Wadden&author=TS%20Bailey&author=LK%20Billings&author=M%20Davies&author=JP%20Frias&volume=325&publication_year=2021&pages=1403&pmid=33625476&doi=10.1001/jama.2021.1831&)]
  * 103. Cowart K. Oral semaglutide: first-in-class oral GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus. Ann Pharmacother (2020) 54(5):478–85. doi: 10.1177/1060028019889064  [[DOI](https://doi.org/10.1177/1060028019889064)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/31744308/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Ann%20Pharmacother&title=Oral%20semaglutide:%20first-in-class%20oral%20GLP-1%20receptor%20agonist%20for%20the%20treatment%20of%20type%202%20diabetes%20mellitus&author=K%20Cowart&volume=54&issue=5&publication_year=2020&pmid=31744308&doi=10.1177/1060028019889064&)]
  * 104. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: The STEP 8 randomized clinical trial . Available at: [https://pubmed.ncbi.nlm.nih.gov/?term=+Effect+of+Weekly+Subcutaneous+Semaglutide+vs+Daily+Liraglutide+on+Body+Weight+in+Adults+With+Overweight+or+Obesity+Without+Diabetes%3A+The+STEP+8+Randomized+Clinical+Trial&size=100](https://pubmed.ncbi.nlm.nih.gov/?term=+Effect+of+Weekly+Subcutaneous+Semaglutide+vs+Daily+Liraglutide+on+Body+Weight+in+Adults+With+Overweight+or+Obesity+Without+Diabetes%3A+The+STEP+8+Randomized+Clinical+Trial&size=100) (Accessed August 10, 2022). [[DOI](https://doi.org/10.1001/jama.2021.23619)] [[PMC free article](/articles/PMC8753508/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/35015037/)]
  * 105. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial . Available at: <https://pubmed.ncbi.nlm.nih.gov/31189511/> (Accessed August 10, 2022). [[DOI](https://doi.org/10.1016/S0140-6736\(19\)31149-3)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/31189511/)]
  * 106. Østergaard L, Frandsen CS, Madsbad S. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review. Expert Rev Clin Pharmacol (2016) 9:241–65. doi: 10.1586/17512433.2016.1121808  [[DOI](https://doi.org/10.1586/17512433.2016.1121808)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26573176/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Rev%20Clin%20Pharmacol&title=Treatment%20potential%20of%20the%20GLP-1%20receptor%20agonists%20in%20type%202%20diabetes%20mellitus:%20a%20review&author=L%20%C3%98stergaard&author=CS%20Frandsen&author=S%20Madsbad&volume=9&publication_year=2016&pmid=26573176&doi=10.1586/17512433.2016.1121808&)]
  * 107. Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT, Botros FT. Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev (2016) 32:776–90. doi: 10.1002/dmrr.2810  [[DOI](https://doi.org/10.1002/dmrr.2810)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27102969/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Metab%20Res%20Rev&title=Efficacy%20and%20safety%20of%20dulaglutide%20in%20the%20treatment%20of%20type%202%20diabetes:%20a%20comprehensive%20review%20of%20the%20dulaglutide%20clinical%20data%20focusing%20on%20the%20AWARD%20phase%203%20clinical%20trial%20program&author=J%20Jendle&author=G%20Grunberger&author=T%20Blevins&author=F%20Giorgino&author=RT%20Hietpas&volume=32&publication_year=2016&pmid=27102969&doi=10.1002/dmrr.2810&)]
  * 108. Barrington P, Chien JY, Showalter HDH, Schneck K, Cui S, Tibaldi F, et al. A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes Metab (2011) 13:426–33. doi: 10.1111/j.1463-1326.2011.01364.x  [[DOI](https://doi.org/10.1111/j.1463-1326.2011.01364.x)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/21251178/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Obes%20Metab&title=A%205-week%20study%20of%20the%20pharmacokinetics%20and%20pharmacodynamics%20of%20LY2189265,%20a%20novel,%20long-acting%20glucagon-like%20peptide-1%20analogue,%20in%20patients%20with%20type%202%20diabetes&author=P%20Barrington&author=JY%20Chien&author=HDH%20Showalter&author=K%20Schneck&author=S%20Cui&volume=13&publication_year=2011&pmid=21251178&doi=10.1111/j.1463-1326.2011.01364.x&)]
  * 109. Dungan KM, Povedano ST, Forst T, González JGG, Atisso C, Sealls W, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet (2014) 384:1349–57. doi: 10.1016/S0140-6736(14)60976-4  [[DOI](https://doi.org/10.1016/S0140-6736\(14\)60976-4)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/25018121/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Lancet&title=Once-weekly%20dulaglutide%20versus%20once-daily%20liraglutide%20in%20metformin-treated%20patients%20with%20type%202%20diabetes%20\(AWARD-6\):%20a%20randomised,%20open-label,%20phase%203,%20non-inferiority%20trial&author=KM%20Dungan&author=ST%20Povedano&author=T%20Forst&author=JGG%20Gonz%C3%A1lez&author=C%20Atisso&volume=384&publication_year=2014&pmid=25018121&doi=10.1016/S0140-6736\(14\)60976-4&)]
  * 110. Umpierrez G, Tofé Povedano S, Pérez Manghi F, Shurzinske L, Pechtner V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care (2014) 37:2168–76. doi: 10.2337/dc13-2759  [[DOI](https://doi.org/10.2337/dc13-2759)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24842985/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Efficacy%20and%20safety%20of%20dulaglutide%20monotherapy%20versus%20metformin%20in%20type%202%20diabetes%20in%20a%20randomized%20controlled%20trial%20\(AWARD-3\)&author=G%20Umpierrez&author=S%20Tof%C3%A9%20Povedano&author=F%20P%C3%A9rez%20Manghi&author=L%20Shurzinske&author=V%20Pechtner&volume=37&publication_year=2014&pmid=24842985&doi=10.2337/dc13-2759&)]
  * 111. Frias JP, Bonora E, Nevarez Ruiz L, Li YG, Yu Z, Milicevic Z, et al. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care (2021) 44:765–73. doi: 10.2337/dc20-1473  [[DOI](https://doi.org/10.2337/dc20-1473)] [[PMC free article](/articles/PMC7896253/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/33397768/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Efficacy%20and%20safety%20of%20dulaglutide%203.0%20mg%20and%204.5%20mg%20versus%20dulaglutide%201.5%20mg%20in%20metformin-treated%20patients%20with%20type%202%20diabetes%20in%20a%20randomized%20controlled%20trial%20\(AWARD-11\)&author=JP%20Frias&author=E%20Bonora&author=L%20Nevarez%20Ruiz&author=YG%20Li&author=Z%20Yu&volume=44&publication_year=2021&pmid=33397768&doi=10.2337/dc20-1473&)]
  * 112. Giorgino F, Benroubi M, Sun J-H, Zimmermann AG, Pechtner V. Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care (2015) 38:2241–9. doi: 10.2337/dc14-1625  [[DOI](https://doi.org/10.2337/dc14-1625)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26089386/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Care&title=Efficacy%20and%20safety%20of%20once-weekly%20dulaglutide%20versus%20insulin%20glargine%20in%20patients%20with%20type%202%20diabetes%20on%20metformin%20and%20glimepiride%20\(AWARD-2\)&author=F%20Giorgino&author=M%20Benroubi&author=J-H%20Sun&author=AG%20Zimmermann&author=V%20Pechtner&volume=38&publication_year=2015&pmid=26089386&doi=10.2337/dc14-1625&)]
  * 113. Zhou Y, Zhu J, Wu H, Deng Y, Ji Q. Pancreatic safety of once-weekly dulaglutide in Chinese patients with type 2 diabetes mellitus: Subgroup analysis by potential influencing factors. Diabetes Ther (2021) 12:2677–90. doi: 10.1007/s13300-021-01139-2  [[DOI](https://doi.org/10.1007/s13300-021-01139-2)] [[PMC free article](/articles/PMC8479006/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34453682/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Ther&title=Pancreatic%20safety%20of%20once-weekly%20dulaglutide%20in%20Chinese%20patients%20with%20type%202%20diabetes%20mellitus:%20Subgroup%20analysis%20by%20potential%20influencing%20factors&author=Y%20Zhou&author=J%20Zhu&author=H%20Wu&author=Y%20Deng&author=Q%20Ji&volume=12&publication_year=2021&pmid=34453682&doi=10.1007/s13300-021-01139-2&)]
  * 114. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol (2012) 8:728–42. doi: 10.1038/nrendo.2012.140  [[DOI](https://doi.org/10.1038/nrendo.2012.140)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/22945360/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Rev%20Endocrinol&title=GLP-1%20receptor%20agonists%20for%20individualized%20treatment%20of%20type%202%20diabetes%20mellitus&author=JJ%20Meier&volume=8&publication_year=2012&pmid=22945360&doi=10.1038/nrendo.2012.140&)]
  * 115. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet (2008) 372:1240–50. doi: 10.1016/S0140-6736(08)61206-4  [[DOI](https://doi.org/10.1016/S0140-6736\(08\)61206-4)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/18782641/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Lancet&title=Exenatide%20once%20weekly%20versus%20twice%20daily%20for%20the%20treatment%20of%20type%202%20diabetes:%20a%20randomised,%20open-label,%20non-inferiority%20study&author=DJ%20Drucker&author=JB%20Buse&author=K%20Taylor&author=DM%20Kendall&author=M%20Trautmann&volume=372&publication_year=2008&pmid=18782641&doi=10.1016/S0140-6736\(08\)61206-4&)]
  * 116. Norwood P, Liutkus JF, Haber H, Pintilei E, Boardman MK, Trautmann ME. Safety of exenatide once weekly in patients with type 2 diabetes mellitus treated with a thiazolidinedione alone or in combination with metformin for 2 years. Clin Ther (2012) 34:2082–90. doi: 10.1016/j.clinthera.2012.09.007  [[DOI](https://doi.org/10.1016/j.clinthera.2012.09.007)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/23031623/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Clin%20Ther&title=Safety%20of%20exenatide%20once%20weekly%20in%20patients%20with%20type%202%20diabetes%20mellitus%20treated%20with%20a%20thiazolidinedione%20alone%20or%20in%20combination%20with%20metformin%20for%202%20years&author=P%20Norwood&author=JF%20Liutkus&author=H%20Haber&author=E%20Pintilei&author=MK%20Boardman&volume=34&publication_year=2012&pmid=23031623&doi=10.1016/j.clinthera.2012.09.007&)]
  * 117. Elkind-Hirsch KE, Chappell N, Seidemann E, Storment J, Bellanger D. Exenatide, dapagliflozin, or Phentermine/Topiramate differentially affect metabolic profiles in polycystic ovary syndrome. J Clin Endocrinol Metab (2021) 106:3019–33. doi: 10.1210/clinem/dgab408  [[DOI](https://doi.org/10.1210/clinem/dgab408)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34097062/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Endocrinol%20Metab&title=Exenatide,%20dapagliflozin,%20or%20Phentermine/Topiramate%20differentially%20affect%20metabolic%20profiles%20in%20polycystic%20ovary%20syndrome&author=KE%20Elkind-Hirsch&author=N%20Chappell&author=E%20Seidemann&author=J%20Storment&author=D%20Bellanger&volume=106&publication_year=2021&pmid=34097062&doi=10.1210/clinem/dgab408&)]
  * 118. Malone J, Trautmann M, Wilhelm K, Taylor K, Kendall DM. Exenatide once weekly for the treatment of type 2 diabetes. Expert Opin Investig Drugs (2009) 18:359–67. doi: 10.1517/13543780902766802  [[DOI](https://doi.org/10.1517/13543780902766802)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/19243286/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Investig%20Drugs&title=Exenatide%20once%20weekly%20for%20the%20treatment%20of%20type%202%20diabetes&author=J%20Malone&author=M%20Trautmann&author=K%20Wilhelm&author=K%20Taylor&author=DM%20Kendall&volume=18&publication_year=2009&pmid=19243286&doi=10.1517/13543780902766802&)]
  * 119. Zhang Y, Li Y, Zhao J, Wang C, Deng B, Zhang Q, et al. Protective effects and mechanisms of polyethylene glycol loxenatide against hyperglycemia and liver injury in db/db diabetic mice. Front Pharmacol (2021) 12:781856. doi: 10.3389/fphar.2021.781856  [[DOI](https://doi.org/10.3389/fphar.2021.781856)] [[PMC free article](/articles/PMC8685428/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34938192/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Front%20Pharmacol&title=Protective%20effects%20and%20mechanisms%20of%20polyethylene%20glycol%20loxenatide%20against%20hyperglycemia%20and%20liver%20injury%20in%20db/db%20diabetic%20mice&author=Y%20Zhang&author=Y%20Li&author=J%20Zhao&author=C%20Wang&author=B%20Deng&volume=12&publication_year=2021&pages=781856&pmid=34938192&doi=10.3389/fphar.2021.781856&)]
  * 120. Guo Z, Wu Y, Zhu L, Wang Y, Wang D, Sun X. PEX-168 improves insulin resistance, inflammatory response and adipokines in simple obese mice: a mechanistic exploration. BMC Endocr Disord (2021) 21:245. doi: 10.1186/s12902-021-00908-1  [[DOI](https://doi.org/10.1186/s12902-021-00908-1)] [[PMC free article](/articles/PMC8686575/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34923973/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=BMC%20Endocr%20Disord&title=PEX-168%20improves%20insulin%20resistance,%20inflammatory%20response%20and%20adipokines%20in%20simple%20obese%20mice:%20a%20mechanistic%20exploration&author=Z%20Guo&author=Y%20Wu&author=L%20Zhu&author=Y%20Wang&author=D%20Wang&volume=21&publication_year=2021&pages=245&pmid=34923973&doi=10.1186/s12902-021-00908-1&)]
  * 121. Shuai Y, Yang G, Zhang Q, Li W, Luo Y, Ma J, et al. Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double-blind, placebo-controlled phase 3a clinical trial. Diabetes Obes Metab (2021) 23:116–24. doi: 10.1111/dom.14198  [[DOI](https://doi.org/10.1111/dom.14198)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/32965075/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetes%20Obes%20Metab&title=Efficacy%20and%20safety%20of%20polyethylene%20glycol%20loxenatide%20monotherapy%20in%20type%202%20diabetes%20patients:%20A%20multicentre,%20randomized,%20double-blind,%20placebo-controlled%20phase%203a%20clinical%20trial&author=Y%20Shuai&author=G%20Yang&author=Q%20Zhang&author=W%20Li&author=Y%20Luo&volume=23&publication_year=2021&pmid=32965075&doi=10.1111/dom.14198&)]
  * 122. Yang G-R, Zhao X-L, Jin F, Shi L-H, Yang J-K. Pharmacokinetics and pharmacodynamics of a polyethylene glycol (PEG)-conjugated GLP-receptor agonist once weekly in Chinese patients with type 2 diabetes. J Clin Pharmacol (2015) 55:152–8. doi: 10.1002/jcph.386  [[DOI](https://doi.org/10.1002/jcph.386)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/25167840/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Pharmacol&title=Pharmacokinetics%20and%20pharmacodynamics%20of%20a%20polyethylene%20glycol%20\(PEG\)-conjugated%20GLP-receptor%20agonist%20once%20weekly%20in%20Chinese%20patients%20with%20type%202%20diabetes&author=G-R%20Yang&author=X-L%20Zhao&author=F%20Jin&author=L-H%20Shi&author=J-K%20Yang&volume=55&publication_year=2015&pmid=25167840&doi=10.1002/jcph.386&)]
  * 123. Wang J, Huang J, Li W, Tang S, Sun J, Zhang X, et al. Polyethylene glycol loxenatide (PEX168) in subjects with renal impairment: A pharmacokinetic study. Br J Clin Pharmacol (2019) 85:2714–20. doi: 10.1111/bcp.14091  [[DOI](https://doi.org/10.1111/bcp.14091)] [[PMC free article](/articles/PMC6955414/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/31396983/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Br%20J%20Clin%20Pharmacol&title=Polyethylene%20glycol%20loxenatide%20\(PEX168\)%20in%20subjects%20with%20renal%20impairment:%20A%20pharmacokinetic%20study&author=J%20Wang&author=J%20Huang&author=W%20Li&author=S%20Tang&author=J%20Sun&volume=85&publication_year=2019&pmid=31396983&doi=10.1111/bcp.14091&)]
  * 124. Seino Y, Fukushima M, Yabe D, Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J Diabetes Investig (2010) 1:8–23. doi: 10.1111/j.2040-1124.2010.00022.x  [[DOI](https://doi.org/10.1111/j.2040-1124.2010.00022.x)] [[PMC free article](/articles/PMC4020673/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24843404/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Diabetes%20Investig&title=GIP%20and%20GLP-1,%20the%20two%20incretin%20hormones:%20Similarities%20and%20differences&author=Y%20Seino&author=M%20Fukushima&author=D%20Yabe&author=Y%20Seino&author=M%20Fukushima&volume=1&publication_year=2010&pages=8-23&pmid=24843404&doi=10.1111/j.2040-1124.2010.00022.x&)]
  * 125. Kleinert M, Sachs S, Habegger KM, Hofmann SM, Müller TD, Kleinert M, et al. Glucagon regulation of energy expenditure. Int J Mol Sci (2019) 20:5407. doi: 10.3390/ijms20215407  [[DOI](https://doi.org/10.3390/ijms20215407)] [[PMC free article](/articles/PMC6862306/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/31671603/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Int%20J%20Mol%20Sci&title=Glucagon%20regulation%20of%20energy%20expenditure&author=M%20Kleinert&author=S%20Sachs&author=KM%20Habegger&author=SM%20Hofmann&author=TD%20M%C3%BCller&volume=20&publication_year=2019&pages=5407&pmid=31671603&doi=10.3390/ijms20215407&)]
  * 126. Zhao F, Zhou Q, Cong Z, Hang K, Zou X, Zhang C, et al. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat Commun (2022) 13:1057. doi: 10.1038/s41467-022-28683-0  [[DOI](https://doi.org/10.1038/s41467-022-28683-0)] [[PMC free article](/articles/PMC8881610/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/35217653/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Commun&title=Structural%20insights%20into%20multiplexed%20pharmacological%20actions%20of%20tirzepatide%20and%20peptide%2020%20at%20the%20GIP,%20GLP-1%20or%20glucagon%20receptors&author=F%20Zhao&author=Q%20Zhou&author=Z%20Cong&author=K%20Hang&author=X%20Zou&volume=13&publication_year=2022&pages=1057&pmid=35217653&doi=10.1038/s41467-022-28683-0&)]
  * 127. Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, et al. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol Metab (2022) 63:101533. doi: 10.1016/j.molmet.2022.101533  [[DOI](https://doi.org/10.1016/j.molmet.2022.101533)] [[PMC free article](/articles/PMC9305623/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/35809773/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Mol%20Metab&title=Next%20generation%20GLP-1/GIP/glucagon%20triple%20agonists%20normalize%20body%20weight%20in%20obese%20mice&author=PJ%20Knerr&author=SA%20Mowery&author=JD%20Douros&author=B%20Premdjee&author=KR%20Hj%C3%B8llund&volume=63&publication_year=2022&pages=101533&pmid=35809773&doi=10.1016/j.molmet.2022.101533&)]
  * 128. Gault VA, Bhat VK, Irwin N, Flatt PR, Gault VA, Bhat VK, et al. A novel glucagon-like peptide-1 (GLP-1)/Glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice. J Biol Chem (2013) 288:35581–91. doi: 10.1074/jbc.M113.512046  [[DOI](https://doi.org/10.1074/jbc.M113.512046)] [[PMC free article](/articles/PMC3853303/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/24165127/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Biol%20Chem&title=A%20novel%20glucagon-like%20peptide-1%20\(GLP-1\)/Glucagon%20hybrid%20peptide%20with%20triple-acting%20agonist%20activity%20at%20glucose-dependent%20insulinotropic%20polypeptide,%20GLP-1,%20and%20glucagon%20receptors%20and%20therapeutic%20potential%20in%20high%20fat-fed%20mice&author=VA%20Gault&author=VK%20Bhat&author=N%20Irwin&author=PR%20Flatt&author=VA%20Gault&volume=288&publication_year=2013&pmid=24165127&doi=10.1074/jbc.M113.512046&)]
  * 129. Nauck MA, D’Alessio DA, Nauck MA, D’Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol (2022) 21:169. doi: 10.1186/s12933-022-01604-7  [[DOI](https://doi.org/10.1186/s12933-022-01604-7)] [[PMC free article](/articles/PMC9438179/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/36050763/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Cardiovasc%20Diabetol&title=Tirzepatide,%20a%20dual%20GIP/GLP-1%20receptor%20co-agonist%20for%20the%20treatment%20of%20type%202%20diabetes%20with%20unmatched%20effectiveness%20regrading%20glycaemic%20control%20and%20body%20weight%20reduction&author=MA%20Nauck&author=DA%20D%E2%80%99Alessio&author=MA%20Nauck&author=DA%20D%E2%80%99Alessio&volume=21&publication_year=2022&pages=169&pmid=36050763&doi=10.1186/s12933-022-01604-7&)]
  * 130. Karagiannis T, Avgerinos I, Liakos A, Del Prato S, Matthews DR, Tsapas A, et al. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia (2022) 65:1251–61. doi: 10.1007/s00125-022-05715-4  [[DOI](https://doi.org/10.1007/s00125-022-05715-4)] [[PMC free article](/articles/PMC9112245/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/35579691/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetologia&title=Management%20of%20type%202%20diabetes%20with%20the%20dual%20GIP/GLP-1%20receptor%20agonist%20tirzepatide:%20a%20systematic%20review%20and%20meta-analysis&author=T%20Karagiannis&author=I%20Avgerinos&author=A%20Liakos&author=S%20Del%20Prato&author=DR%20Matthews&volume=65&publication_year=2022&pmid=35579691&doi=10.1007/s00125-022-05715-4&)]
  * 131. Sánchez-Garrido MA, Brandt SJ, Clemmensen C, Müller TD, DiMarchi RD, Tschöp MH, et al. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia (2017) 60:1851–61. doi: 10.1007/s00125-017-4354-8  [[DOI](https://doi.org/10.1007/s00125-017-4354-8)] [[PMC free article](/articles/PMC6448809/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/28733905/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Diabetologia&title=GLP-1/glucagon%20receptor%20co-agonism%20for%20treatment%20of%20obesity&author=MA%20S%C3%A1nchez-Garrido&author=SJ%20Brandt&author=C%20Clemmensen&author=TD%20M%C3%BCller&author=RD%20DiMarchi&volume=60&publication_year=2017&pmid=28733905&doi=10.1007/s00125-017-4354-8&)]
  * 132. Samms RJ, Coghlan MP, Sloop KW, Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1? Trends Endocrinol Amp Metab (2020) 31:410–21. doi: 10.1016/j.tem.2020.02.006  [[DOI](https://doi.org/10.1016/j.tem.2020.02.006)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/32396843/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Trends%20Endocrinol%20Amp%20Metab&title=How%20may%20GIP%20enhance%20the%20therapeutic%20efficacy%20of%20GLP-1&author=RJ%20Samms&author=MP%20Coghlan&author=KW%20Sloop&author=RJ%20Samms&author=MP%20Coghlan&volume=31&publication_year=2020&pmid=32396843&doi=10.1016/j.tem.2020.02.006&)]
  * 133. Ludwig DS, Ebbeling CB. The carbohydrate-insulin model of obesity. JAMA Intern Med (2018) 178:1098. doi: 10.1001/jamainternmed.2018.2933  [[DOI](https://doi.org/10.1001/jamainternmed.2018.2933)] [[PMC free article](/articles/PMC6082688/)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/29971406/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=JAMA%20Intern%20Med&title=The%20carbohydrate-insulin%20model%20of%20obesity&author=DS%20Ludwig&author=CB%20Ebbeling&volume=178&publication_year=2018&pages=1098&pmid=29971406&doi=10.1001/jamainternmed.2018.2933&)]
  * 134. Perez-Montes DE Oca A, Pellitero S, Puig-Domingo M. Obesity and GLP-1. Minerva Endocrinol (2021) 46:168–76. doi: 10.23736/S2724-6507.20.03369-6  [[DOI](https://doi.org/10.23736/S2724-6507.20.03369-6)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/33213122/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Minerva%20Endocrinol&title=Obesity%20and%20GLP-1&author=A%20Perez-Montes%20DE%20Oca&author=S%20Pellitero&author=M%20Puig-Domingo&volume=46&publication_year=2021&pmid=33213122&doi=10.23736/S2724-6507.20.03369-6&)]
  * 135. Filippatos TD, Derdemezis CS, Gazi IF, Nakou ES, Mikhailidis DP, Elisaf MS. Orlistat-associated adverse effects and drug interactions. Drug Saf (2008) 31:53–65. doi: 10.2165/00002018-200831010-00005  [[DOI](https://doi.org/10.2165/00002018-200831010-00005)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/18095746/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Drug%20Saf&title=Orlistat-associated%20adverse%20effects%20and%20drug%20interactions&author=TD%20Filippatos&author=CS%20Derdemezis&author=IF%20Gazi&author=ES%20Nakou&author=DP%20Mikhailidis&volume=31&publication_year=2008&pages=53-65&pmid=18095746&doi=10.2165/00002018-200831010-00005&)]
  * 136. Greig SL, Keating GM. Naltrexone ER/Bupropion ER: A review in obesity management. Drugs (2015) 75:1269–80. doi: 10.1007/s40265-015-0427-5  [[DOI](https://doi.org/10.1007/s40265-015-0427-5)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/26105116/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Drugs&title=Naltrexone%20ER/Bupropion%20ER:%20A%20review%20in%20obesity%20management&author=SL%20Greig&author=GM%20Keating&volume=75&publication_year=2015&pmid=26105116&doi=10.1007/s40265-015-0427-5&)]
  * 137. Gallwitz B. Glucagon-like peptide–1 analogues for type 2 diabetes mellitus. Drugs (2011) 71:1675–88. doi: 10.2165/11592810-000000000-00000  [[DOI](https://doi.org/10.2165/11592810-000000000-00000)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/21902291/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Drugs&title=Glucagon-like%20peptide%E2%80%931%20analogues%20for%20type%202%20diabetes%20mellitus&author=B%20Gallwitz&volume=71&publication_year=2011&pmid=21902291&doi=10.2165/11592810-000000000-00000&)]
  * 138. Sanders DM. Efficacy of GLP-1 agonists for weight loss in adults without diabetes. (2022). [[Google Scholar](https://scholar.google.com/scholar_lookup?Sanders%20DM.%20Efficacy%20of%20GLP-1%20agonists%20for%20weight%20loss%20in%20adults%20without%20diabetes.%20\(2022\).)]
  * 139. Hirsch IB. The future of the GLP-1 receptor agonists. JAMA (2019) 321:1457. doi: 10.1001/jama.2019.2941  [[DOI](https://doi.org/10.1001/jama.2019.2941)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/30903797/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=JAMA&title=The%20future%20of%20the%20GLP-1%20receptor%20agonists&author=IB%20Hirsch&volume=321&publication_year=2019&pages=1457&pmid=30903797&doi=10.1001/jama.2019.2941&)]
  * 140. Nauck MA. Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes. Horm Metab Res (2004) 36:852–8. doi: 10.1055/s-2004-826175  [[DOI](https://doi.org/10.1055/s-2004-826175)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/15655719/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Horm%20Metab%20Res&title=Glucagon-like%20peptide%201%20\(GLP-1\)%20in%20the%20treatment%20of%20diabetes&author=MA%20Nauck&volume=36&publication_year=2004&pmid=15655719&doi=10.1055/s-2004-826175&)]
  * 141. Meier JJ, Gallwitz B, Salmen S, Goetze O, Holst JJ, Schmidt WE, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab (2003) 88:2719–25. doi: 10.1210/jc.2003-030049  [[DOI](https://doi.org/10.1210/jc.2003-030049)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/12788879/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Clin%20Endocrinol%20Metab&title=Normalization%20of%20glucose%20concentrations%20and%20deceleration%20of%20gastric%20emptying%20after%20solid%20meals%20during%20intravenous%20glucagon-like%20peptide%201%20in%20patients%20with%20type%202%20diabetes&author=JJ%20Meier&author=B%20Gallwitz&author=S%20Salmen&author=O%20Goetze&author=JJ%20Holst&volume=88&publication_year=2003&pmid=12788879&doi=10.1210/jc.2003-030049&)]
  * 142. Stonehouse AH, Holcombe JH, Kendall DM. Management of type 2 diabetes: the role of incretin mimetics. Expert Opin Pharmacother (2006) 7:2095–105. doi: 10.1517/14656566.7.15.2095  [[DOI](https://doi.org/10.1517/14656566.7.15.2095)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/17020435/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Pharmacother&title=Management%20of%20type%202%20diabetes:%20the%20role%20of%20incretin%20mimetics&author=AH%20Stonehouse&author=JH%20Holcombe&author=DM%20Kendall&volume=7&publication_year=2006&pmid=17020435&doi=10.1517/14656566.7.15.2095&)]
  * 143. Pedrosa MR, Franco DR, Gieremek HW, Vidal CM, Bronzeri F, de Cassia Rocha A, et al. GLP-1 agonist to treat obesity and prevent cardiovascular disease: What have we achieved so far? Curr Atheroscler Rep (2022) 24:867–84. doi: 10.1007/s11883-022-01062-2  [[DOI](https://doi.org/10.1007/s11883-022-01062-2)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/36044100/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Curr%20Atheroscler%20Rep&title=GLP-1%20agonist%20to%20treat%20obesity%20and%20prevent%20cardiovascular%20disease:%20What%20have%20we%20achieved%20so%20far&author=MR%20Pedrosa&author=DR%20Franco&author=HW%20Gieremek&author=CM%20Vidal&author=F%20Bronzeri&volume=24&publication_year=2022&pmid=36044100&doi=10.1007/s11883-022-01062-2&)]
  * 144. Liu C, Zou Y, Qian H, Liu C, Zou Y, Qian H. GLP-1R agonists for the treatment of obesity: a patent review (2015-present). Expert Opin Ther Pat (2020) 30:781–94. doi: 10.1080/13543776.2020.1811851  [[DOI](https://doi.org/10.1080/13543776.2020.1811851)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/32799587/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Expert%20Opin%20Ther%20Pat&title=GLP-1R%20agonists%20for%20the%20treatment%20of%20obesity:%20a%20patent%20review%20\(2015-present\)&author=C%20Liu&author=Y%20Zou&author=H%20Qian&author=C%20Liu&author=Y%20Zou&volume=30&publication_year=2020&pmid=32799587&doi=10.1080/13543776.2020.1811851&)]
  * 145. Jensterle M, Janež A, Jensterle M, Janež A. Glucagon-like peptide-1 receptor agonists in the treatment of obesity. Horm Res Paediatr (2021). doi: 10.1159/000521264  [[DOI](https://doi.org/10.1159/000521264)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/34852347/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Horm%20Res%20Paediatr&title=Glucagon-like%20peptide-1%20receptor%20agonists%20in%20the%20treatment%20of%20obesity&author=M%20Jensterle&author=A%20Jane%C5%BE&author=M%20Jensterle&author=A%20Jane%C5%BE&publication_year=2021&pmid=34852347&doi=10.1159/000521264&)]



* * *

Articles from Frontiers in Endocrinology are provided here courtesy of **Frontiers Media SA**

![Close](/static/img/usa-icons/close.svg)

## ACTIONS

  * [ View on publisher site ](https://doi.org/10.3389/fendo.2023.1085799)
  * [ PDF (1.1 MB) ](pdf/fendo-14-1085799.pdf)
  * Cite
  * Collections
  * Permalink

## PERMALINK

Copy




## RESOURCES

###  Similar articles 

###  Cited by other articles 

###  Links to NCBI Databases 

## Cite

  * Copy
  * Download .nbib .nbib
  * Format: AMA  APA  MLA  NLM 




## Add to Collections

Create a new collection

Add to an existing collection

Name your collection *

Choose a collection 

Unable to load your collection due to an error  
Please try again

Add  Cancel 

Follow NCBI 

[ NCBI on X (formerly known as Twitter) ](https://twitter.com/ncbi) [ NCBI on Facebook ](https://www.facebook.com/ncbi.nlm) [ NCBI on LinkedIn ](https://www.linkedin.com/company/ncbinlm) [ NCBI on GitHub ](https://github.com/ncbi) [ NCBI RSS feed ](https://ncbiinsights.ncbi.nlm.nih.gov/)

Connect with NLM 

[ NLM on X (formerly known as Twitter) ](https://twitter.com/nlm_nih) [ NLM on Facebook ](https://www.facebook.com/nationallibraryofmedicine) [ NLM on YouTube ](https://www.youtube.com/user/NLMNIH)

[National Library of Medicine   
8600 Rockville Pike  
Bethesda, MD 20894](https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/%4038.9959508,
            -77.101021,17z/data%3D!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb%3A0x19156f88b27635b8!8m2!3d38.9959508!
            4d-77.0988323)

  * [ Web Policies ](https://www.nlm.nih.gov/web_policies.html)
  * [ FOIA ](https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office)
  * [ HHS Vulnerability Disclosure ](https://www.hhs.gov/vulnerability-disclosure-policy/index.html)


  * [ Help ](https://support.nlm.nih.gov/)
  * [ Accessibility ](https://www.nlm.nih.gov/accessibility.html)
  * [ Careers ](https://www.nlm.nih.gov/careers/careers.html)



  * [ NLM ](https://www.nlm.nih.gov/)
  * [ NIH ](https://www.nih.gov/)
  * [ HHS ](https://www.hhs.gov/)
  * [ USA.gov ](https://www.usa.gov/)



Back to Top
  *[*]: required


url: http://arxiv.org/abs/1503.07441v1
title: [1503.07441v1] Neuroreceptor Activation by Vibration-Assisted Tunneling
scrape_date: 2025-02-28T11:50:24.205189
content_type: markdown
hash: 945f51e289b19d9a3df23188bd7c0ae32bef46e3951d7ab6f21c3a1dd7eba82a
content:
Skip to main content

[![Cornell University](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg)](https://www.cornell.edu/)

We gratefully acknowledge support from the Simons Foundation, [member institutions](https://info.arxiv.org/about/ourmembers.html), and all contributors. [Donate](https://info.arxiv.org/about/donate.html)

[](/IgnoreMe)

[![arxiv logo](/static/browse/0.3.4/images/arxiv-logo-one-color-white.svg)](/) > [physics](/list/physics/recent) > arXiv:1503.07441v1 

[Help](https://info.arxiv.org/help) | [Advanced Search](https://arxiv.org/search/advanced)

All fields Title Author Abstract Comments Journal reference ACM classification MSC classification Report number arXiv identifier DOI ORCID arXiv author ID Help pages Full text

Search

[![arXiv logo](/static/browse/0.3.4/images/arxiv-logomark-small-white.svg)](https://arxiv.org/)

[ ![Cornell University Logo](/static/browse/0.3.4/images/icons/cu/cornell-reduced-white-SMALL.svg) ](https://www.cornell.edu/)

open search

GO

open navigation menu

## quick links

  * [Login](https://arxiv.org/login)
  * [Help Pages](https://info.arxiv.org/help)
  * [About](https://info.arxiv.org/about)



# Physics > Biological Physics

**arXiv:1503.07441v1** (physics) 

[Submitted on 24 Mar 2015]

# Title:Neuroreceptor Activation by Vibration-Assisted Tunneling

Authors:[Ross D. Hoehn](https://arxiv.org/search/physics?searchtype=author&query=Hoehn,+R+D), [David Nichols](https://arxiv.org/search/physics?searchtype=author&query=Nichols,+D), [Hartmut Neven](https://arxiv.org/search/physics?searchtype=author&query=Neven,+H), [Sabre Kais](https://arxiv.org/search/physics?searchtype=author&query=Kais,+S)

View a PDF of the paper titled Neuroreceptor Activation by Vibration-Assisted Tunneling, by Ross D. Hoehn and 3 other authors

[View PDF](/pdf/1503.07441v1)

> Abstract:G protein-coupled receptors (GPCRs) constitute a large family of receptor proteins that sense molecular signals on the exterior of a cell and activate signal transduction pathways within the cell. Modeling how an agonist activates such a receptor is fundamental for an understanding of a wide variety of physiological processes and it is of tremendous value for pharmacology and drug design. Inelastic electron tunneling spectroscopy (IETS) has been proposed as a model for the mechanism by which olfactory GPCRs are activated by a bound agonist. We apply this hypothesis to GPCRs within the mammalian nervous system using quantum chemical modeling. We found that non-endogenous agonists of the serotonin receptor share a particular IET spectral aspect both amongst each other and with the serotonin molecule: a peak whose intensity scales with the known agonist potencies. We propose an experiential validation of this model by utilizing lysergic acid dimethylamide (DAM-57), an ergot derivative, and its deuterated isotopologues; we also provide theoretical predictions for comparison to experiment. If validated our theory may provide new avenues for guided drug design and elevate methods of in silico potency/activity prediction. 

Comments: | Accepted to Scientific Reports; Main text 15 pgs with 4 figs; Sup Materials 10 pgs 7 figs  
---|---  
Subjects: |  Biological Physics (physics.bio-ph); Chemical Physics (physics.chem-ph); Biomolecules (q-bio.BM); Quantum Physics (quant-ph)  
Cite as: | [arXiv:1503.07441](https://arxiv.org/abs/1503.07441) [physics.bio-ph]  
  | (or  [arXiv:1503.07441v1](https://arxiv.org/abs/1503.07441v1) [physics.bio-ph] for this version)   
  |  <https://doi.org/10.48550/arXiv.1503.07441> Focus to learn more arXiv-issued DOI via DataCite  
Journal reference: | Scientific Reports 5, Article number: 9990 Published 2015  
Related DOI:  | <https://doi.org/10.1038/srep09990> Focus to learn more DOI(s) linking to related resources   
  
## Submission history

From: Ross Hoehn Mr [[view email](/show-email/713ed42e/1503.07441)]   
**[v1]** Tue, 24 Mar 2015 14:33:31 UTC (1,945 KB)  


Full-text links:

## Access Paper:

View a PDF of the paper titled Neuroreceptor Activation by Vibration-Assisted Tunneling, by Ross D. Hoehn and 3 other authors

  * [View PDF](/pdf/1503.07441v1)
  * [TeX Source](/src/1503.07441v1)
  * [Other Formats](/format/1503.07441v1)



[view license](http://arxiv.org/licenses/nonexclusive-distrib/1.0/ "Rights to this article")

Current browse context: 

physics.bio-ph

[< prev](/prevnext?id=1503.07441&function=prev&context=physics.bio-ph "previous in physics.bio-ph \(accesskey p\)")   |   [next >](/prevnext?id=1503.07441&function=next&context=physics.bio-ph "next in physics.bio-ph \(accesskey n\)")   


[new](/list/physics.bio-ph/new) |  [recent](/list/physics.bio-ph/recent) | [2015-03](/list/physics.bio-ph/2015-03)

Change to browse by: 

[physics](/abs/1503.07441?context=physics)  
[physics.chem-ph](/abs/1503.07441?context=physics.chem-ph)  
[q-bio](/abs/1503.07441?context=q-bio)  
[q-bio.BM](/abs/1503.07441?context=q-bio.BM)  
[quant-ph](/abs/1503.07441?context=quant-ph)  


### References & Citations

  * [INSPIRE HEP](https://inspirehep.net/arxiv/1503.07441)  

  * [NASA ADS](https://ui.adsabs.harvard.edu/abs/arXiv:1503.07441)
  * [Google Scholar](https://scholar.google.com/scholar_lookup?arxiv_id=1503.07441)
  * [Semantic Scholar](https://api.semanticscholar.org/arXiv:1503.07441)



[a](/static/browse/0.3.4/css/cite.css) export BibTeX citation Loading...

## BibTeX formatted citation

×

loading...

Data provided by: 

### Bookmark

[ ![BibSonomy logo](/static/browse/0.3.4/images/icons/social/bibsonomy.png) ](http://www.bibsonomy.org/BibtexHandler?requTask=upload&url=https://arxiv.org/abs/1503.07441&description=Neuroreceptor Activation by Vibration-Assisted Tunneling "Bookmark on BibSonomy") [ ![Reddit logo](/static/browse/0.3.4/images/icons/social/reddit.png) ](https://reddit.com/submit?url=https://arxiv.org/abs/1503.07441&title=Neuroreceptor Activation by Vibration-Assisted Tunneling "Bookmark on Reddit")

Bibliographic Tools

# Bibliographic and Citation Tools

Bibliographic Explorer Toggle

Bibliographic Explorer _([What is the Explorer?](https://info.arxiv.org/labs/showcase.html#arxiv-bibliographic-explorer))_

Connected Papers Toggle

Connected Papers _([What is Connected Papers?](https://www.connectedpapers.com/about))_

Litmaps Toggle

Litmaps _([What is Litmaps?](https://www.litmaps.co/))_

scite.ai Toggle

scite Smart Citations _([What are Smart Citations?](https://www.scite.ai/))_

Code, Data, Media

# Code, Data and Media Associated with this Article

alphaXiv Toggle

alphaXiv _([What is alphaXiv?](https://alphaxiv.org/))_

Links to Code Toggle

CatalyzeX Code Finder for Papers _([What is CatalyzeX?](https://www.catalyzex.com))_

DagsHub Toggle

DagsHub _([What is DagsHub?](https://dagshub.com/))_

GotitPub Toggle

Gotit.pub _([What is GotitPub?](http://gotit.pub/faq))_

Huggingface Toggle

Hugging Face _([What is Huggingface?](https://huggingface.co/huggingface))_

Links to Code Toggle

Papers with Code _([What is Papers with Code?](https://paperswithcode.com/))_

ScienceCast Toggle

ScienceCast _([What is ScienceCast?](https://sciencecast.org/welcome))_

Demos

# Demos

Replicate Toggle

Replicate _([What is Replicate?](https://replicate.com/docs/arxiv/about))_

Spaces Toggle

Hugging Face Spaces _([What is Spaces?](https://huggingface.co/docs/hub/spaces))_

Spaces Toggle

TXYZ.AI _([What is TXYZ.AI?](https://txyz.ai))_

Related Papers

# Recommenders and Search Tools

Link to Influence Flower

Influence Flower _([What are Influence Flowers?](https://influencemap.cmlab.dev/))_

Core recommender toggle

CORE Recommender _([What is CORE?](https://core.ac.uk/services/recommender))_

  * Author
  * Venue
  * Institution
  * Topic



About arXivLabs 

# arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? [**Learn more about arXivLabs**](https://info.arxiv.org/labs/index.html).

[Which authors of this paper are endorsers?](/auth/show-endorsers/1503.07441) | [Disable MathJax](javascript:setMathjaxCookie\(\)) ([What is MathJax?](https://info.arxiv.org/help/mathjax.html)) 

  * [About](https://info.arxiv.org/about)
  * [Help](https://info.arxiv.org/help)



  * contact arXivClick here to contact arXiv [ Contact](https://info.arxiv.org/help/contact.html)
  * subscribe to arXiv mailingsClick here to subscribe [ Subscribe](https://info.arxiv.org/help/subscribe)



  * [Copyright](https://info.arxiv.org/help/license/index.html)
  * [Privacy Policy](https://info.arxiv.org/help/policies/privacy_policy.html)



  * [Web Accessibility Assistance](https://info.arxiv.org/help/web_accessibility.html)
  * [arXiv Operational Status ](https://status.arxiv.org)  
Get status notifications via [email](https://subscribe.sorryapp.com/24846f03/email/new) or [slack](https://subscribe.sorryapp.com/24846f03/slack/new)



  *[Related DOI]: Digital Object Identifier


title: Medicine
scrape_date: 2025-02-28T11:50:24.524523
content_type: markdown
hash: 4bf0e28a9c64e0fffa8bd88466a7b8c102acc1b325f0d6b67d5a815b555dbd29
url:
https://journals.lww.com/md-journal/fulltext/2024/11010/effect_of_glp_1_receptor_agonists_on_weight_and.56.aspx

content:
![](https://cdn.wolterskluwer.io/wk-logos/1.0.x/favicon.png?rev=43) ![](/_layouts/15/images/spcommon.png?rev=43)

You may be trying to access this site from a secured browser on the server. Please enable scripts and reload this page.

[ ](https://lww.com/pages/default.aspx)

[](javascript:;)

  * __ Log in
  * or
  * [Register](https://journals.lww.com/md-journal/pages/register.aspx?ContextUrl=%2fmd-journal%2ffulltext%2f2024%2f11010%2feffect_of_glp_1_receptor_agonists_on_weight_and.56.aspx)
  * __[ Get new issue alertsGet alerts](javascript:javascript: alerts_ShowSubscribeeTOCPopup\('Medicine','md-journal','eTOC', 'eTOC'\);;)



__

__

****

Enter your Email address:

[Privacy Policy](https://journals.lww.com/md-journal/_layouts/oaks.journals/privacy.aspx)

__

** **

[Subscribe to eTOC](javascript:javascript: alerts_ShowSubscribeeTOCPopup\('Medicine','md-journal','eTOC', 'eTOC'\);;)

### [Secondary Logo ]() __

### [Journal Logo  ](https://journals.lww.com/md-journal/pages/default.aspx)

All Articles Images Videos Podcasts Blogs

__

[Advanced Search](https://journals.lww.com/md-journal/pages/advancedsearch.aspx)

Toggle navigation

[Register](https://journals.lww.com/md-journal/pages/register.aspx?ContextUrl=%2fmd-journal%2ffulltext%2f2024%2f11010%2feffect_of_glp_1_receptor_agonists_on_weight_and.56.aspx) Login

  * Articles & Issues
    * [Current Release](/md-journal/Pages/currenttoc.aspx)
    * [Previous Release](/md-journal/Pages/issuelist.aspx)
  * [Browse by Specialty](/md-journal/Subjects)
  * Channels
    * [Breast Cancer](https://journals.lww.com/md-journal/Pages/breastcancer.aspx)
    * [Gastroenterology and Hepatology](https://journals.lww.com/md-journal/Pages/gastroenterologyandhepatology.aspx)
    * [HIV/AIDS ](https://journals.lww.com/md-journal/Pages/hiv-aids.aspx)
    * [Infectious Diseases](/md-journal/Pages/Infectious-Diseases.aspx)
    * [Oncology](https://journals.lww.com/md-journal/Pages/oncology.aspx)
    * [Radiology](https://journals.lww.com/md-journal/Pages/radiology.aspx)
    * [Surgery](/md-journal/Pages/surgery.aspx)
    * [Cardiovascular](/md-journal/Pages/cardiovascular.aspx)
  * For Authors
    * [Information for Authors](/md-journal/Pages/Instructions-for-Authors.aspx)
    * [Criteria For Acceptance ](/md-journal/Pages/Criteria-for-Acceptance.aspx)
    * [Pre-Submission Checklist](https://journals.lww.com/md-journal/Pages/Pre-Submission-Checklist.aspx)
    * [Author Services ](/md-journal/Pages/Language-and-Editing-Services.aspx)
    * [Medicine FAQ ](/md-journal/Pages/medicineopenaccessfaq.aspx)
    * [Author Advice Gallery](/md-journal/Pages/Author-Advice-Gallery.aspx)
    * [Choosing Medicine](https://journals.lww.com/md-journal/Pages/Choosing-Medicine.aspx)
  * For Reviewers
    * [Guidelines and Information ](https://journals.lww.com/md-journal/Pages/reviewerguidelines.aspx)
    * [CME For Reviewers ](https://journals.lww.com/md-journal/Pages/CME-FAQ.aspx)
    * [Peer Review Training ](https://wkauthorservices.editage.com/peer-reviewer-training-course/)
  * Journal Info
    * [About the Journal](/md-journal/Pages/aboutthejournal.aspx)
    * [Editorial Board - Medicine](/md-journal/Pages/editorialboard.aspx)
    * [Rights and Permissions](/md-journal/_layouts/1033/oaks.journals/rightsandpermissions.aspx)
  * [Submit ](https://preflight.paperpal.com/partner/wolterskluwer/medicine/submit)
  * Collections
    * [High-impact research](/md-journal/Pages/high-impact-research.aspx)



All Articles Images Videos Podcasts Blogs

__

[Advanced Search](https://journals.lww.com/md-journal/pages/advancedsearch.aspx)

[November 01, 2024 - Volume 103 - Issue 44 ](/md-journal/toc/2024/11010)

  * [ Previous Article ](/md-journal/fulltext/2024/11010/pretreatment_systemic_immune_inflammation_index.55.aspx)
  * [ Next Article ](/md-journal/fulltext/2024/11010/prognostic_nomogram_models_for_elderly_patients.57.aspx)



Article as EPUB

[Export All Images to PowerPoint File](/md-journal/fulltext/2024/11010/effect_of_glp_1_receptor_agonists_on_weight_and.56.aspx?Ppt=Article|md-journal:2024:11010:00056|10.1097/md.0000000000040364|) Add to My Favorites

[](javascript:)

** Email to Colleague**

__

Colleague's E-mail is Invalid

Your Name: 

Colleague's Email:

Separate multiple e-mails with a (;).

Message: 

Thought you might appreciate this item(s) I saw in Medicine.

__

  


Your message has been successfully sent to your colleague.

  


__

  


Some error has occurred while processing your request. Please try after some time.

  


[](javascript:)

**Export to**

__

End Note  
---  
Procite  
Reference Manager  
  
Save my selection

Research Article: Narrative Review

# Effect of GLP-1 receptor agonists on weight and cardiovascular outcomes: A review

 __Raza, Fatima Ali MBBS a; Altaf, Rafiya MBBSb; Bashir, Talha MBBSc; Asghar, Fatima MBBSd; Altaf, Rabiya MUDre; Tousif, Sohaib MBBSf; Goyal, Aman MBBSg; Mohammed, Aisha MDh; Mohammad, Mahnoor Faisal MBBSi; __Anan, Mahfuza MBBS j,*; __Ali, Sajjad MBBS k

Author Information __

a Department of Medicine, Karachi Medical and Dental College, Karachi, Pakistan

b Department of Surgery, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan

c Department of Medicine, Karachi Institute of Medical Sciences, Combined Military Hospital Malir, Karachi City, Pakistan

d Department of Medicine, Ras Al Khaimah College of Medical Sciences, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates

e Department of Medicine, Mersey and West Lancashire Teaching Hospitals NHS Trust, Prescot, United Kingdom

f Department of Medicine, Ziauddin University, Karachi City, Pakistan

g Department of Medicine, Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, India

h Department of Medicine, Comanche County Memorial Hospital, Lawton, OK

i Department of Medicine, Liaquat National Hospital and Medical College, Karachi, Pakistan

j Department of Medicine, Bangladesh Medical College, Dhaka, Bangladesh

k Department of Medicine, Ziauddin University, Karachi City, Pakistan.

Received: 22 August 2024 / Received in final form: 14 October 2024 / Accepted: 15 October 2024

The authors have no funding and conflicts of interest to disclose.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

How to cite this article: Raza FA, Altaf R, Bashir T, Asghar F, Altaf R, Tousif S, Goyal A, Mohammed A, Mohammad MF, Anan M, Ali S. Effect of GLP-1 receptor agonists on weight and cardiovascular outcomes: A review. Medicine 2024;103:44(e40364).

*Correspondence: Mahfuza Anan, Department of Medicine, Bangladesh Medical College, Dhaka, Bangladesh (e-mail: [[email protected]](/cdn-cgi/l/email-protection#6409050d08100b5e09050c02111e05050a050a5d5c54240309050d084a070b09)).

This is an open access article distributed under the [Creative Commons Attribution License 4.0 (CCBY)](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Medicine [103(44):p e40364, November 01, 2024.](/md-journal/toc/2024/11010) | DOI: 10.1097/MD.0000000000040364[](http://creativecommons.org/licenses/by/4.0/)

  * Open

____Metrics

## Abstract

Diet and lifestyle modifications remain the foundation of obesity treatment, but they have historically proven insufficient for significant, long-term weight loss. As a result, there is a high demand for new pharmacologic treatments to promote weight loss and prevent life-threatening diseases associated with obesity. Researchers are particularly interested in 1 type of drug, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), because of its promising potential in addressing the limitations of non-pharmacologic treatments. In addition to their role in weight loss, these drugs have shown promising early evidence of cardiovascular benefits in obese patients, further enhancing their clinical relevance. Semaglutide and liraglutide, which were initially approved for the treatment of type 2 diabetes, have since been approved by the Food and Drug Administration as weight loss medications due to their effectiveness in promoting significant and sustained weight loss. In this narrative review, we will explore the mechanism of GLP-1 RAs, their effects on weight loss, cardiovascular risk factors and outcomes, common adverse effects, and strategies for managing these effects.

## 1\. Introduction

Obesity is a major risk factor for cardiovascular disease (CVD) and heart failure, which contributes to higher morbidity and mortality rates worldwide.[1] Historically, weight management strategies have included a variety of approaches, including bariatric surgery and pharmacological treatments; however, these methods have frequently encountered practical limitations or side effects, making them less effective or acceptable.[2] Recent advances in pharmacotherapy have introduced GLP-1 receptor agonists (GLP-1 RAs) and gastric inhibitory polypeptide (GIP) receptor agonists, which have shown promise in both weight loss and CVD prevention.[3] These agents work by increasing insulin secretion, decreasing appetite, and improving glucose metabolism, with a growing number of GLP-1 RAs and GIP analogs now on the market, including liraglutide, semaglutide, and tirzepatide.[4] Ongoing and future trials are investigating their long-term efficacy and safety profiles, with a focus on cost, patient adherence, and side effects.[5] This review investigates the mechanism of glucagon-like peptide 1 receptor agonist (GLP-1 RA), its effects on weight loss, cardiovascular risk (CV) factors and outcomes, common adverse effects and their management, and the drugs’ benefits and limitations, emphasizing the importance of careful patient selection.

## 2\. The link between obesity, CVD, and diabetes

A large body of epidemiological and clinical evidence suggests a link between obesity and CVDs, including hypertension, stroke, coronary heart disease, and, most importantly, heart failure.[6]

### 2.1. Epidemiological evidence

In a meta-analysis comparing new-onset HF among normal-weight and overweight patients, being overweight increased the risk of developing HF by 33%.[7] According to the Framingham Heart Study, each 1-unit increase in body mass index (BMI) is associated with a 5% increased HF risk in men and 7% in women, indicating a dose-dependent relationship.[8] Statistics show that each 5 kg/m2 increase in BMI increases the risk of hemorrhagic stroke and coronary heart disease by 10% and 15%, respectively.[9]

### 2.2. Insulin resistance and CV

Another major concern with weight gain is its direct linear relationship with systolic and diastolic blood pressure (BP), which contributes to a significantly increased risk of primary hypertension.[10] As a result, excess weight gain accounts for 78% of primary (essential) hypertension cases in men and 65% in women.[11] Furthermore, a meta-analysis conducted by Zhu et al[12] found a strong correlation between the prevalence of myocardial infarction (MI) and obesity, as well as the importance of maintaining weight as a preventative measure. Abdominal obesity increases the risk of insulin resistance, a metabolic syndrome component that precedes the development of type 2 diabetes (T2D).[13] Insulin resistance also increases the likelihood of other metabolic risk factors such as atherogenic dyslipidemia, hypertension, glucose intolerance, and a prothrombotic state, all of which are indirect risk factors for CVD.[14] In essence, patients with abdominal obesity are more likely to develop T2D,[15] which puts them at a higher risk of adverse CV events than normoglycemic subjects.[16] The San Antonio Heart Study adds to this notion by demonstrating a 2- to 3-fold increase in mortality risk in subjects with diabetes or metabolic syndrome at baseline.[17]

### 2.3. The impact of weight management on CVD

The question of whether obesity’s associated factors increase the risk of CVD or if obesity is the sole culprit is a source of ongoing debate. Some argue that epidemiological studies are skewed and that a phenotype known as “metabolically healthy obesity” exists, implying that the subset of obese people who do not have any other cardiometabolic abnormalities (such as hypertension, CVD, T2D, or hyperlipidemia) may not be at an increased risk of CVD or death. According to Mendelian randomization studies, the theory of “metabolically healthy obesity” has been debunked by demonstrating that the effect of obesity on CVD is causal.[18] As a result, combating obesity is critical regardless of whether patients have CV risk factors or not, because significant weight loss may potentially reverse the hemodynamic changes that predispose to changes in cardiac performance and morphology.[19]

## 3\. The need for weight loss and antidiabetic pharmacotherapy that improves cardiovascular outcomes

Because obesity is also associated with poor CV outcomes, it is a common misconception that simple weight loss interventions are the definitive solution to reversing these side effects. Even though diet and lifestyle changes remain the cornerstones of obesity treatment,[20] they have historically proven to be insufficient for achieving significant long-term weight loss.[21] Additional evidence calls into question the precise relevance of weight loss to CV outcomes overall. For example, the Look Action for Health in Diabetes trial, which was conducted to investigate the effects of lifestyle interventions on the rates of heart disease, stroke, and CV-related deaths in obese patients, found that weight loss had little to no effect on CV events, rendering it obsolete.[22] Patients who lose a significant amount of weight (>10 kg) may have better CV outcomes, but this is only true for a small subset of the population. Thus, the addition of pharmacotherapy may result in greater and more sustained weight loss.

### 3.1. Early pharmacological interventions

As an alternative, drugs were studied in 2 categories: those that could potentially increase metabolism or those that could suppress appetite. The first drugs to aid in weight loss, such as thyroid hormone, amphetamines (which also suppress appetite), and dinitrophenol, had short-lived success due to the CV effects of thyroid hormones, the potential for abuse with amphetamines, neuropathy, and cataracts with dinitrophenol.[23]

### 3.2. Appetite suppressants

Unfortunately, the early appetite suppressants did not produce positive results either. In 1997, a widely used anti-obesity drug called fenfluramine, which was used in the combination drug fen-phen (fenfluramine and phentermine), was recalled in the United States after echocardiography revealed that 30% of patients had valvular heart disease.[24] Sibutramine, a serotonin and epinephrine uptake inhibitor, was approved the same year for appetite suppression; however, it was discontinued in 2010 after a post-marketing study revealed statistical evidence of increased stroke and MIs in patients with preexisting CVD or diabetes.[25] Lorcaserin was one of the most recent drugs to be removed from the market due to its questionable safety profile, which revealed an increased risk of cancer that far outweighed its appetite-suppressing benefit.[26]

### 3.3. Bariatric surgery

Bariatric Surgery, which encompasses restrictive procedures (adjustable peri-gastric ring and sleeve gastrectomy) and malabsorptive procedures (gastric bypass and biliary pancreatic shunts), is a more effective and long-term solution for patients in need of excessive weight loss.[27] However, these surgeries come with a long list of postoperative risks, including bleeding, herniation, anastomotic leak, and “dumping syndrome,” to name a few.[28,29] Furthermore, surgery is not considered the first line of treatment for everyone because it requires patients to meet the eligibility criteria, which include a BMI ≥40, the presence of one or more obesity-related comorbidities (heart disease, stroke, hypertension, and T2D), and the inability to maintain a healthy weight over time.[30]

### 3.4. Regulatory changes and safety trials

As previously discussed, CVD is linked to diabetes; in fact, CVD is the leading cause of death in patients with diabetes mellitus, emphasizing the importance of antidiabetic pharmacotherapy that not only maintains CV neutrality but also reduces CV risk.[16] Until recently, antidiabetic drugs were not required to demonstrate CV safety. However, following the safety concerns raised by rosiglitazone and its potential side effects such as an increased risk of death and MI,[31] the Food and Drug Administration (FDA) mandated that innovative antidiabetic therapies for T2D be scrutinized by conducting safety trials to confirm their CV neutrality.[32] This is critical because certain antidiabetic medications can worsen heart failure or increase the risk of potentially fatal lactic acidosis.[33]

## 4\. The interest in GLP-1 RAs as weight loss agents

Over the last decade, there have been several advances in the development of safe antidiabetic pharmacotherapy, resulting in the introduction of a class of incretin mimetic drugs; recently, 1 such specific drug, GLP-1 RA, has received significant attention due to its promising potential as a weight loss agent. Despite the fact that the GIP hormone was the first insulin-stimulating factor discovered in the 1960s,[34] it demonstrated an impaired insulinotropic effect in patients with type 2 diabetes mellitus (T2DM), disappointing incretin enthusiasts.[35]

### 4.1. Discovery of glucagon-like peptide

Subsequent resection experiments revealed the existence of an additional incretin, glucagon-like peptide (GLP), which was an unexpected processing fragment of the newly discovered proglucagon.[36] It was then isolated from the gut and found to stimulate insulin and inhibit glucagon secretion.[37,38] Unlike GIP, this peptide could maintain its effects in patients with T2D and was quickly recognized as having remarkable antidiabetic effects in clinical studies.[39] One major limitation in the use of GLP-1 peptide was its extremely short half-life (1.5–5 minutes) due to rapid cleavage and degradation by the enzyme dipeptidyl peptidase-4 (DPP-4),[40] so DPP-4 resistant GLP-1 RAs were developed for longer-lasting effects.[41]

### 4.2. GLP-1 RAs in the treatment of T2DM and weight loss effects

GLP-1 RAs were licensed for the treatment of T2DM due to their ability to lower A1C and achieve the hemoglobin A1c (HbA1c) goal of <7%. They also normalize fasting and prandial blood glucose levels.[42,43] It is suggested that starting GLP-1 RA with insulin as an add-on therapy before or after 90 days resulted in more patients achieving blood sugar levels of <7% or 8%, and patients lowering their blood sugar levels by ≤%1 to 2% at 6 and 12 months.[44] Unexpectedly, trials on diabetic patients revealed impressive weight loss,[45] sparking researchers’ interest in the potential use of GLP-1 RA drugs as weight loss therapy.

## 5\. Pharmacodynamics of GLP-1 RA mediated weight loss

### 5.1. Mechanism of action

To understand their mechanism, we must first understand the normal physiology of the incretin molecule’s pathway, as well as the changes that GLP-1 RA undergoes during obesity. GLP-1 is produced by proglucagon cleavage in L-cells in the intestinal mucosa, α-cells in pancreatic islets, and neurons in the solitary tract nucleus.[46] This hormone regulates energy homeostasis and feeding behavior by stimulating receptors on islet β-cells. It enhances insulin secretion, promotes β-cell proliferation, inhibits glucagon production, and increases resistance to apoptosis.[47] In addition to its incretin effects, GLP-1 functions as a satiety signaling molecule, delaying gastric emptying and gastric acid secretion.[48–50]

### 5.2. Impact of obesity on GLP-1 function

Obesity, according to documented evidence, may contribute to GLP-1 function impairment. In a study of 51 subjects with BMIs ranging from 20 to 61 kg/m2, Muscelli et al discovered an inverse correlation between the incretin effect and BMI.[51] The underlying pathophysiology for this reduced effect has not been definitively determined, but there are 2 plausible theories. The first is reduced GLP-1 secretion as a result of L-cells losing sensitivity to carbohydrates in obese people.[52] Another reason for lower GLP-1 levels could be increased resistance to leptin, which is thought to regulate GLP-1 secretion.[53] The second explanation for the decreased incretin effect in obese patients is a reduction in GLP-1’s insulinotropic effectiveness. This hypothesis is supported by the Knop et al study, which found that a decrease in the incretin effect was not accompanied by a decrease in the secretion of these hormones.[54,55] Even though the exact underlying cause of impairment is unknown, it is undeniable that obesity influences GLP-1, as evidence shows that weight loss, whether diet-induced[56] or following Roux-en-Y gastric bypass, can increase GLP-1 secretion.[57] Finally, the impairment of GLP-1 and its effects on satiety explains why weight loss may appear impossible for obese people, trapping them in a never-ending cycle of overeating and weight gain that leads to additional incretin dysfunction. As a result, GLP-1 receptor analogs are required to aid in weight loss by pharmacologically reproducing appetite-suppressing effects such as delayed gastric emptying[58] and direct stimulation of satiety centers in the hindbrain and hypothalamus[59] ([Fig. 1](javascript:void\(0\))).

[![F1](javascript:void\(0\);)](javascript:void\(0\))[Figure 1.: ](javascript:void\(0\))

The mechanism of action of GLP-1 analogs (DPP-4 resistant). DPP-4 = dipeptidyl peptidase-4, GLP-1 = glucagon-like peptide.

## 6\. Cardiovascular effects of GLP-1 RAs

GLP-1 RA’s weight loss effect is thus well established in both diabetic and nondiabetic individuals. However, as previously discussed, weight loss without improvement in CV outcomes is futile. Once again, clinical applications of GLP-1 RA have demonstrated its status as the gold standard; despite being initially studied for incretin and weight loss effects, evidence has shown that GLP-1 RA is a multipurpose drug due to its non-glycemic effects, which can interact with CV risk factors while also providing beneficial effects on CV outcomes.[60]

### 6.1. Mechanisms of cardiovascular benefit

The discovery of GLP-1R on cardiomyocytes, endothelial cells, and the autonomic nervous system strongly suggests direct and indirect effects on the heart and vessels ([Fig. 2](javascript:void\(0\))).[61–64] To begin, GLP-1 improves microvascular blood flow by increasing endothelial function and microvascular perfusion.[65–68] Long-term studies of GLP-1 RA showed moderate BP reductions, which could be attributed to altered salt homeostasis, weight loss, sympathetic nervous system involvement, or serum atrial natriuretic peptide.[62]

[![F2](javascript:void\(0\);)](javascript:void\(0\))[Figure 2.: ](javascript:void\(0\))

The direct and indirect effect of GLP-1R on the heart and vessels. GLP-1R = GLP-1 receptor.

### 6.2. Impact on cardiovascular markers

The meta-analysis concludes that GLP-1 RAs exenatide and liraglutide reduced systolic and diastolic BP by 1 to 5 mm Hg in T2DM patients compared to other antidiabetic drugs.[69] Another CV marker affected by the GLP-1 peptide is heart rate, which is acutely increased in response to a suggested increase in sympathetic nervous system activity or direct sinoatrial node stimulation.[64,70,71] Finally, GLP-1 RA improves lipid profiles by lowering postprandial triglyceride levels, apo B-48, apo C-III, remnant lipoprotein cholesterol, and remnant lipoprotein triglycerides.[72] Overall, placebo-controlled clinical trials with GLP-1 RA revealed a consistent 0.2–0.3 mmol/L decrease in triglyceride concentrations.[73] Semaglutide treatment has been shown to significantly reduce postprandial triglyceride, very low-density lipoprotein, and apoB-48 levels.[74] These findings clearly indicate that the potential anti-atherosclerotic effects of GLP-1 RA correspond to a decrease in lipids. As previously stated, GLP-1 RAs are clearly recognized for reducing weight and HbA1c, which may have a positive impact on CV outcomes overall.[75,76]

## 7\. Currently approved GLP-1 RAs and their indications

Several different GLP-1 RA drugs have been developed and released into the market over the years. They are distinguished by their molecular structure, pharmacokinetics, administration, storage, efficacy, tolerability, patient satisfaction, half-life, similarity to GLP-1, clearance, dose, and short- or long-acting mechanisms.[77]

### 7.1. Overview of approved GLP-1 RAs

Exenatide (twice daily), liraglutide, lixisenatide (both once daily), oral semaglutide (once daily), and the once-weekly agents exenatide (Bydureon), albiglutide, semaglutide, and dulaglutide are among the GLP-1 RAs currently approved in the United States.[78–85] These drugs were initially only used to treat T2D because they effectively reduced A1C and weight. The first GLP-1 RA drug to receive FDA approval and be officially classified as a weight loss medication was liraglutide.[86]

### 7.2. Liraglutide and semaglutide

In 2014, this under the skin injection was approved as an adjunct to diet and exercise for adults with a BMI of ≥30 (obese) or ≥27 (overweight) and at least one weight-related condition (hypertension, T2D, dyslipidemia). The initial dosage of liraglutide is 0.6 mg daily, regardless of meals, and is increased weekly by 0.6 mg until the target dosage of 3 mg per day is met. Patients who can tolerate the 3 mg dosage can continue with treatment, while others are advised to discontinue, as are patients who are unable to lose 4% of their baseline body weight after 4 months of treatment or who do not show weight fluctuations after a year of medication. Patients may experience gastrointestinal (GI) side effects including nausea, diarrhea, constipation, and vomiting. Furthermore, approximately 1 in every 4 patients with T2D will experience symptomatic hypoglycemia at some point during the year.[87] Nonetheless, liraglutide remains the superior weight loss agent when compared to orlistat (Xenical).[88] The next drug to join liraglutide on the list of GLP-1 RA drugs used for chronic weight management was weekly semaglutide, 2.4 mg.[89] This agent is also injected subcutaneously (SC), meets the same inclusion criteria as liraglutide, and has nearly identical side effects, with nausea being the most common.[90] In comparison to liraglutide, semaglutide causes significantly more weight loss but may also cause more side effects.[91] semaglutide is the only GLP-1 RA that provides the advantages of a highly effective GLP-1 RA in both injectable and oral formulations[92]; however, oral semaglutide has yet to be approved as a weight loss medication.

### 7.3. Cardiovascular indications and future developments

Lastly, dulaglutide, liraglutide, and injectable semaglutide have been approved to reduce major adverse cardiovascular events (MACE) in adults with T2D who have established CVD or multiple CV risk factors.[93–95] In contrast, none of the GIP RA drugs have been approved by the FDA, but tirzepatide, a dual-GIP and GLP-1 RA, is thought to have undiscovered potential. It is currently in phase 3 development for managing blood glucose in adults with T2D, chronic weight management, and heart failure with preserved ejection fraction (HFpEF).[96]

## 8\. Trials involving GLP-1 RA

### 8.1. Semaglutide

#### 8.1.1. Cardiovascular outcome trials in patients with diabetes

The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with semaglutide in Subjects with Type 2 Diabetes was a noninferiority trial that compared once-weekly injectable semaglutide (0.5 or 1.0 mg) to placebo in terms of CV safety over a 2.1-year median observation period.[97] This trial included 3927 people with T2D, with 83% having preexisting CVD, chronic kidney disease, or both. Despite the fact that the goal of this study was not to determine superiority, the findings revealed a significant 26% reduction in the risk of the 3-point MACE endpoint among patients taking semaglutide. The reduction was primarily driven by a 39% decrease in nonfatal stroke (_P_ = .04) and a 26% decrease in nonfatal MI (_P_ = .12), with no significant effect on CV mortality (_P_ = .79). Compared to placebo, semaglutide 0.5 and 1.0 mg significantly reduced body weight (−2.9 and −4.3 kg, respectively; _P_ < .001) and A1C levels (−0.7% and −1.0%, respectively; _P_ < .001 for both). Semaglutide 1.0 mg reduced mean systolic BP by 2.6 mm Hg compared to placebo (_P_ < .001).

Similarly, Peptide Innovation for Early Diabetes Treatment 6 was a preapproved noninferiority trial with an identical endpoint to assess the CV safety of oral semaglutide versus placebo among patients with T2D who were at high CV risk.[98] A total of 3183 patients (84.7% with established CVD or renal disease) were followed up for a median of 15.9 months. The 3-point MACE endpoint occurred in 3.8% of patients receiving oral semaglutide compared to 4.8% receiving placebo, demonstrating noninferiority (_P_ < .001) but not superiority (_P_ = .17). Analyzing the individual components of the primary outcome revealed a nominally significant reduction in the risk of dying from CV causes in the semaglutide group. At 62 weeks, the oral semaglutide group had lower glycated hemoglobin levels than the placebo group (−1.0% vs −0.3%), as well as lower body weight (−4.2 vs −0.8 kg). The oral semaglutide group had slightly lower systolic BP, low-density lipoprotein cholesterol, and triglyceride levels.

#### 8.1.2. Weight loss trials in patients with diabetes

The Semaglutide Treatment Effect in People with Obesity (STEP) 2 trial compared the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg to semaglutide 1.0 mg and placebo for weight management in obese or overweight adults with T2D[99] participants were considered eligible if they reported at least 1 unsuccessful dietary attempt to lose weight, had a body mass index of at least 27 kg/m2, an HbA1c of 7% to 10%, and had been diagnosed with T2D at least 180 days prior to screening. A total of 1210 participants were randomly assigned in a 1:1:1 ratio to receive either semaglutide 2.4 mg, semaglutide 1.0 mg, or a matching placebo once a week for 68 weeks, along with a lifestyle intervention that included dietary counseling and increased physical activity for 150 minutes weekly. The co-primary endpoints were percentage change in bodyweight and a weight loss of at least 5%. At week 68, the average change in body weight from baseline was −9.64% in the 2.4 mg semaglutide group and −3.42% in the placebo group (_P_ < .001). Weight loss of ≥5% was more common in the 2.4 mg semaglutide group compared to the placebo group (68.8% vs 28.5%; _P_ < .001). In conclusion, semaglutide 2.4 mg achieved a clinically significant decrease in bodyweight compared to placebo. At week 68, semaglutide 2.4 mg reduced HbA1c from baseline by −1.6%, resulting in more than two-thirds of patients reaching their target HbA1c of 6.5% or lower. Semaglutide 2.4 mg improved cardiometabolic risk factors, lipid profile, and inflammatory markers compared to placebo. Semaglutide 2.4 mg significantly improved systolic BP compared to placebo (−3.9 vs −0.5 mm Hg).

#### 8.1.3. Weight loss trials in patients with obesity

Similar to STEP 2, trials such as STEP 1, 3, 4, and 5 evaluate the efficacy of semaglutide at a higher dose of 2.4 mg/wk, specifically for promoting weight loss in obese patients who do not have diabetes.[100–103] These phase 3 multicenter, randomized, double-blind trials are some of the most important clinical trial programs for obesity management. These trials have similar inclusion criteria: adults with at least 1 unsuccessful dietary effort, a BMI of ≥30 or ≥27 kg/m2, and 1 or more weight-related coexisting conditions (hypertension, CVD, or sleep apnea). These trials were only for people without diabetes, as those with a hemoglobin A1C of ≥6.5% were excluded. The primary endpoints for all of these trials were the percentage change in body weight from baseline to the end of the trial, as well as a weight loss of at least 5%, with the exception of the STEP 4 trial, which had only 1 endpoint: the percentage change in body weight from weeks 20 to 68. The STEP 1 trial sought to demonstrate the superiority of semaglutide 2.4 mg over placebo as an adjunct to lifestyle intervention (dietary counseling and increased physical activity for 150 minutes per week).98 This trial included 1961 participants who were randomly assigned in a 2:1 ratio to 9 semaglutide group experienced a 14.9% decrease in body weight from baseline to week 68, compared to a 2.4% decrease with placebo (_P_ < .001). Additionally, 86.4% of participants in the semaglutide group lost at least 5% of their body weight, compared to 31.5% in the placebo group (_P_ < .001). The STEP 3 trial included 611 participants who were randomly assigned to receive either once weekly 2.4 mg of semaglutide SC or a placebo.[101] This trial sought to demonstrate the maximum effect of semaglutide by supplementing the drug with a low-calorie diet for the first 8 weeks and intensive behavioral therapy for the remaining 68 weeks. At week 68, the semaglutide group lost an average of 16.0% of their body weight, while the placebo group lost 5.7% (_P_ < .001). In the semaglutide group, 86.6% of participants lost at least 5% of their body weight, compared to 47.6% in the placebo group (_P_ < .001). The STEP 4 trial investigated the impact of continued treatment with 2.4 mg of subcutaneous semaglutide on the maintenance of body weight loss in addition to lifestyle changes.[102] A total of 902 participants received semaglutide 2.4 for 20 weeks, with a mean weight change of 11.3 (−10.6%) kg from baseline. After the 20-week run-in period, they were randomized in a 2:1 ratio to continue treatment with subcutaneous semaglutide or placebo for the remaining 48 weeks. Participants who continued taking semaglutide after randomization lost an additional 7.9% of their bodyweight, adding up to a total weight loss of 17.4% over the course of the trial. Those who switched to placebo regained an average of 6.9%, giving a total weight loss of 5.0% (_P_ < .001). The long-term STEP 5 trial lasted 2 years and involved 304 participants who were randomly assigned in a 1:1 ratio to receive semaglutide 2.4 mg or placebo, along with lifestyle interventions.[103] Semaglutide significantly decreased body weight from baseline to week 104 compared to placebo (−15.2% vs −2.6%, _P_ < .0001). The study found that adults with overweight or obesity were more likely to lose at least 5% of their body weight with semaglutide compared to placebo (77.1% vs 34.4%; _P_ < .0001). In terms of semaglutide’s safety profile, the most commonly reported adverse effects were GI, including nausea, vomiting, diarrhea, and constipation. In all the 68-week trials, weight loss with semaglutide was accompanied by greater improvements than placebo with respect to cardiometabolic risk factors, including reductions in waist circumference, BP, C-reactive protein, glycated hemoglobin levels, and lipid levels.

#### 8.1.4. Cardiovascular outcome trials in patients with obesity

Although these increases in CV markers suggest that the use of GLP-1 RA may induce weight loss while also improving CV outcomes, trials specifically designed to investigate CV outcomes in patients with diabetes and obesity have yet to be completed. Semaglutide 2.4 mg SC once weekly, for example, is currently being investigated for the treatment of obesity in the Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial.[104] This 5-year, randomized, double-blind, parallel-group trial aims to enroll 17,500 obese patients with preexisting CVD to determine whether semaglutide is superior to placebo when added to standard of care for preventing MACE. The SELECT trial is open to patients over 45 years old with a BMI of 27 kg/m2 or higher and a history of CVD. Patients with an HbA1c level >48 mmol/mol (6.5%), a history of type 1 or T2D, or evidence of a previous MI, stroke, hospitalization for unstable angina pectoris, or transient ischemic attack within 60 days of screening are excluded. The primary CV endpoint is the time from randomization to the first occurrence of MACE, while the confirmatory secondary endpoints are the time from randomization to CV death and all-cause death. To summarize, the SELECT trial is the first of its kind because it assesses superiority in MACE reduction for an anti-obesity medication in patients without diabetes; thus, it has a high potential for advancing an innovative approach to CVD risk reduction while concurrently combating obesity.

#### 8.1.5. Indications and dosage

In conclusion, injectable semaglutide is sold under 2 brand names: Ozempic and Wegovy. Ozempic is prescribed to adults with T2DM in conjunction with diet and exercise to improve glycemic control and reduce the risk of MACE in adults with T2D and established CVD,[84] whereas Wegovy is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adults with a BMI >30 or 27 kg/m2 with at least 1 weight-related comorbid condition.[84] The current Ozempic guidelines recommend starting semaglutide at a dose of 0.25 mg once weekly and increasing to 0.5 mg once weekly after 4 weeks. If adequate glycemic control is not achieved after another 4 weeks, the dose can be increased to 1 mg once weekly.[79] Wegovy initial dose of 0.25 mg is gradually increased over a 4-week period until a maintenance dose of 2.4 mg weekly is achieved.[89] Finally, the most common side effects of these drugs included nausea, vomiting, diarrhea, stomach pain, and constipation. Oral semaglutide, Rybelsus tablets 7 or 14 mg, is prescribed once daily for the treatment of T2DM in conjunction with diet and exercise.[81]

### 8.2. Exenatide

#### 8.2.1. Cardiovascular outcome trials in patients with diabetes

The “Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes” (EXSCEL) study looked at the CV effects of once-weekly exenatide in T2D patients (the median baseline HgA1c was 8%).[105] This trial enrolled 14,752 patients (73.1% of whom had preexisting CVD) who were randomly assigned to receive exenatide once weekly or placebo for a median of 3.2 years. The study found that 11.4% of patients in the exenatide group experienced the primary composite outcome (3-point MACE) compared to 12.2% in the placebo group, indicating noninferiority (_P_ < .001), but not superiority (_P_ = .06). Furthermore, secondary outcomes (rate of death from CV causes, fatal or nonfatal MI, fatal or nonfatal stroke, and hospitalization for HF) showed no significant difference between groups. After 6 months, the exenatide group had a 0.7 percentage point lower mean glycated hemoglobin level than the placebo group. This difference narrowed over the trial period (_P_ < .001). Exenatide resulted in lower mean values for body weight (−1.27 kg), systolic blood pressure (−1.57 mm Hg), low-density lipoprotein cholesterol (−1.5 mg/dL), and triglycerides (−1.8 mg/dL) compared to placebo.

#### 8.2.2. Weight loss trials in patients with diabetes

A meta-analysis of weight loss in patients with obesity and T2DM found that taking exenatide 20 mcg twice daily resulted in an additional 1.4 kg weight loss, while taking exenatide 2 mg once weekly resulted in an additional 1.6 kg weight loss when compared to placebo.[106] Apovian et al[107] conducted a 24-week study in which participants with obesity and T2D were given exenatide in addition to a lifestyle modification program that included a 600 kcal/d deficit and at least 2.5 hours of increased physical activity per week. In this trial, 194 patients were randomized to either 5 μg of exenatide twice daily SC with intensive lifestyle modification program or placebo with lifestyle modification program. Exenatide combined with lifestyle modification resulted in greater weight loss (−6.16 ± 0.54 vs −3.97 ± 0.52 kg, _P_ = .003), hemoglobin A1c (−1.21% ± 0.09% vs − 0.73% ± 0.09%, _P_ < .0001), systolic (−9.44 ± 1.40 vs − 1.97 ± 1.40 mm Hg, _P_ < .001), and diastolic (−2.22 ± 1). Exenatide and lifestyle modification program participants experienced higher rates of nausea compared to the placebo and lifestyle modification program groups (44.8% vs 19.4%, respectively, _P_ < .001). There was no significant difference between the 2 groups in terms of withdrawal rates (4.2% vs 5.1%, _P_ = 1.0) or hypoglycemia rates.

#### 8.2.3. Weight loss trials in patients with obesity

A 35-week study of 41 obese and diabetic women was conducted to determine the effect of exenatide treatment versus placebo on weight loss.[108] Results showed that subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared to a 0.43 ± 0.63 kg weight gain during placebo treatment (_P_ < .01). In total, 30% of subjects responded well and lost ≥5% of their body weight (−7.96% ± 0.52%); 39% responded modestly and lost <5% of their body weight (−2.43% ± 0.45%); and 31% had no response and gained weight (1.93% ± 0.53%). The exenatide group showed greater reductions than the placebo group in systolic blood pressure (−2.48 vs −1.26 mm Hg), fasting plasma glucose (0.45 vs 3.10 mg/dL), and waist circumference (−1.68 vs 0.94 cm). Furthermore, nausea was the most common adverse effect in 56% of subjects receiving exenatide, compared to 21% of patients receiving placebo.

#### 8.2.4. Indications and dosage

In conclusion, exenatide, sold under the brand names Byetta and Bydureon, is approved as an adjunct to diet and exercise for improving glycemic control in adults with T2DM.[78,109] However, Byetta and Bydureon have different dosages. For example, Byetta is injected twice daily at an initial dose of 5 mcg and is increased to 10 mcg twice daily after 1 month based on clinical response, whereas Bydureon is administered once weekly at a dose of 2 mg. Commonly reported adverse effects included nausea, diarrhea, and vomiting.

### 8.3. Liraglutide

#### 8.3.1. Cardiovascular outcome trials in patients with diabetes

##### 8.3.1.1. The liraglutide effect and action in diabetes

Evaluation of Cardiovascular Outcome Results (LEADER) trial randomly assigned 9340 diabetic participants aged more than 50 years with known CVD or over 60 years with at least 1 CV risk factor to receive liraglutide or placebo.[110] The median follow-up was 3.8 years. At baseline, 81.3% of participants had established CVD, 24.7% had chronic kidney disease stage 3 or higher, and the average HgA1c was 8.7%. The primary outcome was the first occurrence of a composite CV outcome, which included death from CV causes, nonfatal MI, or nonfatal stroke. The study found that 13% of participants in the liraglutide group experienced the primary composite outcome, compared to 14.9% in the placebo group (_P_ < .001 for noninferiority; _P_ = .01 for superiority). The improvement in MACE was primarily due to lower CV death (_P_ = .007) and all-cause mortality (_P_ = .02). The liraglutide group outperformed the placebo group in terms of cardiometabolic risk factors, with 2.3 kg more weight loss, 1.2 mm Hg lower systolic blood pressure, and −0.40 percentage points lower HbA1c.

#### 8.3.2. Weight loss trials in patients with diabetes

The Satiety and Clinical Adiposity—Liraglutide Evidence (SCALE) program consists of 4 large-scale multicenter phase III trials that were conducted to determine the efficacy of liraglutide as a weight loss agent.[111–114] The SCALE-diabetes trial was specifically designed to look into the efficacy of liraglutide for weight loss in obese or overweight diabetic patients.[111] In this 56-week double-blind, placebo-controlled trial, 846 participants were randomized in a 2:1:1 ratio to once-daily liraglutide 3 mg, liraglutide 1.8 mg, or placebo, with a 500-kcal deficit per day and increased physical activity of ≥150 min/wk. The inclusion criteria required a BMI of 27.0 or higher, participants taking 0 to 3 oral hypoglycemic agents (metformin, thiazolidinedione, sulfonylurea) with stable body weight, and a glycated hemoglobin level of 7.0% to 10.0%. This trial had 3 co-primary endpoints: percentage change in weight, proportion of patients who lost 5% or more, and 10% or more of baseline weight. Weight loss rates were 6.0% (6.4 kg) with liraglutide 3 mg, 4.7% (5.0 kg) with liraglutide 1.8 mg, and 2.0% (2.2 kg) with placebo (_P_ < .001). The proportion of patients who lost more than 5% of their initial weight was 54.3% with liraglutide 3.0 mg, 40.4% with liraglutide 1.8 mg, and 21.4% with placebo (_P_ < .001). The proportion of patients who lost more than 5% of their initial weight was 54.3% with liraglutide 3.0 mg, 40.4% with liraglutide 1.8 mg, and 21.4% with placebo (_P_ < .001). Similarly, liraglutide 3 (25.2%) mg and liraglutide 1.8 (15.9%) mg resulted in a higher proportion of participants losing at least 10% body weight than placebo (6.7%). Furthermore, liraglutide 3.0 mg was associated with improved glycemic control in terms of HbA1c level change, proportion of participants meeting HbA1c targets, and fasting plasma glucose level when compared to placebo. Liraglutide 3.0 mg significantly increased total cholesterol, very low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels when compared to placebo. The mean systolic blood pressure was significantly lower with liraglutide (regardless of dose) than placebo. Finally, adverse events such as GI disorders (particularly nausea) and hypoglycemic episodes were more common with liraglutide 3.0 mg than liraglutide 1.8 mg or placebo.

#### 8.3.3. Weight loss trials in patients with obesity

The SCALE Obesity and Prediabetes trial was a 3-year, randomized, double-blind, placebo-controlled study. It included a 56-week initial study period followed by a 2-year follow-up on patients with prediabetes.112 Patients with a BMI of at least 30 or a BMI of at least 27 with treated or untreated dyslipidaemia or hypertension were considered eligible, while those with diabetes were excluded. A total of 3731 participants were randomized 2:1 to receive once-daily liraglutide 3.0 mg SC or placebo, as well as lifestyle modification counseling sessions. The co-primary end points included body weight change, proportion of participants losing at least 5%, and more than 10% weight loss from baseline. At week 56, patients in the liraglutide group lost more body weight than placebo (8.4 vs 2.8 kg, _P_ < .001). Liraglutide significantly increased the proportion of patients who lost at least 5% (63.2% vs 27.1%) and 10% (33.1% vs 10.6%) of their body weight compared to placebo (_P_ < .001). The fasting lipid profile improved significantly after liraglutide treatment. Liraglutide significantly decreased HbA1c, fasting plasma glucose, systolic and diastolic blood pressures compared to placebo (_P_ < .001).

The SCALE maintenance trial investigated the efficacy of liraglutide in maintaining weight loss achieved with a low-calorie diet.[113] Participants in this randomized, double-blind, placebo-controlled trial had a BMI ≥30 (obese) or ≥27 (overweight) kg/m2 with comorbidities.[114] They had to lose at least 5% of their initial weight in a 4 to 12-week low-calorie diet run-in period to be considered eligible for randomization. Out of 551 participants, 422 met the goal and were randomly assigned to receive either liraglutide 3.0 mg or placebo. Throughout the trial, lifestyle interventions such as diet and exercise counseling were offered. Co-primary endpoints included the percentage change in body weight after randomization, the proportion of participants who maintained their initial weight loss of ≥5% during the run-in period, and the proportion who lost ≥5% of their randomization weight. At week 56, liraglutide significantly reduced weight compared to placebo (6.2% vs 0.2%, _P_ < .0001). Patients taking liraglutide lost at least 5% of their randomization weight (50.5% vs 21.8%) and maintained a 5% run-in weight loss (81.4% vs 48.9%). Finally, improvements in some CV risk factors were observed, with liraglutide-treated participants achieving significantly greater decreases in BMI, waist circumference, mean systolic blood pressure, HbA1c, and fasting plasma glucose than patients given placebo. In the SCALE Maintenance and SCALE-obesity and prediabetes trials, the most commonly reported adverse event with liraglutide 3 mg was mild or moderate nausea.

#### 8.3.4. Indications and dosage

Liraglutide was previously marketed as an antidiabetic treatment under the brand name Victoza, but it has now been approved as a weight reduction medication under the new trade name Saxenda.[79,87] Victoza is a multifunctional medication that reduces the risk of significant adverse CV events in persons with T2DM or existing CVD. Victoza is dosed initially at 0.6 mg SC once daily for a week to relieve GI problems. After 1 week, the dose is increased to 1.2 mg once daily; if glycemic control is not attained, the dose may be increased to 1.8 mg SC once daily. Saxenda is administered SC once daily at a dose of 0.6 mg, which is increased weekly until the target dose of 3 mg SC once daily is met. Both drugs have common side effects such as nausea, diarrhea, vomiting, and constipation.

## 9\. Other GLP-1 RA

As for other GLP-1 RAs such as dulaglutide, albiglutide, and lixisenatide, data based on trials solely investigating the effects of these drugs on weight loss in patients with obesity is scarce; however, an abundance of trials have tested the CV effects of these drugs in patients with diabetes.

### 9.1. Dulaglutide and cardiovascular outcomes

One such trial was the Researching Cardiovascular Events with a Weekly Incretin in Diabetes trial which investigated dulaglutide’s effect on MACE in individuals with T2D.[115] In this study, 9901 patients with an HbA1c >7% and proven CVD or CV risk factors, were randomized to weekly dulaglutide 1.5 mg or placebo. The primary composite outcome was the first occurrence of CV death, nonfatal MI, or nonfatal stroke. During a median follow-up of 5·4 years, the primary endpoint occurred in 12% of participants in the dulaglutide group compared with 13.4% in the placebo group, which was significant (_P_ = .026). The analysis of secondary CV outcomes showed that nonfatal stroke was also significantly lower in the dulaglutide group compared with placebo (2.7% vs 3.5%, _P_ = .017), however, dulaglutide did not show any effects on all-cause mortality (_P_ = .067).

### 9.2. Lixisenatide and cardiovascular outcomes

The first trial which evaluated lixisenatide, published in 2016, was the Evaluation of Lixisenatide in Acute Coronary Syndrome trial which included 6068 patients with T2DM who had sustained an acute coronary event within 180 days before randomization.[116] They were assigned to either lixisenatide or placebo for a median of 25 months. The primary endpoint was the first occurrence of one of the following: death from CV causes, nonfatal stroke, nonfatal MI, or hospitalization for unstable angina. Results showed an insignificant effect of lixisenatide compared with placebo on the occurrence of the primary composite outcome (13.4% vs 13.2% in the placebo group, _P_ < .001 for noninferiority, p ¼ 0.81 for superiority) proving noninferiority of lixisenatide, but not superiority.

### 9.3. Albiglutide and cardiovascular outcomes

In 2018, the trial on albiglutide and CV outcomes in patients with T2DM and CV disease (Heart Attack Reduction with Medications Organized as New Therapies Outcomes) was performed on 9463 participants who were followed for a median duration of 1.6 years; all patients had a preexisting coronary, cerebrovascular, or peripheral artery disease.[117] In patients receiving standard care, addition of once-weekly albiglutide reduced the risk of the primary composite outcome (3-point MACE) by 22%, compared with the addition of placebo. These results indicated that albiglutide was superior to placebo (_P_ < .0001 for noninferiority; _P_ = .0006 for superiority).

## 10\. Clinical application of GLP-1 RAs

### 10.1. Patient selection criteria

To summarize, GLP-1 RAs are particularly effective for individuals with T2D requiring enhanced glycemic control and especially beneficial for overweight or obese patients, as they help promote weight loss.[118] Approved for weight management, GLP-1 RAs, such as liraglutide and semaglutide, are recommended for individuals with a BMI of 30 kg/m² or greater or 27 kg/m² with related comorbidities like hypertension.[119] They are also preferred for type 2 diabetic patients with established CVD or those at high risk, given the significant reductions in MACE seen in trials like LEADER and Semaglutide in Subjects with Type 2 Diabetes.[97,110] Liraglutide also has reno-protective properties, making it suitable for patients with mild to moderate chronic kidney disease, although caution is necessary in advanced cases due to dehydration risks.[120] Patient should be thoroughly screened for a history of pancreatitis or medullary thyroid carcinoma, due to GLP-1 RAs potential exacerbation of these diseases.[121] When considering patient preferences, those seeking weight loss or wanting to avoid hypoglycemia risks associated with insulin or sulfonylureas are suitable candidates.[122]

### 10.2. Monitoring strategies

Additionally, regular monitoring plays a crucial role in maximizing treatment efficacy. HbA1c evaluations conducted every 3 to 6 months are critical for assessing glycemic control, with anticipated decreases of 0.5% to 1.5%.[123] Consistent weight monitoring is also crucial, as patients may experience a 5% to 10% reduction in body weight during the initial year.[124] For individuals with compromised kidney function, it is advisable to monitor serum creatinine and eGFR to avoid acute kidney injury.[125] Healthcare professionals should also be vigilant for common digestive side effects, including nausea, vomiting, and diarrhea, which can be addressed through gradual dose increases.[126] Although GLP-1 RAs have a low hypoglycemia risk, it is crucial to educate patients about symptom recognition, particularly if they are using other glucose-lowering medications.[127] To ensure patient safety, it is essential to monitor for indications of pancreatitis and thyroid function, especially in those with a family history of thyroid cancer.[128]

### 10.3. Potential challenges

While GLP-1 RAs offer numerous advantages, their effective implementation in clinical settings faces several obstacles. The high cost of these medications, coupled with limited insurance coverage, can impede patients’ ability to maintain long-term treatment.[129] Moreover, the need for injection may deter individuals who are averse to needles, although oral semaglutide presents a non-injectable option with specific usage instructions.[130] It is important for patients to be educated on the medication and to have realistic expectations about treatment outcomes, including the timeframe for improvements in blood sugar levels and weight reduction.[131] For elderly patients, it is crucial to weigh the risks associated with multiple medications and potential drug interactions, as GI side effects could increase the risk of dehydration.[132]

## 11\. Future direction and trials

### 11.1. GLP-1 RAs in nonalcoholic fatty liver disease treatment

Concurrent with the obesity epidemic, the prevalence of nonalcoholic fatty liver disease (NAFLD) has risen dramatically, becoming the most prevalent liver disorder in Western nations.[133] At present, no FDA-approved medications exist for NAFLD treatment, with the primary recommendation being lifestyle modifications aimed at weight reduction, which is often challenging to achieve and sustain.[134] Consequently, innovative therapeutic advancements like GLP-1 RAs are crucial. These drugs not only facilitate weight loss but also contribute to reducing liver inflammation and fibrosis.[135] For instance, liraglutide has shown promise in enhancing nonalcoholic steatohepatitis histology and decelerating fibrosis progression in the “Liraglutide Efficacy and Action in Diabetes” (LEAD) study, while semaglutide has also exhibited potential in NAFLD treatment.[136,137] Despite these encouraging results, many GLP-1 RAs still require thorough investigation for NAFLD treatment, necessitating additional clinical trials to confirm their effectiveness.[135]

### 11.2. Emerging research areas

Another promising area of investigation is the potential neuroprotective effects of GLP-1 RAs in conditions such as Alzheimer disease. Preliminary studies indicate that GLP-1 RAs may mitigate neuroinflammation, enhance brain insulin sensitivity, and safeguard against cognitive decline.[138] Further investigation into CV and renal benefits is underway, particularly concerning heart failure and chronic kidney disease, with ongoing research assessing whether these benefits extend to nondiabetic populations.[139] Personalized medicine approaches are gaining traction, with research focusing on identifying biomarkers and genetic profiles to predict patient response to GLP-1 RAs, potentially improving treatment outcomes.[140]

### 11.3. Conclusion

The future of GLP-1 RAs is promising, with expanding indications and ongoing trials that could transform the management of metabolic, liver, neurodegenerative, and CVDs.[133–138] Addressing challenges related to safety, cost, and access will be crucial to maximizing their potential in clinical practice.

## Author contributions

**Conceptualization:** Fatima Ali Raza.

**Formal analysis:** Fatima Ali Raza, Rafiya Altaf, Talha Bashir, Sohaib Tousif, Mahnoor Faisal Mohammad.

**Project administration:** Fatima Ali Raza, Sajjad Ali.

**Resources:** Fatima Ali Raza, Rabiya Altaf, Mahnoor Faisal Mohammad.

**Validation:** Fatima Ali Raza, Rabiya Altaf, Aman Goyal, Aisha Mohammed, Mahfuza Anan, Sajjad Ali.

**Writing—original draft:** Fatima Ali Raza, Rafiya Altaf, Talha Bashir, Fatima Asghar, Rabiya Altaf, Sohaib Tousif, Aman Goyal, Sajjad Ali.

**Investigation:** Rafiya Altaf, Fatima Asghar, Rabiya Altaf, Sohaib Tousif.

**Methodology:** Rafiya Altaf, Talha Bashir, Fatima Asghar, Rabiya Altaf, Sohaib Tousif, Aman Goyal, Mahnoor Faisal Mohammad, Mahfuza Anan.

**Funding acquisition:** Talha Bashir, Aman Goyal, Aisha Mohammed.

**Software:** Talha Bashir, Aisha Mohammed.

**Data curation:** Fatima Asghar, Sohaib Tousif, Mahnoor Faisal Mohammad.

**Visualization:** Fatima Asghar, Sajjad Ali.

**Supervision:** Aman Goyal, Aisha Mohammed, Mahfuza Anan, Sajjad Ali.

**Writing—review & editing:** Aman Goyal, Aisha Mohammed, Mahnoor Faisal Mohammad, Mahfuza Anan, Sajjad Ali.

## Abbreviations:

apo
    apolipoprotein
BMI
    body mass index
BP
    blood pressure
CV
    cardiovascular
CVD
    cardiovascular disease
FDA
    Food and Drug Administration
FPG
    fasting plasma glucose
GIP
    gastric inhibitory polypeptide
GLP-1
    glucagon-like peptide 1
GLP-1 RA
    GLP-1 receptor agonist
HbA1c
    hemoglobin A1c
HF
    heart failure
kcal
    kilocalories
kg/m²
    kilograms per square meter
LEAD
    liraglutide efficacy and action in diabetes
MACE
    major adverse cardiovascular events
mg
    milligrams
MI
    myocardial infarction
NAFLD
    nonalcoholic fatty liver disease
NASH
    nonalcoholic steatohepatitis
Ozempic
    Brand name for injectable semaglutide for type 2 diabetes management
P = 
    probability value (P value)
SCALE
    Satiety and Clinical Adiposity-Liraglutide Evidence
SELECT
    Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity
STEP
    Semaglutide Treatment Effect in People with Obesity
T2DM
    type 2 diabetes mellitus
Wegovy
    Brand name for injectable semaglutide for weight management

## References

[1]. Powell-Wiley TM, Poirier P, Burke LE, et al.; American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Stroke Council. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143:e984–e1010.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Obesity+and+cardiovascular+disease%3a+a+scientific+statement+from+the+American+Heart+Association.&publication_year=2021&author=TM+Powell-Wiley&author=P+Poirier&author=LE+Burke)



[2]. Sjöström L, Narbro K, Sjöström CD, et al.; Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007a;357:741–52.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effects+of+bariatric+surgery+on+mortality+in+Swedish+obese+subjects.&publication_year=2007&author=L+Sj%c3%b6str%c3%b6m&author=K+Narbro&author=CD+Sj%c3%b6str%c3%b6m)



[3]. Michos ED, Lopez-Jimenez F, Gulati M. Role of glucagon-like peptide-1 receptor agonists in achieving weight loss and improving cardiovascular outcomes in people with overweight and obesity. J Am Heart Assoc. 2023;12.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Role+of+glucagon-like+peptide-1+receptor+agonists+in+achieving+weight+loss+and+improving+cardiovascular+outcomes+in+people+with+overweight+and+obesity.&publication_year=2023&author=ED+Michos&author=F+Lopez-Jimenez&author=M+Gulati)



[4]. Mariam Z, Niazi SK. Glucagon‐like peptide agonists: a prospective review. Endocrinol Diabetes Metab. 2023;7.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Glucagon%e2%80%90like+peptide+agonists%3a+a+prospective+review.&publication_year=2023&author=Z+Mariam&author=SK+Niazi)



[5]. Ciardullo S, Morieri ML, Daniele G, et al. GLP1-GIP receptor co-agonists: a promising evolution in the treatment of type 2 diabetes. Acta Diabetol. 2024;61:941–50.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP1-GIP+receptor+co-agonists%3a+a+promising+evolution+in+the+treatment+of+type+2+diabetes.&publication_year=2024&author=S+Ciardullo&author=ML+Morieri&author=G+Daniele)



[6]. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham heart study. Circulation. 1983;67:968–77.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Obesity+as+an+independent+risk+factor+for+cardiovascular+disease%3a+a+26-year+follow-up+of+participants+in+the+Framingham+heart+study.&publication_year=1983&author=HB+Hubert&author=M+Feinleib&author=PM+McNamara&author=WP+Castelli)



[7]. Krittanawong C, Tunhasiriwet A, Wang Z, et al. Meta-analysis comparing frequency of overweight versus normal weight in patients with new-onset heart failure. Am J Cardiol. 2018;121:836–43.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Meta-analysis+comparing+frequency+of+overweight+versus+normal+weight+in+patients+with+new-onset+heart+failure.&publication_year=2018&author=C+Krittanawong&author=A+Tunhasiriwet&author=Z+Wang)



[8]. Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305–13.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Obesity+and+the+risk+of+heart+failure.&publication_year=2002&author=S+Kenchaiah&author=JC+Evans&author=D+Levy)



[9]. Rosengren A. Obesity and cardiovascular health: the size of the problem. Eur Heart J. 2021;42:3404–6.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Obesity+and+cardiovascular+health%3a+the+size+of+the+problem.&publication_year=2021&author=A+Rosengren)



[10]. Hall JE. The kidney, hypertension, and obesity. Hypertension. 2003;41:625–33.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+kidney%2c+hypertension%2c+and+obesity.&publication_year=2003&author=JE+Hall)



[11]. Garrison RJ, Kannel WB, Stokes J, Castelli WP. Incidence and precursors of hypertension in young adults: the Framingham offspring study. Prev Med. 2004;16:235–51.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Incidence+and+precursors+of+hypertension+in+young+adults%3a+the+Framingham+offspring+study.&publication_year=2004&author=RJ+Garrison&author=WB+Kannel&author=J+Stokes&author=WP+Castelli)



[12]. Zhu J, Su X, Li G, Chen J, Tang B, Yang Y. The incidence of acute myocardial infarction in relation to overweight and obesity: a meta-analysis. Arch Med Sci. 2014;10:855–62.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+incidence+of+acute+myocardial+infarction+in+relation+to+overweight+and+obesity%3a+a+meta-analysis.&publication_year=2014&author=J+Zhu&author=X+Su&author=G+Li&author=J+Chen&author=B+Tang&author=Y+Yang)



[13]. Pouliot M-C, Després J-P, Nadeau A, et al. Visceral obesity in men: associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 2013;41:826–34.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Visceral+obesity+in+men%3a+associations+with+glucose+tolerance%2c+plasma+insulin%2c+and+lipoprotein+levels.&publication_year=2013&author=M-C+Pouliot&author=J-P+Despr%c3%a9s&author=A+Nadeau)



[14]. Ferrannini E. Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. Endocr Rev. 1998;19:477–90.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Insulin+resistance+versus+insulin+deficiency+in+non-insulin-dependent+diabetes+mellitus%3a+problems+and+prospects.&publication_year=1998&author=E+Ferrannini)



[15]. Freemantle N, Holmes J, Hockey A, Kumar S. How strong is the association between abdominal obesity and the incidence of type 2 diabetes? Int J Clin Pract. 2008;62:1391–6.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=How+strong+is+the+association+between+abdominal+obesity+and+the+incidence+of+type+2+diabetes%3f&publication_year=2008&author=N+Freemantle&author=J+Holmes&author=A+Hockey&author=S+Kumar)



[16]. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017. Cardiovasc Diabetol. 2018;17:83.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Prevalence+of+cardiovascular+disease+in+type+2+diabetes%3a+a+systematic+literature+review+of+scientific+evidence+from+across+the+world+in+2007%e2%80%932017.&publication_year=2018&author=TR+Einarson&author=A+Acs&author=C+Ludwig&author=UH+Panton)



[17]. Haffner SM. Obesity and the metabolic syndrome: the San Antonio heart study. Br J Nutr. 2008;83:S67–70.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Obesity+and+the+metabolic+syndrome%3a+the+San+Antonio+heart+study.&publication_year=2008&author=SM+Haffner)



[18]. Riaz H, Shahzeb Khan M, Jamal Siddiqi T, et al. Association between obesity and cardiovascular outcomes. JAMA Network Open. 2018;1:e183788.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Association+between+obesity+and+cardiovascular+outcomes.&publication_year=2018&author=H+Riaz&author=M+Shahzeb+Khan&author=T+Jamal+Siddiqi)



[19]. Alpert MA, Karthikeyan K, Abdullah O, Ghadban R. Obesity and cardiac remodeling in adults: mechanisms and clinical implications. Prog Cardiovasc Dis. 2018;61:114–23.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Obesity+and+cardiac+remodeling+in+adults%3a+mechanisms+and+clinical+implications.&publication_year=2018&author=MA+Alpert&author=K+Karthikeyan&author=O+Abdullah&author=R+Ghadban)



[20]. Executive summary. Obes Res. 1998;6:51S–179S.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Executive+summary.&publication_year=1998)



[21]. Franz MJ, Boucher JL, Rutten-Ramos S, VanWormer JJ. Lifestyle weight-loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta-analysis of randomized clinical trials. J Acad Nutr Diet. 2015;115:1447–63.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Lifestyle+weight-loss+intervention+outcomes+in+overweight+and+obese+adults+with+type+2+diabetes%3a+a+systematic+review+and+meta-analysis+of+randomized+clinical+trials.&publication_year=2015&author=MJ+Franz&author=JL+Boucher&author=S+Rutten-Ramos&author=JJ+VanWormer)



[22]. Pi-Sunyer X. The Look AHEAD trial: a review and discussion of its outcomes. Curr Nutr Rep. 2014;3:387–91.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+Look+AHEAD+trial%3a+a+review+and+discussion+of+its+outcomes.&publication_year=2014&author=X+Pi-Sunyer)



[23]. Bersoux S, Byun TH, Chaliki SS, Poole KG. Pharmacotherapy for obesity: what you need to know. Cleve Clin J Med. 2017;84:951–8.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Pharmacotherapy+for+obesity%3a+what+you+need+to+know.&publication_year=2017&author=S+Bersoux&author=TH+Byun&author=SS+Chaliki&author=KG+Poole)



[24]. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine–phentermine. N Engl J Med. 2002;337:581–8.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Valvular+heart+disease+associated+with+fenfluramine%e2%80%93phentermine.&publication_year=2002&author=HM+Connolly&author=JL+Crary&author=MD+McGoon)



[25]. James WPT, Caterson ID, Coutinho W, et al.; SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363:905–17.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+sibutramine+on+cardiovascular+outcomes+in+overweight+and+obese+subjects.&publication_year=2010&author=WPT+James&author=ID+Caterson&author=W+Coutinho)



[26]. Otto MA. Lorcaserin (Belviq) withdrawn from US market due to cancer risk. Medscape. Available at: <https://www.medscape.com/viewarticle/925253>. Accessed April 3, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Lorcaserin+\(Belviq\)+withdrawn+from+US+market+due+to+cancer+risk.&author=MA+Otto)



[27]. Arterburn DE, Courcoulas AP. Bariatric surgery for obesity and metabolic conditions in adults. BMJ. 2014;349:g3961.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Bariatric+surgery+for+obesity+and+metabolic+conditions+in+adults.&publication_year=2014&author=DE+Arterburn&author=AP+Courcoulas)



[28]. Lim R, Beekley A, Johnson DC, Davis KA. Early and late complications of bariatric operation. Trauma Surg Acute Care Open. 2018;3:e000219.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Early+and+late+complications+of+bariatric+operation.&publication_year=2018&author=R+Lim&author=A+Beekley&author=DC+Johnson&author=KA+Davis)



[29]. Ahmad A, Baldwin Kornrich D, Krasner H, et al. Prevalence of dumping syndrome after laparoscopic sleeve gastrectomy and comparison with laparoscopic Roux-En-Y gastric bypass. Obes Surg. 2019;29:1506–13.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Prevalence+of+dumping+syndrome+after+laparoscopic+sleeve+gastrectomy+and+comparison+with+laparoscopic+Roux-En-Y+gastric+bypass.&publication_year=2019&author=A+Ahmad&author=D+Baldwin+Kornrich&author=H+Krasner)



[30]. Sjöholm K, Anveden A, Peltonen M, et al. Evaluation of current eligibility criteria for bariatric surgery: diabetes prevention and risk factor changes in the Swedish obese Subjects (SOS) Study. Diabetes Care. 2013;36:1335–40.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Evaluation+of+current+eligibility+criteria+for+bariatric+surgery%3a+diabetes+prevention+and+risk+factor+changes+in+the+Swedish+obese+Subjects+\(SOS\)+Study.&publication_year=2013&author=K+Sj%c3%b6holm&author=A+Anveden&author=M+Peltonen)



[31]. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+rosiglitazone+on+the+risk+of+myocardial+infarction+and+death+from+cardiovascular+causes.&publication_year=2007&author=SE+Nissen&author=K+Wolski)



[32]. Federal Register. Draft guidance for industry on diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention; availability. Available at: <https://www.federalregister.gov/documents/2008/03/03/E8-3974/draft-guidance-for-industry-on-diabetes-mellitus-developing-drugs-and-therapeutic-biologics-for>. Accessed March 3, 2008.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Draft+guidance+for+industry+on+diabetes+mellitus%3a+developing+drugs+and+therapeutic+biologics+for+treatment+and+prevention%3b+availability.)



[33]. Masoudi FA, Wang Y, Inzucchi SE, et al. Metformin and thiazolidinedione use in medicare patients with heart failure. JAMA. 2003;290:81–5.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Metformin+and+thiazolidinedione+use+in+medicare+patients+with+heart+failure.&publication_year=2003&author=FA+Masoudi&author=Y+Wang&author=SE+Inzucchi)



[34]. Pederson RA, Hs McIntosh C. Discovery of gastric inhibitory polypeptide and its subsequent fate: personal reflections. J Diabetes Investig. 2016;7(Suppl 1):4–7.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Discovery+of+gastric+inhibitory+polypeptide+and+its+subsequent+fate%3a+personal+reflections.&publication_year=2016&author=RA+Pederson&author=+Hs+McIntosh+C)



[35]. Krarup T, Saurbrey N, Moody AJ, Kühl C, Madsbad S. Effect of porcine gastric inhibitory polypeptide on β-cell function in type I and type II diabetes mellitus. Metabolism. 1987;36:677–82.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+porcine+gastric+inhibitory+polypeptide+on+%ce%b2-cell+function+in+type+I+and+type+II+diabetes+mellitus.&publication_year=1987&author=T+Krarup&author=N+Saurbrey&author=AJ+Moody&author=C+K%c3%bchl&author=S+Madsbad)



[36]. Whalley NM, Pritchard LE, Smith DM, White A. Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells? J Endocrinol. 2011;211:99–106.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Processing+of+proglucagon+to+GLP-1+in+pancreatic+%ce%b1-cells%3a+is+this+a+paracrine+mechanism+enabling+GLP-1+to+act+on+%ce%b2-cells%3f&publication_year=2011&author=NM+Whalley&author=LE+Pritchard&author=DM+Smith&author=A+White)



[37]. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409–39.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+physiology+of+glucagon-like+peptide+1.&publication_year=2007&author=JJ+Holst)



[38]. Ramracheya R, Chapman C, Chibalina M, et al. GLP‐1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels. Physiol Rep. 2018;6:e13852.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP%e2%80%901+suppresses+glucagon+secretion+in+human+pancreatic+alpha-cells+by+inhibition+of+P%2fQ-type+Ca+channels.&publication_year=2018&author=R+Ramracheya&author=C+Chapman&author=M+Chibalina)



[39]. Hvidberg A, Nielsen MT, Hilsted J, Ørskov C, Holst JJ. Effect of glucagon-like peptide-1 (proglucagon 78-107amide) on hepatic glucose production in healthy man. Metabolism. 2004;43:104–8.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+glucagon-like+peptide-1+\(proglucagon+78-107amide\)+on+hepatic+glucose+production+in+healthy+man.&publication_year=2004&author=A+Hvidberg&author=MT+Nielsen&author=J+Hilsted&author=C+%c3%98rskov&author=JJ+Holst)



[40]. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 1993;214:829–35.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Dipeptidyl-peptidase+IV+hydrolyses+gastric+inhibitory+polypeptide%2c+glucagon-like+peptide-1\(7%e2%80%9336\)amide%2c+peptide+histidine+methionine+and+is+responsible+for+their+degradation+in+human+serum.&publication_year=1993&author=R+Mentlein&author=B+Gallwitz&author=WE+Schmidt)



[41]. Guglielmi V, Sbraccia P. GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products. Eat Weight Disord. 2017;22:231–40.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP-1+receptor+independent+pathways%3a+emerging+beneficial+effects+of+GLP-1+breakdown+products.&publication_year=2017&author=V+Guglielmi&author=P+Sbraccia)



[42]. Peng XV, McCrimmon RJ, Shepherd L, et al. Glycemic control following GLP-1 RA or basal insulin initiation in real-world practice: a retrospective, observational, longitudinal cohort study. Diabetes Ther. 2020;11:2629–45.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Glycemic+control+following+GLP-1+RA+or+basal+insulin+initiation+in+real-world+practice%3a+a+retrospective%2c+observational%2c+longitudinal+cohort+study.&publication_year=2020&author=XV+Peng&author=RJ+McCrimmon&author=L+Shepherd)



[43]. Dietle AL. PharmD Assistant Professor of Pharmacy Practice MCPHS University Worcester, Massachusetts Marisa C. Campanale, PharmD Clinical Pharmacist Holyoke Health Center, Inc. Holyoke, Massachusetts Jared L. Ostroff, PharmD, BCACP Clinical Assistant Professor of Pharmacy Practice Western New England University Springfield, Massachusetts. (2016, October 14). GLP-1 Receptor Agonists: An Alternative for Rapid-Acting Insulin? US Pharmacist. Available at: <https://www.uspharmacist.com/article/glp1-receptor-agonists-an-alternative-for-rapidacting-insulin>. Accessed April 3, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=PharmD+Assistant+Professor+of+Pharmacy+Practice+MCPHS+University+Worcester%2c+Massachusetts+Marisa+C.+Campanale%2c+PharmD+Clinical+Pharmacist+Holyoke+Health+Center%2c+Inc.+Holyoke%2c+Massachusetts+Jared+L.+Ostroff%2c+PharmD%2c+BCACP+Clinical+Assistant+Professor+of+Pharmacy+Practice+Western+New+England+University+Springfield%2c+Massachusetts.+\(2016%2c+October+14\).+GLP-1+Receptor+Agonists%3a+An+Alternative+for+Rapid-Acting+Insulin%3f+US+Pharmacist.&author=AL+Dietle)



[44]. PharmaNewsIntelligence. Insulin, GLP-1 RA combo improves blood sugar control for diabetics. PharmaNewsIntelligence, Available at: <https://pharmanewsintel.com/news/insulin-glp-1-ra-combo-improves-blood-sugar-control-for-diabetics>. Accessed June 24, 2020.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Insulin%2c+GLP-1+RA+combo+improves+blood+sugar+control+for+diabetics.+PharmaNewsIntelligence%2c)



[45]. Weiss T, Yang L, Carr RD, et al. Real-world weight change, adherence, and discontinuation among patients with type 2 diabetes initiating glucagon-like peptide-1 receptor agonists in the UK. BMJ Open Diabetes Res Care. 2022;10:e002517.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Real-world+weight+change%2c+adherence%2c+and+discontinuation+among+patients+with+type+2+diabetes+initiating+glucagon-like+peptide-1+receptor+agonists+in+the+UK.&publication_year=2022&author=T+Weiss&author=L+Yang&author=RD+Carr)



[46]. D’Alessio D. Is GLP-1 a hormone: whether and when? J Diabetes Investig. 2016;7:50–5.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Is+GLP-1+a+hormone%3a+whether+and+when%3f&publication_year=2016&author=D+D%e2%80%99Alessio)



[47]. Doyle ME, Egan JM. Mechanisms of action of GLP-1 in the pancreas. Pharmacol Ther. 2007;113:546–93.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Mechanisms+of+action+of+GLP-1+in+the+pancreas.&publication_year=2007&author=ME+Doyle&author=JM+Egan)



[48]. Larsen PJ, Tang-Christensen M, Jessop DS. Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology. 1997;138:4445–55.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Central+administration+of+glucagon-like+peptide-1+activates+hypothalamic+neuroendocrine+neurons+in+the+rat.&publication_year=1997&author=PJ+Larsen&author=M+Tang-Christensen&author=DS+Jessop)



[49]. Deane AM, Nguyen NQ, Stevens JE, et al. Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia. J Clin Endocrinol Metabolism. 2010 15–21.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Endogenous+glucagon-like+peptide-1+slows+gastric+emptying+in+healthy+subjects%2c+attenuating+postprandial+glycemia.&publication_year=2010&author=AM+Deane&author=NQ+Nguyen&author=JE+Stevens)



[50]. Wettergren A, Wojdemann M, Meisner S, Stadil F, Holst JJ. The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut. 2014;40:597–601.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+inhibitory+effect+of+glucagon-like+peptide-1+\(GLP-1\)+7-36+amide+on+gastric+acid+secretion+in+humans+depends+on+an+intact+vagal+innervation.&publication_year=2014&author=A+Wettergren&author=M+Wojdemann&author=S+Meisner&author=F+Stadil&author=JJ+Holst)



[51]. Muscelli E, Mari A, Casolaro A, et al. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes. 2007;57:1340–8.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Separate+impact+of+obesity+and+glucose+tolerance+on+the+incretin+effect+in+normal+subjects+and+type+2+diabetic+patients.&publication_year=2007&author=E+Muscelli&author=A+Mari&author=A+Casolaro)



[52]. Attenuated GLP-1 secretion in obesity: cause or consequence?|Gut. Available at: <https://gut.bmj.com/content/38/6/916.long>. Accessed April 4, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Attenuated+GLP-1+secretion+in+obesity%3a+cause+or+consequence%3f%7cGut.)



[53]. Ranganath LR, Beety JM, Morgan LM, Wright JW, Howland R, Marks V. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut. 2007;38:916–9.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Attenuated+GLP-1+secretion+in+obesity%3a+cause+or+consequence%3f&publication_year=2007&author=LR+Ranganath&author=JM+Beety&author=LM+Morgan&author=JW+Wright&author=R+Howland&author=V+Marks)



[54]. Toft-Nielsen M-B, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:3717–23.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Determinants+of+the+impaired+secretion+of+glucagon-like+peptide-1+in+type+2+diabetic+patients.&publication_year=2001&author=M-B+Toft-Nielsen&author=MB+Damholt&author=S+Madsbad)



[55]. Knop FK, Aaboe K, Vilsbøll T, et al. Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab. 2012;14:500–10.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Impaired+incretin+effect+and+fasting+hyperglucagonaemia+characterizing+type+2+diabetic+subjects+are+early+signs+of+dysmetabolism+in+obesity.&publication_year=2012&author=FK+Knop&author=K+Aaboe&author=T+Vilsb%c3%b8ll)



[56]. Verdich C, Toubro S, Buemann B, Lysgård Madsen J, Juul Holst J, Astrup A. The role of postprandial releases of insulin and incretin hormones in meal-induced satiety—effect of obesity and weight reduction. Int J Obes Relat Metab Disord. 2001;25:1206–14.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+role+of+postprandial+releases+of+insulin+and+incretin+hormones+in+meal-induced+satiety%e2%80%94effect+of+obesity+and+weight+reduction.&publication_year=2001&author=C+Verdich&author=S+Toubro&author=B+Buemann&author=J+Lysg%c3%a5rd+Madsen&author=J+Juul+Holst&author=A+Astrup)



[57]. Dirksen C, Jørgensen NB, Bojsen-Møller KN, et al. Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. Diabetologia. 2012;55:1890–901.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Mechanisms+of+improved+glycaemic+control+after+Roux-en-Y+gastric+bypass.&publication_year=2012&author=C+Dirksen&author=NB+J%c3%b8rgensen&author=KN+Bojsen-M%c3%b8ller)



[58]. Jones KL, Huynh LQ, Hatzinikolas S, et al. Exenatide once weekly slows gastric emptying of solids and liquids in healthy, overweight people at steady-state concentrations. Diabetes Obes Metab. 2020;22:788–97.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Exenatide+once+weekly+slows+gastric+emptying+of+solids+and+liquids+in+healthy%2c+overweight+people+at+steady-state+concentrations.&publication_year=2020&author=KL+Jones&author=LQ+Huynh&author=S+Hatzinikolas)



[59]. van Bloemendaal L, Ten Kulve JS, la Fleur SE, Ijzerman RG, Diamant M. Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. J Endocrinol. 2013;221:T1–T16.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effects+of+glucagon-like+peptide+1+on+appetite+and+body+weight%3a+focus+on+the+CNS.&publication_year=2013&author=L+van+Bloemendaal&author=JS+Ten+Kulve&author=SE+la+Fleur&author=RG+Ijzerman&author=M+Diamant)



[60]. Heuvelman VD, Van Raalte DH, Smits MM. Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes. Cardiovasc Res. 2019;116:916–30.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Cardiovascular+effects+of+glucagon-like+peptide+1+receptor+agonists%3a+from+mechanistic+studies+in+humans+to+clinical+outcomes.&publication_year=2019&author=VD+Heuvelman&author=DH+Van+Raalte&author=MM+Smits)



[61]. Pyke C, Scott Heller R, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014;155:1280–90.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP-1+receptor+localization+in+monkey+and+human+tissue%3a+novel+distribution+revealed+with+extensively+validated+monoclonal+antibody.&publication_year=2014&author=C+Pyke&author=R+Scott+Heller&author=RK+Kirk)



[62]. Kim M, Platt MJ, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19:567–75.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP-1+receptor+activation+and+Epac2+link+atrial+natriuretic+peptide+secretion+to+control+of+blood+pressure.&publication_year=2013&author=M+Kim&author=MJ+Platt)



[63]. Helmstädter J, Frenis K, Filippou K, et al. Endothelial GLP-1 (glucagon-like peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension. Arterioscler Thromb Vasc Biol. 2020;40:145–58.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Endothelial+GLP-1+\(glucagon-like+peptide-1\)+receptor+mediates+cardiovascular+protection+by+liraglutide+in+mice+with+experimental+arterial+hypertension.&publication_year=2020&author=J+Helmst%c3%a4dter&author=K+Frenis&author=K+Filippou)



[64]. Baggio LL, Ussher JR, McLean BA, Cao X, Kabir MG, Mulvihill EE, Mighiu AS, et al. The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice. Mol Metab. 2017;6:1339–49.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+autonomic+nervous+system+and+cardiac+GLP-1+receptors+control+heart+rate+in+mice.&publication_year=2017&author=LL+Baggio&author=JR+Ussher&author=BA+McLean&author=X+Cao&author=MG+Kabir&author=EE+Mulvihill&author=AS+Mighiu)



[65]. Love KM, Liu J, Regensteiner JG, Reusch JEB, Liu Z. GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes. J Diabetes. 2020;12:488–98.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP-1+and+insulin+regulation+of+skeletal+and+cardiac+muscle+microvascular+perfusion+in+type+2+diabetes.&publication_year=2020&author=KM+Love&author=J+Liu&author=JG+Regensteiner&author=JEB+Reusch&author=Z+Liu)



[66]. Ivy JR, Bailey MA. Pressure natriuresis and the renal control of arterial blood pressure. J Physiol. 2014;592:3955–67.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Pressure+natriuresis+and+the+renal+control+of+arterial+blood+pressure.&publication_year=2014&author=JR+Ivy&author=MA+Bailey)



[67]. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:728–42.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP-1+receptor+agonists+for+individualized+treatment+of+type+2+diabetes+mellitus.&publication_year=2012&author=JJ+Meier)



[68]. Katsurada K, Nakata M, Saito T, et al. Central glucagon-like peptide-1 receptor signaling via brainstem catecholamine neurons counteracts hypertension in spontaneously hypertensive rats. Sci Rep. 2019;9:12986.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Central+glucagon-like+peptide-1+receptor+signaling+via+brainstem+catecholamine+neurons+counteracts+hypertension+in+spontaneously+hypertensive+rats.&publication_year=2019&author=K+Katsurada&author=M+Nakata&author=T+Saito)



[69]. Wang B, Zhong J, Lin H, et al. Blood pressure-lowering effects of GLP‐1 receptor agonists exenatide and liraglutide: a meta-analysis of clinical trials. Diabetes Obes Metab. 2013;15:737–49.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Blood+pressure-lowering+effects+of+GLP%e2%80%901+receptor+agonists+exenatide+and+liraglutide%3a+a+meta-analysis+of+clinical+trials.&publication_year=2013&author=B+Wang&author=J+Zhong&author=H+Lin)



[70]. Lorenz M, Lawson F, Owens D, et al. Differential effects of glucagon-like peptide-1 receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16:6.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Differential+effects+of+glucagon-like+peptide-1+receptor+agonists+on+heart+rate.&publication_year=2017&author=M+Lorenz&author=F+Lawson&author=D+Owens)



[71]. Linnebjerg H, Seger M, Kothare PA, Hunt T, Wolka AM, Mitchell MI. A thorough QT study to evaluate the effects of singledose Exenatide 10 Μg on cardiac repolarization in healthy subjects. Int J Clin Pharmacol Ther. 2011;49:594–604.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=A+thorough+QT+study+to+evaluate+the+effects+of+singledose+Exenatide+10+%ce%9cg+on+cardiac+repolarization+in+healthy+subjects.&publication_year=2011&author=H+Linnebjerg&author=M+Seger&author=PA+Kothare&author=T+Hunt&author=AM+Wolka&author=MI+Mitchell)



[72]. Sun F, Wu S, Wang J, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther. 2014;37:225–41.e8.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+glucagon-like+peptide-1+receptor+agonists+on+lipid+profiles+among+type+2+diabetes%3a+a+systematic+review+and+network+meta-analysis.&publication_year=2014&author=F+Sun&author=S+Wu&author=J+Wang)



[73]. Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M, Drucker DJ. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation. 2017;136:849–70.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Cardiovascular+actions+and+clinical+outcomes+with+glucagon-like+peptide-1+receptor+agonists+and+dipeptidyl+peptidase-4+inhibitors.&publication_year=2017&author=MA+Nauck&author=JJ+Meier&author=MA+Cavender&author=M+Abd+El+Aziz&author=DJ+Drucker)



[74]. Hjerpsted JB, Flint A, Brooks A, Axelsen MB, Kvist T, Blundell J. Semaglutide improves postprandial glucose and lipid metabolism, and delays first‐hour gastric emptying in subjects with obesity. Diabetes Obes Metab. 2018;20:610–9.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Semaglutide+improves+postprandial+glucose+and+lipid+metabolism%2c+and+delays+first%e2%80%90hour+gastric+emptying+in+subjects+with+obesity.&publication_year=2018&author=JB+Hjerpsted&author=A+Flint&author=A+Brooks&author=MB+Axelsen&author=T+Kvist&author=J+Blundell)



[75]. Shah M, Vella A. Effects of GLP-1 on appetite and weight. Rev Endocr Metab Disord. 2014;15:181–7.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effects+of+GLP-1+on+appetite+and+weight.&publication_year=2014&author=M+Shah&author=A+Vella)



[76]. Eeg-Olofsson K, Cederholm J, Nilsson PM, et al. New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish national diabetes register (NDR)’. J Intern Med. 2010;268:471–82.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=New+aspects+of+HbA1c+as+a+risk+factor+for+cardiovascular+diseases+in+type+2+diabetes%3a+an+observational+study+from+the+Swedish+national+diabetes+register+\(NDR\)%e2%80%99.&publication_year=2010&author=K+Eeg-Olofsson&author=J+Cederholm&author=PM+Nilsson)



[77]. Nauck MA, Meier JJ. Management of endocrine disease: are all GLP-1 agonists equal in the treatment of type 2 diabetes? Eur J Endocrinol. 2019;181:R211–34.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Management+of+endocrine+disease%3a+are+all+GLP-1+agonists+equal+in+the+treatment+of+type+2+diabetes%3f&publication_year=2019&author=MA+Nauck&author=JJ+Meier)



[78]. BYETTA® (Exenatide) prescribing information|AZ Medical Information. Available at: <https://medicalinformation.astrazeneca-us.com/home/prescribing-information/byetta.html>. Accessed April 6, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=BYETTA%c2%ae+\(Exenatide\)+prescribing+information%7cAZ+Medical+Information.)



[79]. Victoza [prescribing information]. Available at: <https://www.novo-pi.com/victoza.pdf>. Accessed September 16, 2019.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Victoza+%5bprescribing+information%5d.)



[80]. Adlyxin [prescribing information]. Available at: <https://products.sanofi.us/Adlyxin/Adlyxin.pdf>. Accessed August 30, 2019.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Adlyxin+%5bprescribing+information%5d.)



[81]. Commissioner, Office of the. FDA approves first oral GLP-1 treatment for type 2 diabetes. FDA. Available at: <https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-glp-1-treatment-type-2-diabetes>. Accessed March 24, 2020.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=FDA+approves+first+oral+GLP-1+treatment+for+type+2+diabetes.)



[82]. Bydureon [prescribing information]. Available at: <https://www.azpicentral.com/bydureon/bydureon.pdf#page=1>. Accessed August 30, 2019.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Bydureon+%5bprescribing+information%5d.)



[83]. Pharmaceutical Technology. FDA approves GSK’s Tanzeum injection for type 2 diabetes treatment. Available at: <https://www.pharmaceutical-technology.com/news/newsfda-approves-gsks-tanzeum-injection-for-type-2-diabetes-treatment-4215179/>. Accessed April 15, 2014.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=FDA+approves+GSK%e2%80%99s+Tanzeum+injection+for+type+2+diabetes+treatment.)



[84]. Ozempic [prescribing information]. Available at: <https://www.novo-pi.com/ozempic.pdf>. Accessed August 30, 2019.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Ozempic+%5bprescribing+information%5d.)



[85]. Trulicity [prescribing information]. Available at: <https://uspl.lilly.com/trulicity/trulicity.html#pi>. Accessed August 30, 2019.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Trulicity+%5bprescribing+information%5d.)



[86]. Inc, Novo Nordisk. Novo Nordisk receives FDA approval for Saxenda® (Liraglutide [RDNA Origin] Injection) for chronic weight management. Available at: <https://www.prnewswire.com/news-releases/novo-nordisk-receives-fda-approval-for-saxenda-liraglutide-rdna-origin-injection-for-chronic-weight-management-300013975.html>. Accessed April 7, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Novo+Nordisk+receives+FDA+approval+for+Saxenda%c2%ae+\(Liraglutide+%5bRDNA+Origin%5d+Injection\)+for+chronic+weight+management.)



[87]. Whitten JS. Liraglutide (Saxenda) for weight loss. Am Fam Physician. 2016;94:161–6.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Liraglutide+\(Saxenda\)+for+weight+loss.&publication_year=2016&author=JS+Whitten)



[88]. Gorgojo‐Martínez JJ, Basagoiti‐Carreño B, Sanz‐Velasco A, Serrano‐Moreno C, Almodóvar-Ruiz F. Effectiveness and tolerability of orlistat and liraglutide in patients with obesity in a real-world setting: the XENSOR study. Int J Clin Pract. 2019;73.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effectiveness+and+tolerability+of+orlistat+and+liraglutide+in+patients+with+obesity+in+a+real-world+setting%3a+the+XENSOR+study.&publication_year=2019&author=JJ+Gorgojo%e2%80%90Mart%c3%adnez&author=B+Basagoiti%e2%80%90Carre%c3%b1o&author=A+Sanz%e2%80%90Velasco&author=C+Serrano%e2%80%90Moreno&author=F+Almod%c3%b3var-Ruiz)



[89]. Commissioner, Office of the. FDA approves new drug treatment for chronic weight management, first since 2014. FDA. Available at: <https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014>. Accessed June 21, 2021.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=FDA+approves+new+drug+treatment+for+chronic+weight+management%2c+first+since+2014.)



[90]. Wharton S, Calanna S, Davies M, et al. Gastrointestinal tolerability of once-weekly semaglutide 2.4 Mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Diabetes Obes Metab. 2022;24:94–105.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Gastrointestinal+tolerability+of+once-weekly+semaglutide+2.4+Mg+in+adults+with+overweight+or+obesity%2c+and+the+relationship+between+gastrointestinal+adverse+events+and+weight+loss.&publication_year=2022&author=S+Wharton&author=S+Calanna&author=M+Davies)



[91]. Reyes A. Comparison of Semaglutide versus Liraglutide for Weight Loss in Patients with Obesity. Diabetes in Control. A Free Weekly Diabetes Newsletter for Medical Professionals. Available at: <https://www.diabetesincontrol.com/comparison-of-semaglutide-versus-liraglutide-for-weight-loss-in-patients-with-obesity/>. Accessed October 24, 2024.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Comparison+of+Semaglutide+versus+Liraglutide+for+Weight+Loss+in+Patients+with+Obesity.+Diabetes+in+Control.+A+Free+Weekly+Diabetes+Newsletter+for+Medical+Professionals.&author=A+Reyes)



[92]. Meier JJ. Efficacy of semaglutide in a subcutaneous and an oral formulation. Front Endocrinol. 2021;12:645617.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+of+semaglutide+in+a+subcutaneous+and+an+oral+formulation.&publication_year=2021&author=JJ+Meier)



[93]. Trulicity® (Dulaglutide) is the first and only type 2 diabetes medicine approved to reduce cardiovascular events in adults with and without established cardiovascular disease|Eli Lilly and Company. Available at: <https://investor.lilly.com/news-releases/news-release-details/trulicityr-dulaglutide-first-and-only-type-2-diabetes-medicine>. Accessed April 7, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Trulicity%c2%ae+\(Dulaglutide\)+is+the+first+and+only+type+2+diabetes+medicine+approved+to+reduce+cardiovascular+events+in+adults+with+and+without+established+cardiovascular+disease%7cEli+Lilly+and+Company.)



[94]. Nordisk Novo. Victoza® (Liraglutide) is approved in the US as the only type 2 diabetes treatment indicated to reduce the risk of three major adverse cardiovascular events. Available at: <https://www.prnewswire.com/news-releases/victoza-liraglutide-is-approved-in-the-us-as-the-only-type-2-diabetes-treatment-indicated-to-reduce-the-risk-of-three-major-adverse-cardiovascular-events-300509713.html>. Accessed April 7, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Victoza%c2%ae+\(Liraglutide\)+is+approved+in+the+US+as+the+only+type+2+diabetes+treatment+indicated+to+reduce+the+risk+of+three+major+adverse+cardiovascular+events.&author=Novo+Nordisk)



[95]. AJMC. Semaglutide approved for cardiovascular risk reduction in adults with T2D. Available at: <https://www.ajmc.com/view/semaglutide-approved-for-cardiovascular-risk-reduction-in-adults-with-t2d>. Accessed April 7, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Semaglutide+approved+for+cardiovascular+risk+reduction+in+adults+with+T2D.)



[96]. Tirzepatide results published in the Lancet show superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes with increased cardiovascular risk|Eli Lilly and Company. Available at: <https://investor.lilly.com/news-releases/news-release-details/tirzepatide-results-published-lancet-show-superior-a1c-and-body>. Accessed April 7, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+results+published+in+the+Lancet+show+superior+A1C+and+body+weight+reductions+compared+to+insulin+glargine+in+adults+with+type+2+diabetes+with+increased+cardiovascular+risk%7cEli+Lilly+and+Company.)



[97]. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Semaglutide+and+cardiovascular+outcomes+in+patients+with+type+2+diabetes.&publication_year=2016&author=SP+Marso&author=SC+Bain&author=A+Consoli)



[98]. Husain M, Birkenfeld AL, Donsmark M, et al.; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381:841–51.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Oral+semaglutide+and+cardiovascular+outcomes+in+patients+with+type+2+diabetes.&publication_year=2019&author=M+Husain&author=AL+Birkenfeld&author=M+Donsmark)



[99]. Davies M, Færch L, Jeppesen OK, et al.; STEP 2 Study Group. Semaglutide 2·4 Mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397:971–84.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Semaglutide+2%c2%b74+Mg+once+a+week+in+adults+with+overweight+or+obesity%2c+and+type+2+diabetes+\(STEP+2\)%3a+a+randomised%2c+double-blind%2c+double-dummy%2c+placebo-controlled%2c+phase+3+trial.&publication_year=2021&author=M+Davies&author=L+F%c3%a6rch&author=OK+Jeppesen)



[100]. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384:989–1002.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Once-weekly+semaglutide+in+adults+with+overweight+or+obesity.&publication_year=2021&author=JPH+Wilding&author=RL+Batterham&author=S+Calanna)



[101]. Wadden TA, Bailey TS, Billings LK, et al.; STEP 3 Investigators. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021;325:1403–13.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+subcutaneous+semaglutide+vs+placebo+as+an+adjunct+to+intensive+behavioral+therapy+on+body+weight+in+adults+with+overweight+or+obesity%3a+the+STEP+3+randomized+clinical+trial.&publication_year=2021&author=TA+Wadden&author=TS+Bailey&author=LK+Billings)



[102]. Rubino D, Abrahamsson N, Davies M, et al.; STEP 4 Investigators. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325:1414–25.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+continued+weekly+subcutaneous+semaglutide+vs+placebo+on+weight+loss+maintenance+in+adults+with+overweight+or+obesity%3a+the+STEP+4+randomized+clinical+trial.&publication_year=2021&author=D+Rubino&author=N+Abrahamsson&author=M+Davies)



[103]. Garvey WT, Batterham RL, Bhatta M, et al.; STEP 5 Study Group. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022;28:2083–91.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Two-year+effects+of+semaglutide+in+adults+with+overweight+or+obesity%3a+the+STEP+5+trial.&publication_year=2022&author=WT+Garvey&author=RL+Batterham&author=M+Bhatta)



[104]. Novo Nordisk A/S. Semaglutide effects on cardiovascular outcomes in people with overweight or obesity. Clinicaltrials.gov. Available at: <https://clinicaltrials.gov/study/NCT03574597>. Accessed February 13, 2024.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Semaglutide+effects+on+cardiovascular+outcomes+in+people+with+overweight+or+obesity.+Clinicaltrials.gov.&author=A%2fS+Novo+Nordisk)



[105]. Holman RR, Bethel MA, Mentz RJ, et al.; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effects+of+once-weekly+exenatide+on+cardiovascular+outcomes+in+type+2+diabetes.&publication_year=2017&author=RR+Holman&author=MA+Bethel&author=RJ+Mentz)



[106]. Potts JE, Gray LJ, Brady EM, Khunti K, Davies MJ, Bodicoat DH. The effect of glucagon-like peptide 1 receptor agonists on weight loss in type 2 diabetes: a systematic review and mixed treatment comparison meta-analysis. PLoS One. 2015;10:e0126769.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+effect+of+glucagon-like+peptide+1+receptor+agonists+on+weight+loss+in+type+2+diabetes%3a+a+systematic+review+and+mixed+treatment+comparison+meta-analysis.&publication_year=2015&author=JE+Potts&author=LJ+Gray&author=EM+Brady&author=K+Khunti&author=MJ+Davies&author=DH+Bodicoat)



[107]. Apovian CM, Bergenstal RM, Cuddihy RM, et al. Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. Am J Med. 2010;123:468.e9–17.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effects+of+exenatide+combined+with+lifestyle+modification+in+patients+with+type+2+diabetes.&publication_year=2010&author=CM+Apovian&author=RM+Bergenstal&author=RM+Cuddihy)



[108]. Dushay J, Gao C, Gopalakrishnan GS, et al. Short-term exenatide treatment leads to significant weight loss in a subset of obese women without diabetes. Diabetes Care. 2012;35:4–11.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Short-term+exenatide+treatment+leads+to+significant+weight+loss+in+a+subset+of+obese+women+without+diabetes.&publication_year=2012&author=J+Dushay&author=C+Gao&author=GS+Gopalakrishnan)



[109]. RxList. Bydureon (exenatide): uses, dosage, side effects, interactions, warning. Available at: <https://www.rxlist.com/bydureon-drug.htm>. Accessed April 7, 2022.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Bydureon+\(exenatide\)%3a+uses%2c+dosage%2c+side+effects%2c+interactions%2c+warning.)



[110]. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Liraglutide+and+cardiovascular+outcomes+in+type+2+diabetes.&publication_year=2016&author=SP+Marso&author=GH+Daniels&author=K+Brown-Frandsen)



[111]. Davies MJ, Bergenstal R, Bode B, et al.; NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314:687–99.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+of+liraglutide+for+weight+loss+among+patients+with+type+2+diabetes%3a+the+SCALE+diabetes+randomized+clinical+trial.&publication_year=2015&author=MJ+Davies&author=R+Bergenstal&author=B+Bode)



[112]. Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 Mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE sleep apnea randomized clinical trial. Int J Obes. 2016;40:1310–19.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+liraglutide+3.0+Mg+in+individuals+with+obesity+and+moderate+or+severe+obstructive+sleep+apnea%3a+the+SCALE+sleep+apnea+randomized+clinical+trial.&publication_year=2016&author=A+Blackman&author=GD+Foster&author=G+Zammit)



[113]. Wadden TA, Hollander P, Klein S, et al.; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE maintenance randomized study. Int J Obes (Lond). 2013;37:1443–51.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Weight+maintenance+and+additional+weight+loss+with+liraglutide+after+low-calorie-diet-induced+weight+loss%3a+the+SCALE+maintenance+randomized+study.&publication_year=2013&author=TA+Wadden&author=P+Hollander&author=S+Klein)



[114]. Pi-Sunyer X, Astrup A, Fujioka K, et al.; SCALE Obesity and Prediabetes NN8022-1839 Study Group. A randomized, controlled trial of 3.0 Mg of liraglutide in weight management. N Engl J Med. 2015;373:11–22.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=A+randomized%2c+controlled+trial+of+3.0+Mg+of+liraglutide+in+weight+management.&publication_year=2015&author=X+Pi-Sunyer&author=A+Astrup&author=K+Fujioka)



[115]. Gerstein HC, Colhoun HM, Dagenais GR, et al.; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394:121–30.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Dulaglutide+and+cardiovascular+outcomes+in+type+2+diabetes+\(REWIND\)%3a+a+double-blind%2c+randomised+placebo-controlled+trial.&publication_year=2019&author=HC+Gerstein&author=HM+Colhoun&author=GR+Dagenais)



[116]. Pfeffer MA, Claggett B, Diaz R, et al.; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Lixisenatide+in+patients+with+type+2+diabetes+and+acute+coronary+syndrome.&publication_year=2015&author=MA+Pfeffer&author=B+Claggett&author=R+Diaz)



[117]. Hernandez AF, Green JB, Janmohamed S, et al.; Harmony Outcomes committees and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392:1519–29.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Albiglutide+and+cardiovascular+outcomes+in+patients+with+type+2+diabetes+and+cardiovascular+disease+\(Harmony+outcomes\)%3a+a+double-blind%2c+randomised+placebo-controlled+trial.&publication_year=2018&author=AF+Hernandez&author=JB+Green&author=S+Janmohamed)



[118]. Mihaela Simona P, Păduraru L, Yahya G, Yahya G, Cavalu S. Emerging role of GLP-1 agonists in obesity: a comprehensive review of randomised controlled trials. Int J Mol Sci . 2023;24:10449.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Emerging+role+of+GLP-1+agonists+in+obesity%3a+a+comprehensive+review+of+randomised+controlled+trials.&publication_year=2023&author=P+Mihaela+Simona&author=L+P%c4%83duraru&author=G+Yahya&author=G+Yahya&author=S+Cavalu)



[119]. Jensterle M, Rizzo M, Haluzík M, Janež A. Efficacy of GLP-1 RA approved for weight management in patients with or without diabetes: a narrative review. Adv Ther. 2022;39:2452–67.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+of+GLP-1+RA+approved+for+weight+management+in+patients+with+or+without+diabetes%3a+a+narrative+review.&publication_year=2022&author=M+Jensterle&author=M+Rizzo&author=M+Haluz%c3%adk&author=A+Jane%c5%be)



[120]. Górriz JL, Romera I, Cobo A, O’Brien PD, Merino-Torres JF. Glucagon-like peptide-1 receptor agonist use in people living with type 2 diabetes mellitus and chronic kidney disease: a narrative review of the key evidence with practical considerations. Diabetes Ther. 2022;13:389–421.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Glucagon-like+peptide-1+receptor+agonist+use+in+people+living+with+type+2+diabetes+mellitus+and+chronic+kidney+disease%3a+a+narrative+review+of+the+key+evidence+with+practical+considerations.&publication_year=2022&author=JL+G%c3%b3rriz&author=I+Romera&author=A+Cobo&author=PD+O%e2%80%99Brien&author=JF+Merino-Torres)



[121]. Lisco G, De Tullio A, Disoteo O, et al. Glucagon-like peptide 1 receptor agonists and thyroid cancer: is it the time to be concerned? Endocr Connect. 2023;12.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Glucagon-like+peptide+1+receptor+agonists+and+thyroid+cancer%3a+is+it+the+time+to+be+concerned%3f&publication_year=2023&author=G+Lisco&author=A+De+Tullio&author=O+Disoteo)



[122]. Mitchell SL, Leon DAC, Chaugai S, et al. Pharmacogenetics of hypoglycemia associated with sulfonylurea therapy in usual clinical care. Pharmacogenomics J. 2020;20:831–9.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Pharmacogenetics+of+hypoglycemia+associated+with+sulfonylurea+therapy+in+usual+clinical+care.&publication_year=2020&author=SL+Mitchell&author=DAC+Leon&author=S+Chaugai)



[123]. Chen H, Li XZ, Chen JQ, et al. Comparative efficacy and safety of glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes: a network meta-analysis. Medicine (Baltimore). 2023;102:e34122.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Comparative+efficacy+and+safety+of+glucagon-like+peptide+1+receptor+agonists+for+the+treatment+of+type+2+diabetes%3a+a+network+meta-analysis.&publication_year=2023&author=H+Chen&author=XZ+Li&author=JQ+Chen)



[124]. Moll H, Frey E, Gerber P, et al. GLP-1 receptor agonists for weight reduction in people living with obesity but without diabetes: a living benefit–harm modelling study. EClinicalMedicine. 2024;73:102661–102661.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP-1+receptor+agonists+for+weight+reduction+in+people+living+with+obesity+but+without+diabetes%3a+a+living+benefit%e2%80%93harm+modelling+study.&publication_year=2024&author=H+Moll&author=E+Frey&author=P+Gerber)



[125]. Dong S, Sun C. Can glucagon-like peptide-1 receptor agonists cause acute kidney injury? An analytical study based on post-marketing approval pharmacovigilance data. Front Endocrinol. 2022;13.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Can+glucagon-like+peptide-1+receptor+agonists+cause+acute+kidney+injury%3f+An+analytical+study+based+on+post-marketing+approval+pharmacovigilance+data.&publication_year=2022&author=S+Dong&author=C+Sun)



[126]. Gorgojo-Martínez JJ, Mezquita-Raya P, Carretero-Gómez J, et al. Clinical recommendations to manage gastrointestinal adverse events in patients treated with GLP-1 receptor agonists: a multidisciplinary expert consensus. J Clin Med. 2023;12:145.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Clinical+recommendations+to+manage+gastrointestinal+adverse+events+in+patients+treated+with+GLP-1+receptor+agonists%3a+a+multidisciplinary+expert+consensus.&publication_year=2023&author=JJ+Gorgojo-Mart%c3%adnez&author=P+Mezquita-Raya&author=J+Carretero-G%c3%b3mez)



[127]. Zhao Z, Tang Y, Hu Y, Zhu H, Chen X, Zhao B. Hypoglycemia following the use of glucagon-like peptide-1 receptor agonists: a real-world analysis of post-marketing surveillance data. Ann Transl Med. 2021;9:1482–1482.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Hypoglycemia+following+the+use+of+glucagon-like+peptide-1+receptor+agonists%3a+a+real-world+analysis+of+post-marketing+surveillance+data.&publication_year=2021&author=Z+Zhao&author=Y+Tang&author=Y+Hu&author=H+Zhu&author=X+Chen&author=B+Zhao)



[128]. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1–based therapies. Gastroenterology. 2011;141:150–6.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Pancreatitis%2c+pancreatic%2c+and+thyroid+cancer+with+glucagon-like+peptide-1%e2%80%93based+therapies.&publication_year=2011&author=M+Elashoff&author=AV+Matveyenko&author=B+Gier&author=R+Elashoff&author=PC+Butler)



[129]. Essien UR, Singh B, Swabe G, et al. Association of prescription co-payment with adherence to glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter-2 inhibitor therapies in patients with heart failure and diabetes. JAMA Netw Open. 2023;6:e2316290.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Association+of+prescription+co-payment+with+adherence+to+glucagon-like+peptide-1+receptor+agonist+and+sodium-glucose+cotransporter-2+inhibitor+therapies+in+patients+with+heart+failure+and+diabetes.&publication_year=2023&author=UR+Essien&author=B+Singh&author=G+Swabe)



[130]. Meier JJ, Gallwitz B, Giorgino F. Efficacy of semaglutide in a subcutaneous and an oral formulation. Front Endocrinol. 2021;12:760153.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+of+semaglutide+in+a+subcutaneous+and+an+oral+formulation.&publication_year=2021&author=JJ+Meier&author=B+Gallwitz&author=F+Giorgino)



[131]. Wang JY, Wang QW, Yang XY, et al. GLP−1 receptor agonists for the treatment of obesity: role as a promising approach. Front Endocrinol. 2023;14:1085799.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP%e2%88%921+receptor+agonists+for+the+treatment+of+obesity%3a+role+as+a+promising+approach.&publication_year=2023&author=JY+Wang&author=QW+Wang&author=XY+Yang)



[132]. Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse effects of GLP-1 receptor agonists. Rev Diabetic Stud. 2014;11:202–30.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Adverse+effects+of+GLP-1+receptor+agonists.&publication_year=2014&author=TD+Filippatos&author=TV+Panagiotopoulou&author=MS+Elisaf)



[133]. Samji NS, Verma R, Satapathy SK. Magnitude of nonalcoholic fatty liver disease: western perspective. J Clin Exp Hepatol. 2019;9:497–505.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Magnitude+of+nonalcoholic+fatty+liver+disease%3a+western+perspective.&publication_year=2019&author=NS+Samji&author=R+Verma&author=SK+Satapathy)



[134]. Shen K, Singh AD, Modaresi Esfeh J, Wakim-Fleming J. Therapies for non-alcoholic fatty liver disease: a 2022 update. World J Hepatol. 2022;14:1718–29.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Therapies+for+non-alcoholic+fatty+liver+disease%3a+a+2022+update.&publication_year=2022&author=K+Shen&author=AD+Singh&author=J+Modaresi+Esfeh&author=J+Wakim-Fleming)



[135]. Nevola R, Raffaella E, Imbriani S, et al. GLP-1 receptor agonists in non-alcoholic fatty liver disease: current evidence and future perspectives. N Engl J Med. 2023;24:1703–1703.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=GLP-1+receptor+agonists+in+non-alcoholic+fatty+liver+disease%3a+current+evidence+and+future+perspectives.&publication_year=2023&author=R+Nevola&author=E+Raffaella&author=S+Imbriani)



[136]. Tang A, Rabasa-Lhoret R, Castel H, et al. Effects of insulin glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes: a randomized trial. Diabetes Care. 2015;38:1339–46.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Effects+of+insulin+glargine+and+liraglutide+therapy+on+liver+fat+as+measured+by+magnetic+resonance+in+patients+with+type+2+diabetes%3a+a+randomized+trial.&publication_year=2015&author=A+Tang&author=R+Rabasa-Lhoret&author=H+Castel)



[137]. Zhu K, Kakkar R, Chahal D, Yoshida EM, Hussaini T. Efficacy and safety of semaglutide in non-alcoholic fatty liver disease. World J Gastroenterol. 2023;29:5327–38.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+and+safety+of+semaglutide+in+non-alcoholic+fatty+liver+disease.&publication_year=2023&author=K+Zhu&author=R+Kakkar&author=D+Chahal&author=EM+Yoshida&author=T+Hussaini)



[138]. Reich N, Hölscher C. The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: an in-depth review. Front Neurosci. 2022;16:970925.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=The+neuroprotective+effects+of+glucagon-like+peptide+1+in+Alzheimer%e2%80%99s+and+Parkinson%e2%80%99s+disease%3a+an+in-depth+review.&publication_year=2022&author=N+Reich&author=C+H%c3%b6lscher)



[139]. Swamy S, Noor SM, Mathew RO. Cardiovascular disease in diabetes and chronic kidney disease. J Clin Med. 2023;12:6984.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Cardiovascular+disease+in+diabetes+and+chronic+kidney+disease.&publication_year=2023&author=S+Swamy&author=SM+Noor&author=RO+Mathew)



[140]. Villikudathil AT, Mc Guigan DH, English A. Computational approaches for clinical, genomic and proteomic markers of response to glucagon-like peptide-1 therapy in type-2 diabetes mellitus: an exploratory analysis with machine learning algorithms. Diabetes Metab Syndr. 2024;18:103086.

  * Cited Here | 
  * [Google Scholar](https://scholar.google.com/scholar_lookup?title=Computational+approaches+for+clinical%2c+genomic+and+proteomic+markers+of+response+to+glucagon-like+peptide-1+therapy+in+type-2+diabetes+mellitus%3a+an+exploratory+analysis+with+machine+learning+algorithms.&publication_year=2024&author=AT+Villikudathil&author=DH+Mc+Guigan&author=A+English)



**Keywords:**

cardiovascular; GLP-1 agonists; outcomes; weight

Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.

View full article text

__

### 

#### Source

[Effect of GLP-1 receptor agonists on weight and cardiovascular outcomes: A review](javascript:void\(0\);)

Medicine103(44):e40364, November 01, 2024. 

____

[__](javascript:void\(0\); "Previous") [__](javascript:void\(0\); "Next")

  * [ __ Full-Size ](javascript:void\(0\);)
  * [ __ Email ](javascript:void\(0\);)
  * __ \+ Favorites
  * __ Export
  * [ __ View in Gallery ](javascript:void\(0\);)



[](javascript:)

** Email to Colleague**

__

Colleague's E-mail is Invalid

Your Name: 

Colleague's Email:

Separate multiple e-mails with a (;).

Message: 

Thought you might appreciate this item(s) I saw in Medicine.

__

  


Your message has been successfully sent to your colleague.

  


__

  


Some error has occurred while processing your request. Please try after some time.

  


##  Readers Of this Article Also Read 

  * ### [Effect of SARS-CoV-2 vaccination on the outcomes of assisted reproductive...](https://journals.lww.com/md-journal/fulltext/2024/08160/effect_of_sars_cov_2_vaccination_on_the_outcomes.14.aspx)

  * ### [Research progress on human papillomavirus-negative cervical cancer: A review](https://journals.lww.com/md-journal/fulltext/2024/10110/research_progress_on_human_papillomavirus_negative.88.aspx)

  * ### [A novel KIAA0196 mutation in a Chinese patient with spastic paraplegia 8: A...](https://journals.lww.com/md-journal/fulltext/2018/05180/a_novel_kiaa0196_mutation_in_a_chinese_patient.41.aspx)

  * ### [Reconstruction methods after radical proximal gastrectomy: A systematic review](https://journals.lww.com/md-journal/fulltext/2018/03160/reconstruction_methods_after_radical_proximal.14.aspx)

  * ### [Effect of perioperative oral care on prevention of postoperative pneumonia...](https://journals.lww.com/md-journal/fulltext/2017/08180/effect_of_perioperative_oral_care_on_prevention_of.4.aspx)




__Back to Top

![Current Issue Cover Image](https://images.journals.lww.com/md-journal/XLargeThumb.00005792-202502210-00000.CV.jpeg)

#### Never Miss an Issue

Get new journal Tables of Contents sent right to your email inbox Get New Issue Alerts

#### Browse Journal Content

  * [Most Popular](/md-journal/pages/viewallmostpopulararticles.aspx)
  * [For Authors](/md-journal/_layouts/1033/oaks.journals/informationforauthors.aspx)
  * [About the Journal](/md-journal/pages/aboutthejournal.aspx)
  * [Past Issues](/md-journal/pages/issuelist.aspx)
  * [Current Issue](/md-journal/pages/currenttoc.aspx)
  * [Register on the website](https://journals.lww.com/md-journal/pages/register.aspx?ContextUrl=%2fmd-journal%2ffulltext%2f2024%2f11010%2feffect_of_glp_1_receptor_agonists_on_weight_and.56.aspx)
  * [Get eTOC Alerts](javascript:javascript: alerts_ShowSubscribeeTOCPopup\('Medicine','md-journal','eTOC', 'eTOC'\);;)



#### For Journal Authors

  * [Submit an article](https://preflight.paperpal.com/partner/wolterskluwer/medicine/submit)
  * [How to publish with us](https://wkauthorservices.editage.com/)



#### Customer Service

__ Live Chat

__ Chat Offline

  * [Browse the help center](https://wkhlrp.my.site.com/LippincottOnlineHelpCenter/s/)
  * [Help](https://wkhealth.force.com/lwwonline/s/topic/0TO0V000001YgLZWA0/lww-online?tabset-ddbfe=2)
  * Contact us at:
    * Support:

[Submit a Service Request](https://www.tfaforms.com/4966570)
    * TEL: (USA):

TEL: (Int’l):

800-638-3030 (within USA)

301-223-2300 (international)



  * Cookie Settings



  * [ ![]() __](https://www.facebook.com/medicinelww/ "Facebook")
  * [ ![]() __](https://X.com/Medicinelww "X")



  * [Privacy Policy](https://journals.lww.com/md-journal/_layouts/oaks.journals/privacy.aspx)
  * [Legal Disclaimer](https://journals.lww.com/md-journal/_layouts/oaks.journals/disclaimer.aspx)
  * [Terms of Use](https://journals.lww.com/md-journal/_layouts/oaks.journals/terms.aspx)
  * [Open Access Policy](https://www.wolterskluwer.com/en/solutions/lippincott-journals/lippincott-open-access)
  * [ ![]() __Feedback](/md-journal/Secure/Pages/feedback.aspx)
  * [ ![]() __Sitemap](http://journals.lww.com/md-journal/_layouts/1033/oaks.journals/sitemap.aspx)
  * [ ![]() __RSS Feeds](/md-journal/_layouts/OAKS.Journals/feeds.aspx)
  * [ ![]() __LWW Journals](https://lww.com/)
  * [Your California Privacy Choices](https://privacyportal-de.onetrust.com/webform/2217e117-526b-4696-8a98-8c402f8f2b81/5b049ba3-0106-4b77-a7da-5d12238c90a4) ![California Consumer Privacy Act \(CCPA\) Opt-Out Icon](/_layouts/1033/IMAGES/OAKS.Journals/CAPrivacyPolicy.png)


  * Copyright (C) 2025
  * [The Authors. Published by Wolters Kluwer Health, Inc.](https://www.wolterskluwer.com/en/health)


url: https://www.mdpi.com/2079-9721/12/9/204
scrape_date: 2025-02-28T11:50:24.803331
content_type: markdown
hash: fc2b497e95feb83e5cbced20896a2e91f9d51d64bd9588851afd55f8156084e8
title:
The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies

content:
__

Next Article in Journal  


[Medication-Related Osteonecrosis of the Jaw: A Systematic Review of Case Reports and Case Series](/2079-9721/12/9/205)

Next Article in Special Issue  


[Mitochondrial Dysfunction and Risk Factors for Noncommunicable Diseases: From Basic Concepts to Future Prospective](/2079-9721/12/11/277)

__

Previous Article in Journal  


[Uptake and Effectiveness of Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine during Pregnancy in Africa: A Scoping Review](/2079-9721/12/9/203)

Previous Article in Special Issue  


[Therapeutic Effects of Semaglutide on Nonalcoholic Fatty Liver Disease with Type 2 Diabetes Mellitus and Obesity: An Open-Label Controlled Trial](/2079-9721/12/8/186)

## Journals

[Active Journals](/about/journals) [Find a Journal](/about/journalfinder) [Journal Proposal](/about/journals/proposal) [Proceedings Series](/about/proceedings)

## [Topics ](/topics)

## Information

[For Authors](/authors) [For Reviewers](/reviewers) [For Editors](/editors) [For Librarians](/librarians) [For Publishers](/publishing_services) [For Societies](/societies) [For Conference Organizers](/conference_organizers)

[Open Access Policy](/openaccess) [Institutional Open Access Program](/ioap) [Special Issues Guidelines](/special_issues_guidelines) [Editorial Process](/editorial_process) [Research and Publication Ethics](/ethics) [Article Processing Charges](/apc) [Awards](/awards) [Testimonials](/testimonials)

## [Author Services ](/authors/english)

## Initiatives

[Sciforum](https://sciforum.net) [MDPI Books](https://www.mdpi.com/books) [Preprints.org](https://www.preprints.org) [Scilit](https://www.scilit.com) [SciProfiles](https://sciprofiles.com) [Encyclopedia](https://encyclopedia.pub) [JAMS](https://jams.pub) [Proceedings Series](/about/proceedings)

## About

[Overview](/about) [Contact](/about/contact) [Careers](https://careers.mdpi.com) [News](/about/announcements) [Press](/about/press) [Blog](http://blog.mdpi.com/)

[Sign In / Sign Up](/user/login)

## Notice

You can make submissions to other journals [here](https://susy.mdpi.com/user/manuscripts/upload). 

_clear_

## Notice

You are accessing a machine-readable page. In order to be human-readable, please install an RSS reader. 

Continue Cancel

_clear_

All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to <https://www.mdpi.com/openaccess>. 

Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial original Article that involves several techniques or approaches, provides an outlook for future research directions and describes possible research applications. 

Feature papers are submitted upon individual invitation or recommendation by the scientific editors and must receive positive feedback from the reviewers. 

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal. 

Original Submission Date Received: . 

You seem to have javascript disabled. Please note that many of the page functionalities won't work as expected without javascript enabled. 

[ ![](https://pub.mdpi-res.com/img/design/mdpi-pub-logo-black-small1.svg?da3a8dcae975a41c?1740558760) ](/)

_clear_ [ _zoom_out_map_ ](/toggle_desktop_layout_cookie "Toggle desktop layout") _search_ _menu_

[ ![](https://pub.mdpi-res.com/img/design/mdpi-pub-logo-black-small1.svg?da3a8dcae975a41c?1740558760) ](/)

  * [Journals](/about/journals)
    *       * [ Active Journals ](/about/journals)
      * [ Find a Journal ](/about/journalfinder)
      * [ Journal Proposal ](/about/journals/proposal)
      * [ Proceedings Series ](/about/proceedings)

  * [Topics](/topics)
  * [Information](/authors)
    *       * [For Authors](/authors)
      * [For Reviewers](/reviewers)
      * [For Editors](/editors)
      * [For Librarians](/librarians)
      * [For Publishers](/publishing_services)
      * [For Societies](/societies)
      * [For Conference Organizers](/conference_organizers)

      * [Open Access Policy](/openaccess)
      * [Institutional Open Access Program](/ioap)
      * [Special Issues Guidelines](/special_issues_guidelines)
      * [Editorial Process](/editorial_process)
      * [Research and Publication Ethics](/ethics)
      * [Article Processing Charges](/apc)
      * [Awards](/awards)
      * [Testimonials](/testimonials)

  * [Author Services](/authors/english)
  * [Initiatives](/about/initiatives)
    *       * [ Sciforum ](https://sciforum.net)
      * [ MDPI Books ](https://www.mdpi.com/books)
      * [ Preprints.org ](https://www.preprints.org)
      * [ Scilit ](https://www.scilit.com)
      * [ SciProfiles ](https://sciprofiles.com)
      * [ Encyclopedia ](https://encyclopedia.pub)
      * [ JAMS ](https://jams.pub)
      * [ Proceedings Series ](/about/proceedings)

  * [About](/about)
    *       * [ Overview ](/about)
      * [ Contact ](/about/contact)
      * [ Careers ](https://careers.mdpi.com)
      * [ News ](/about/announcements)
      * [ Press ](/about/press)
      * [ Blog ](http://blog.mdpi.com/)




[Sign In / Sign Up](/user/login) [Submit](            https://susy.mdpi.com/user/manuscripts/upload?journal=diseases
    )

 

 

Search for Articles:

Title / Keyword

Author / Affiliation / Email

Journal

All Journals Acoustics  Acta Microbiologica Hellenica (AMH)  Actuators  Adhesives  Administrative Sciences  Adolescents  Advances in Respiratory Medicine (ARM)  Aerobiology  Aerospace  Agriculture  AgriEngineering  Agrochemicals  Agronomy  AI  AI Sensors  Air  Algorithms  Allergies  Alloys  Analytica  Analytics  Anatomia  Anesthesia Research  Animals  Antibiotics  Antibodies  Antioxidants  Applied Biosciences  Applied Mechanics  Applied Microbiology  Applied Nano  Applied Sciences  Applied System Innovation (ASI)  AppliedChem  AppliedMath  Aquaculture Journal  Architecture  Arthropoda  Arts  Astronomy  Atmosphere  Atoms  Audiology Research  Automation  Axioms  Bacteria  Batteries  Behavioral Sciences  Beverages  Big Data and Cognitive Computing (BDCC)  BioChem  Bioengineering  Biologics  Biology  Biology and Life Sciences Forum  Biomass  Biomechanics  BioMed  Biomedicines  BioMedInformatics  Biomimetics  Biomolecules  Biophysica  Biosensors  Biosphere  BioTech  Birds  Blockchains  Brain Sciences  Buildings  Businesses  C (Journal of Carbon Research)  Cancers  Cardiogenetics  Catalysts  Cells  Ceramics  Challenges  ChemEngineering  Chemistry  Chemistry Proceedings  Chemosensors  Children  Chips  CivilEng  Clean Technologies (Clean Technol.)  Climate  Clinical and Translational Neuroscience (CTN)  Clinical Bioenergetics  Clinics and Practice  Clocks & Sleep  Coasts  Coatings  Colloids and Interfaces  Colorants  Commodities  Complexities  Complications  Compounds  Computation  Computer Sciences & Mathematics Forum  Computers  Condensed Matter  Conservation  Construction Materials  Corrosion and Materials Degradation (CMD)  Cosmetics  COVID  Craniomaxillofacial Trauma & Reconstruction (CMTR)  Crops  Cryo  Cryptography  Crystals  Current Issues in Molecular Biology (CIMB)  Current Oncology  Dairy  Data  Dentistry Journal  Dermato  Dermatopathology  Designs  Diabetology  Diagnostics  Dietetics  Digital  Disabilities  Diseases  Diversity  DNA  Drones  Drugs and Drug Candidates (DDC)  Dynamics  Earth  Ecologies  Econometrics  Economies  Education Sciences  Electricity  Electrochem  Electronic Materials  Electronics  Emergency Care and Medicine  Encyclopedia  Endocrines  Energies  Energy Storage and Applications (ESA)  Eng  Engineering Proceedings  Entropy  Environmental and Earth Sciences Proceedings  Environments  Epidemiologia  Epigenomes  European Burn Journal (EBJ)  European Journal of Investigation in Health, Psychology and Education (EJIHPE)  Fermentation  Fibers  FinTech  Fire  Fishes  Fluids  Foods  Forecasting  Forensic Sciences  Forests  Fossil Studies  Foundations  Fractal and Fractional (Fractal Fract)  Fuels  Future  Future Internet  Future Pharmacology  Future Transportation  Galaxies  Games  Gases  Gastroenterology Insights  Gastrointestinal Disorders  Gastronomy  Gels  Genealogy  Genes  Geographies  GeoHazards  Geomatics  Geometry  Geosciences  Geotechnics  Geriatrics  Glacies  Gout, Urate, and Crystal Deposition Disease (GUCDD)  Grasses  Green Health  Hardware  Healthcare  Hearts  Hemato  Hematology Reports  Heritage  Histories  Horticulturae  Hospitals  Humanities  Humans  Hydrobiology  Hydrogen  Hydrology  Hygiene  Immuno  Infectious Disease Reports  Informatics  Information  Infrastructures  Inorganics  Insects  Instruments  Intelligent Infrastructure and Construction  International Journal of Environmental Research and Public Health (IJERPH)  International Journal of Financial Studies (IJFS)  International Journal of Molecular Sciences (IJMS)  International Journal of Neonatal Screening (IJNS)  International Journal of Orofacial Myology and Myofunctional Therapy (IJOM)  International Journal of Plant Biology (IJPB)  International Journal of Topology  International Journal of Translational Medicine (IJTM)  International Journal of Turbomachinery, Propulsion and Power (IJTPP)  International Medical Education (IME)  Inventions  IoT  ISPRS International Journal of Geo-Information (IJGI)  J  Journal of Ageing and Longevity (JAL)  Journal of Cardiovascular Development and Disease (JCDD)  Journal of Clinical & Translational Ophthalmology (JCTO)  Journal of Clinical Medicine (JCM)  Journal of Composites Science (J. Compos. Sci.)  Journal of Cybersecurity and Privacy (JCP)  Journal of Dementia and Alzheimer's Disease (JDAD)  Journal of Developmental Biology (JDB)  Journal of Experimental and Theoretical Analyses (JETA)  Journal of Eye Movement Research (JEMR)  Journal of Functional Biomaterials (JFB)  Journal of Functional Morphology and Kinesiology (JFMK)  Journal of Fungi (JoF)  Journal of Imaging (J. Imaging)  Journal of Intelligence (J. Intell.)  Journal of Low Power Electronics and Applications (JLPEA)  Journal of Manufacturing and Materials Processing (JMMP)  Journal of Marine Science and Engineering (JMSE)  Journal of Market Access & Health Policy (JMAHP)  Journal of Mind and Medical Sciences (JMMS)  Journal of Molecular Pathology (JMP)  Journal of Nanotheranostics (JNT)  Journal of Nuclear Engineering (JNE)  Journal of Otorhinolaryngology, Hearing and Balance Medicine (JOHBM)  Journal of Parks  Journal of Personalized Medicine (JPM)  Journal of Pharmaceutical and BioTech Industry (JPBI)  Journal of Respiration (JoR)  Journal of Risk and Financial Management (JRFM)  Journal of Sensor and Actuator Networks (JSAN)  Journal of the Oman Medical Association (JOMA)  Journal of Theoretical and Applied Electronic Commerce Research (JTAER)  Journal of Vascular Diseases (JVD)  Journal of Xenobiotics (JoX)  Journal of Zoological and Botanical Gardens (JZBG)  Journalism and Media  Kidney and Dialysis  Kinases and Phosphatases  Knowledge  LabMed  Laboratories  Land  Languages  Laws  Life  Limnological Review  Lipidology  Liquids  Literature  Livers  Logics  Logistics  Lubricants  Lymphatics  Machine Learning and Knowledge Extraction (MAKE)  Machines  Macromol  Magnetism  Magnetochemistry  Marine Drugs  Materials  Materials Proceedings  Mathematical and Computational Applications (MCA)  Mathematics  Medical Sciences  Medical Sciences Forum  Medicina  Medicines  Membranes  Merits  Metabolites  Metals  Meteorology  Methane  Methods and Protocols (MPs)  Metrics  Metrology  Micro  Microbiology Research  Micromachines  Microorganisms  Microplastics  Microwave  Minerals  Mining  Modelling  Modern Mathematical Physics  Molbank  Molecules  Multimedia  Multimodal Technologies and Interaction (MTI)  Muscles  Nanoenergy Advances  Nanomanufacturing  Nanomaterials  NDT  Network  Neuroglia  Neurology International  NeuroSci  Nitrogen  Non-Coding RNA (ncRNA)  Nursing Reports  Nutraceuticals  Nutrients  Obesities  Oceans  Onco  Optics  Oral  Organics  Organoids  Osteology  Oxygen  Parasitologia  Particles  Pathogens  Pathophysiology  Pediatric Reports  Pets  Pharmaceuticals  Pharmaceutics  Pharmacoepidemiology  Pharmacy  Philosophies  Photochem  Photonics  Phycology  Physchem  Physical Sciences Forum  Physics  Physiologia  Plants  Plasma  Platforms  Pollutants  Polymers  Polysaccharides  Populations  Poultry  Powders  Proceedings  Processes  Prosthesis  Proteomes  Psychiatry International  Psychoactives  Psychology International  Publications  Purification  Quantum Beam Science (QuBS)  Quantum Reports  Quaternary  Radiation  Reactions  Real Estate  Receptors  Recycling  Regional Science and Environmental Economics (RSEE)  Religions  Remote Sensing  Reports  Reproductive Medicine (Reprod. Med.)  Resources  Rheumato  Risks  Robotics  Ruminants  Safety  Sci  Scientia Pharmaceutica (Sci. Pharm.)  Sclerosis  Seeds  Sensors  Separations  Sexes  Signals  Sinusitis  Smart Cities  Social Sciences  Société Internationale d’Urologie Journal (SIUJ)  Societies  Software  Soil Systems  Solar  Solids  Spectroscopy Journal  Sports  Standards  Stats  Stresses  Surfaces  Surgeries  Surgical Techniques Development  Sustainability  Sustainable Chemistry  Symmetry  SynBio  Systems  Targets  Taxonomy  Technologies  Telecom  Textiles  Thalassemia Reports  Therapeutics  Thermo  Time and Space  Tomography  Tourism and Hospitality  Toxics  Toxins  Transplantology  Trauma Care  Trends in Higher Education  Tropical Medicine and Infectious Disease (TropicalMed)  Universe  Urban Science  Uro  Vaccines  Vehicles  Venereology  Veterinary Sciences  Vibration  Virtual Worlds  Viruses  Vision  Waste  Water  Wild  Wind  Women  World  World Electric Vehicle Journal (WEVJ)  Youth  Zoonotic Diseases 

Article Type

All Article Types Article Review Communication Editorial Abstract Book Review Brief Communication Brief Report Case Report Clinicopathological Challenge Comment Commentary Concept Paper Conference Report Correction Creative Data Descriptor Discussion Entry Essay Expression of Concern Extended Abstract Field Guide Giants in Urology Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Urology around the World Viewpoint

 

 

Advanced Search

 

Section

Special Issue

Volume

Issue

Number

Page

 

Logical OperatorOperator

AND OR

Search Text

Search Type

All fields Title Abstract Keywords Authors Affiliations Doi Full Text References

 

_add_circle_outline_

_remove_circle_outline_

 

 

[Journals](/about/journals)

[Diseases](/journal/diseases)

[Volume 12](/2079-9721/12)

[Issue 9](/2079-9721/12/9)

10.3390/diseases12090204

[ ![diseases-logo](https://pub.mdpi-res.com/img/journals/diseases-logo.png?8600e93ff98dbf14) ](/journal/diseases)

[ Submit to this Journal ](https://susy.mdpi.com/user/manuscripts/upload?form%5Bjournal_id%5D%3D126) [ Review for this Journal ](https://susy.mdpi.com/volunteer/journals/review) [ Propose a Special Issue ](/journalproposal/sendproposalspecialissue/diseases)

► ▼ Article Menu 

## Article Menu

  * Academic Editor

[![](/bundles/mdpisciprofileslink/img/unknown-user.png)Pedro Bullon](https://sciprofiles.com/profile/107503?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)

  * [Subscribe SciFeed](/2079-9721/12/9/204/scifeed_display)
  * Related Info Links

    * [PubMed/Medline](http://www.ncbi.nlm.nih.gov/sites/entrez/39329873)
    * [Google Scholar](https://scholar.google.com/scholar?q=The%20Effect%20of%20Tirzepatide%20on%20Body%20Composition%20in%20People%20with%20Overweight%20and%20Obesity%3A%20A%20Systematic%20Review%20of%20Randomized%2C%20Controlled%20Studies)

  * More by Authors Links

    * on DOAJ

      * [Rochira, V.](http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Vincenzo%20Rochira%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D)
      *       * [Greco, C.](http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Carla%20Greco%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D)
      *       * [Boni, S.](http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Stefano%20Boni%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D)
      *       * [Costantino, F.](http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Francesco%20Costantino%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D)
      *       * [Dalla Valentina, L.](http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Leonardo%20Dalla%20Valentina%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D)
      *       * [Zanni, E.](http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Eleonora%20Zanni%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D)
      *       * [Itani, L.](http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Leila%20Itani%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D)
      *       * [El Ghoch, M.](http://doaj.org/search/articles?source=%7B%22query%22%3A%7B%22query_string%22%3A%7B%22query%22%3A%22%5C%22Marwan%20El%20Ghoch%5C%22%22%2C%22default_operator%22%3A%22AND%22%2C%22default_field%22%3A%22bibjson.author.name%22%7D%7D%7D)
      *     * on Google Scholar

      * [Rochira, V.](https://scholar.google.com/scholar?q=Vincenzo%20Rochira)
      *       * [Greco, C.](https://scholar.google.com/scholar?q=Carla%20Greco)
      *       * [Boni, S.](https://scholar.google.com/scholar?q=Stefano%20Boni)
      *       * [Costantino, F.](https://scholar.google.com/scholar?q=Francesco%20Costantino)
      *       * [Dalla Valentina, L.](https://scholar.google.com/scholar?q=Leonardo%20Dalla%20Valentina)
      *       * [Zanni, E.](https://scholar.google.com/scholar?q=Eleonora%20Zanni)
      *       * [Itani, L.](https://scholar.google.com/scholar?q=Leila%20Itani)
      *       * [El Ghoch, M.](https://scholar.google.com/scholar?q=Marwan%20El%20Ghoch)
      *     * on PubMed

      * [Rochira, V.](http://www.pubmed.gov/?cmd=Search&term=Vincenzo%20Rochira)
      *       * [Greco, C.](http://www.pubmed.gov/?cmd=Search&term=Carla%20Greco)
      *       * [Boni, S.](http://www.pubmed.gov/?cmd=Search&term=Stefano%20Boni)
      *       * [Costantino, F.](http://www.pubmed.gov/?cmd=Search&term=Francesco%20Costantino)
      *       * [Dalla Valentina, L.](http://www.pubmed.gov/?cmd=Search&term=Leonardo%20Dalla%20Valentina)
      *       * [Zanni, E.](http://www.pubmed.gov/?cmd=Search&term=Eleonora%20Zanni)
      *       * [Itani, L.](http://www.pubmed.gov/?cmd=Search&term=Leila%20Itani)
      *       * [El Ghoch, M.](http://www.pubmed.gov/?cmd=Search&term=Marwan%20El%20Ghoch)
      * 
/ajax/scifeed/subscribe

Article Views

Citations -

  * Table of Contents




Altmetric _share_ Share _announcement_ Help [ _format_quote_ Cite ](javascript:void\(0\);) [ _question_answer_ Discuss in SciProfiles ](https://sciprofiles.com/discussion-groups/public/10.3390/diseases12090204?utm_source=mpdi.com&utm_medium=publication&utm_campaign=discuss_in_sciprofiles "Discuss in Sciprofiles")

## Need Help?

### Support

Find support for a specific problem in the support section of our website. 

[ Get Support ](/about/contactform)

### Feedback

Please let us know what you think of our products and services. 

[ Give Feedback ](/feedback/send)

### Information

Visit our dedicated information section to learn more about MDPI. 

[ Get Information ](/authors)

_clear_

## JSmol Viewer

_clear_

_first_page_

[ __Download PDF](/2079-9721/12/9/204/pdf?version=1725595471)

_settings_

[ Order Article Reprints ](/2079-9721/12/9/204/reprints)

Font Type: 

_Arial_ _Georgia_ _Verdana_

Font Size:

Aa Aa Aa

Line Spacing:

__ __ __

Column Width:

__ __ __

Background:

__

__

__

Open AccessSystematic Review

#  The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies 

by 

Vincenzo Rochira

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Vincenzo Rochira

[ SciProfiles ](https://sciprofiles.com/profile/1441639?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Vincenzo%20Rochira)[ Preprints.org ](https://www.preprints.org/search?search1=Vincenzo%20Rochira&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Vincenzo%20Rochira)

1,2[ __](/cdn-cgi/l/email-protection#022d616c662f61656b2d6e2d676f636b6e2f72706d766761766b6d6c21323233643534333a33373331333a3261333b373a3236333b3337336733643236333531343231333a33643360333b32363331373a33643230)[![](https://pub.mdpi-res.com/img/design/orcid.png?0465bc3812adeb52?1740558760)](https://orcid.org/0000-0001-8169-0696),

Carla Greco

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Carla Greco

[ SciProfiles ](https://sciprofiles.com/profile/1783311?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Carla%20Greco)[ Preprints.org ](https://www.preprints.org/search?search1=Carla%20Greco&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Carla%20Greco)

1,2[ __](/cdn-cgi/l/email-protection#b59ad6dbd198d6d2dc9ad99ad0d8d4dcd998c5c7dac1d0d6c1dcdadb96858585878386848485d38587858184848583858585d68786848385d185d485d085d68484858381d185d48482)[![](https://pub.mdpi-res.com/img/design/orcid.png?0465bc3812adeb52?1740558760)](https://orcid.org/0000-0002-9675-3677),

Stefano Boni

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Stefano Boni

[ SciProfiles ](https://sciprofiles.com/profile/3757593?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Stefano%20Boni)[ Preprints.org ](https://www.preprints.org/search?search1=Stefano%20Boni&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Stefano%20Boni)

1,2[ __](/cdn-cgi/l/email-protection#88a7ebe6eca5ebefe1a7e4a7ede5e9e1e4a5f8fae7fcedebfce1e7e6abb8b8b8bfbfbbb9beb9bdb9bab9ecb9ebbdecb9b9b9ecb9ebbbbbb9bcb9edb9bab9e9b9eebdecb9b8b9ebb9ed),

Francesco Costantino

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Francesco Costantino

[ SciProfiles ](https://sciprofiles.com/profile/3259557?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Francesco%20Costantino)[ Preprints.org ](https://www.preprints.org/search?search1=Francesco%20Costantino&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Francesco%20Costantino)

1,2[ __](/cdn-cgi/l/email-protection#5e713d303a733d39377132713b333f3732732e2c312a3b3d2a3731307d6e6e6a6668686e6b6e676f6b6f6c6e696e666f6c6e386e666e676b386b6e6c686e6f6e3c6e696e386e3f6a666e6b6e676e3c),

Leonardo Dalla Valentina

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Leonardo Dalla Valentina

[ SciProfiles ](https://sciprofiles.com/profile/3758193?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Leonardo%20Dalla%20Valentina)[ Preprints.org ](https://www.preprints.org/search?search1=Leonardo%20Dalla%20Valentina&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Leonardo%20Dalla%20Valentina)

1,2[ __](/cdn-cgi/l/email-protection#1b3478757f36787c723477347e767a7277366b69746f7e786f727475382b2b2b222d782b282b292b7f2a7e2b232b282b232b7f2b2b2b2b2b7f2a7a2b7f2b2b2b222b292a232b2e2b292b7f29782b282a222a232b2b2b282b282b2c2f292b2e2a23),

Eleonora Zanni

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Eleonora Zanni

[ SciProfiles ](https://sciprofiles.com/profile/author/U1hQNDZFRjloZ0cwZUxiY3hrRXpjMUdId3BnemU4dnVIbjVydTlzRmZxYz0=?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Eleonora%20Zanni)[ Preprints.org ](https://www.preprints.org/search?search1=Eleonora%20Zanni&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Eleonora%20Zanni)

1,2[ __](/cdn-cgi/l/email-protection#436c202d276e20242a6c2f6c262e222a2f6e33312c372620372a2c2d607373737a7576737373227321732272747377772172257377732173217320767776207620767371767371737b73777320737a772173757322737b),

Leila Itani

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Leila Itani

[ SciProfiles ](https://sciprofiles.com/profile/1474872?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Leila%20Itani)[ Preprints.org ](https://www.preprints.org/search?search1=Leila%20Itani&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Leila%20Itani)

3[ __](/cdn-cgi/l/email-protection#f2dd919c96df91959bdd9edd979f939b9edf82809d869791869b9d9cd1c2c2c6c0c491c2c7c3cac296c2c0c2c7c091c297c296c3cbc6c0c2cbc2cac3cbc6c0c2c2c297)[![](https://pub.mdpi-res.com/img/design/orcid.png?0465bc3812adeb52?1740558760)](https://orcid.org/0000-0003-3166-4945)and

Marwan El Ghoch

![](/profiles/57246/thumb/Marwan_El_Ghoch.png)Marwan El Ghoch

[ SciProfiles ](https://sciprofiles.com/profile/57246?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Marwan%20El%20Ghoch)[ Preprints.org ](https://www.preprints.org/search?search1=Marwan%20El%20Ghoch&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Marwan%20El%20Ghoch)

4,*[__](/cdn-cgi/l/email-protection#28074b464c054b4f410744074d4549414405585a475c4d4b5c4147460b18181c1b1e4c181018191849181d181a184d181d1a4c1910181b181c1818181a194e18101c1b181c1911)[![](https://pub.mdpi-res.com/img/design/orcid.png?0465bc3812adeb52?1740558760)](https://orcid.org/0000-0003-4277-4752)

1

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, Italy

2

Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria of Modena, 41126 Modena, Italy

3

Department of Nutrition and Dietetics, Faculty of Health Sciences, Beirut Arab University, Riad El Solh, Beirut 11072809, Lebanon

4

Center for the Study of Metabolism, Body Composition and Lifestyle, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy

*

Author to whom correspondence should be addressed. 

_Diseases_ **2024** , _12_(9), 204; <https://doi.org/10.3390/diseases12090204>

Submission received: 7 August 2024 / Revised: 26 August 2024 / Accepted: 3 September 2024 / Published: 5 September 2024

(This article belongs to the Special Issue [Body Composition, Energy Expenditure and Lifestyle During Obesity Management](        
    /journal/diseases/special_issues/FK3NO7UCMZ
))  


Download _keyboard_arrow_down_

[Download PDF](/2079-9721/12/9/204/pdf?version=1725595471)   
Download PDF with Cover   
Download XML   
[Download Epub](/2079-9721/12/9/204/epub)   


Browse Figure

[ ](https://pub.mdpi-res.com/diseases/diseases-12-00204/article_deploy/html/images/diseases-12-00204-g001.png?1725595590 "
                        <strong>Figure 1</strong><br/>
                                                    <p>The flowchart summarizing the study selection procedure.</p>
                                                ")

[Review Reports](/2079-9721/12/9/204/review_report) [Versions Notes](/2079-9721/12/9/204/notes)

## Abstract

**:**

Tirzepatide (TZP) is a new anti-obesity drug, and little is currently known about its effect on body composition (BC) in people with overweight or obesity. The aim of this study is to conduct a systematic review on the impact of TZP on BC compartments in this population during weight loss programs. Literature searches, study selection, method development, and quality appraisal were performed. The data were synthesized using a narrative approach, in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Of the 1379 papers retrieved, 6 randomized controlled trials met the inclusion criteria and were reviewed, revealing the following findings. Firstly, TZP was shown to result in a significant reduction in total fat mass (FM), visceral adipose tissue (VAT) and waist circumference (WC) between baseline and short as well as intermediate follow-ups. Compared to other anti-obesity medications (e.g., dulaglutide and semaglutide) taken over the same duration, TZP showed a superior decrease in body fat compartments (i.e., total FM, VAT and WC). Finally, the effect of TZP on fat-free mass (FFM) is still uncertain because the findings remain inconclusive. In conclusion, TZP appears to be an effective strategy for achieving significant improvements in body fat and its distribution, but additional investigations are still needed to determine the impact of TZP on lean mass in this population.

Keywords: 

[body composition](/search?q=body+composition); [obesity](/search?q=obesity); [randomized controlled trials](/search?q=randomized+controlled+trials); [systematic review](/search?q=systematic+review); [tirzepatide](/search?q=tirzepatide)




##  1\. Introduction

Obesity is a chronic disease, which represents an increasing global problem, and it has become one of the most serious health conditions worldwide [1]. It is associated with several medical and psychosocial comorbidities that lead to an increase in disability and mortality [2,3]. This has prompted international guidelines to recommend a wide range of weight loss interventions [4,5,6,7]. Several strategies are currently available and used for the management of obesity [2]. The first step and cornerstone approach is weight loss through lifestyle modification programs based on strategies to determine behavioral changes, combined with increased physical activity levels and nutritional recommendations (i.e., low-calorie Mediterranean diets) [8,9]. However, these programs are not always successful, especially in the long term [10]. At the other end of the spectrum, bariatric surgery is a very effective strategy for weight loss [11], but is mostly indicated for individuals with severe obesity (i.e., body mass index (BMI) ≥ 40 kg/m2 or ≥35 kg/m2 with obesity-associated comorbidities) [12]. In addition, it is not exempt from risks and complications [13], and not always a reversible procedure [14]. Moreover, its availability is limited [15], due to the high cost to healthcare systems [16].

In the middle of this spectrum is the anti-obesity drugs strategy. This field has evolved greatly in the past few years, achieving significant advances and determining a new era of obesity management [17]. In particular, a new drug has been developed called Tirzepatide (TZP), which is a combination of glucagon-like peptide-1 (GLP-1) and a glucose-dependent insulin tropic-polypeptide (GIP) receptor co-agonist [18]. This medication showed a high effectiveness in terms of weight loss outcomes that reached almost a 25% weight loss percentage (WL%) over a period of 1.5 years [18]. In addition, TZP was revealed to have beneficial effects in terms of obesity comorbidities beyond WL [19], such as improvements in type 2 diabetes (T2D) [20], as well as cardiovascular diseases (CVDs) [21], non-alcoholic fatty liver disease (NAFLD) [22] and obstructive sleep apnea syndrome (OSAS) [23]. However, TZP has some adverse effects that are mainly gastrointestinal in nature, and among these, nausea and diarrhea are the most frequently reported [24]. Finally, with regard to drug interactions, while initiating TZP, a dose reduction of concomitantly administered insulin or insulin secretagogues (e.g., sulfonylureas) should be carefully considered to avoid hypoglycemia [25]. Moreover, since TZP is known to delay gastric emptying, this can impact the absorption of concomitantly administered oral medications. Caution is therefore needed in relation to medications, as their efficacy is based on threshold concentrations—in particular, those with a narrow range of therapeutic index (e.g., warfarin) [25]. Similarly, patients on oral contraceptives should be instructed to switch to non-oral contraceptive methods [25].

As per its definition, obesity is characterized by an excessive and abnormal accumulation of body fat, especially in the central regions (visceral adipose tissue, VAT) [26]. In addition, a high proportion of people with obesity (40–50%)—especially those in weight management settings, regardless of their age and gender—are also affected by reduced muscle mass and strength and identified as having the commonly referred phenotype of sarcopenic obesity (SO) [27]. In this context, recent studies have been conducted on the effect of TZP on BC compartments. However, overall its impact in this area is still unclear. If we keep in mind the great magnitude of WL determined by TZP, two clinical considerations should be taken into account: first, it is expected that TZP may have a superior effect in terms of FM reduction in comparison to other obesity medications. Second, at the same time it is legitimately questionable whether TZP may also determine a pronounced reduction in FFM due to a high rate of WL, leading to a deterioration in the above-mentioned condition prevalent in people with obesity or, in other words, SO [28]. To the best of our knowledge, no systematic review posing this issue as a primary outcome (i.e., the effect of TZP on BC compartments) has yet been conducted in order to provide an unbiased interpretation of the evidence published to date. In the light of these considerations, the aim of the current study is to systematically review the published literature to determine the effect of TZP on total and segmental BC compartments according to the following population, intervention, comparison, outcome (PICO) statements [29].

####  PICO Statements

We conducted a systematic review on the topic in adherence with the PICO framework [29] as follows:

  * Population (P): Participants with overweight or obesity, however defined (i.e., body mass index (BMI), waist circumference (WC), fat mass (FM), visceral adipose tissue (VAT), etc.), estimated (anthropometry, skinfold thickness, or bioelectrical impedance analysis (BIA)), or measured (dual-energy x-ray absorptiometry (DXA), air displacement plethysmography (ADP), computed tomography (CT) scan, or magnetic resonance imagining (MRI)), with or without comorbidities.

  * Intervention (I): Short-, intermediate-, or long-term weight loss whether or not followed by a period of weight maintenance by means of anti-obesity or anti-diabetes drugs or other interventions (i.e., lifestyle modification).

  * Comparison (C): Weight loss programs involving TZP as a treatment for obesity/overweight, compared to any other anti-obesity or anti-diabetes drug or placebo defined by the authors (whenever available).

  * Outcome (O): Changes in BC variables directly or indirectly measured and their surrogates as follows:

(i)
    

Waist circumference (WC) 

    * Mean difference in WC (cm) between baseline and last available follow-up in the TZP group, however expressed.

    * Comparison in changes in WC (cm) between the TZP group vs. any other anti-obesity or anti-diabetes drugs or placebo, however expressed.

(ii)
    

Fat mass (FM) 

    * Mean difference in FM (kg) between baseline and last available follow-up within the TZP group, however expressed.

    * Comparison in changes in FM (kg) between TZP vs. any other anti-obesity or anti-diabetes drugs or placebo, however expressed.

(iii)
    

Visceral adipose tissue (VAT) 

    * Mean difference in VAT (g, cm2 or liters) between baseline and last available follow-up within the TZP group, however expressed.

    * Comparison in changes in VAT (g, cm2 or liters) in TZP vs. other anti-obesity or anti-diabetes drugs or placebo, however expressed.

(iv)
    

Fat-free mass (FFM) 

    * Mean difference in FFM (kg) between baseline and last available follow-up within TZP group, however expressed.

    * Comparison in changes in FFM (kg) between TZP vs. other anti-obesity or anti-diabetes drugs or placebos, however expressed.




##  2\. Methods

The systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [30] and registered with the International Prospective Register of Systematic Reviews (PROSPERO) as “The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized Controlled Studies” (CRD42024573477).

####  2.1. Inclusion and Exclusion Criteria

We included all papers that considered TZP as an anti-obesity drug for weight loss intervention and evaluated the changes in BC compartments, however they were expressed, before and after TZP, if they met the following inclusion criteria: (i) publications written in English and (ii) original articles exclusively defined as randomized controlled trials (RCTs). Any other work that was identified with another design, such as a prospective/retrospective observational, experimental, or quasi-experimental non-controlled study, as well as review, cross-sectional, non-controlled, or non-original articles (i.e., case reports, editorials, letters to the editor, and book chapters), was excluded.

####  2.2. Information Sources and Search Strategy

The literature search was performed independently and in duplicate by two authors involved in the conduct of the systematic review. The PubMed and Scopus databases were systematically screened using the following Medical Subject Headings (MeSH) terms and their combinations: #1 Tirzepatide; #2 LY3298176; #3 zepbound; #4 body composition*; #5 lean mass; #6 muscle*; #7 muscle loss; #8 fat mass distribution; #9 fat mass; #10 lean mass loss; #11 appendicular lean mass; #12 appendicular lean mass; #13 sarcopenic obesity; #14 sarcopenia; #15 sarco* #16 dual energy x-ray absorptiometry; #17 DXA; #18 DEXA; #19 bioimped*; #20 BIA; #21 VAT; #22 waist circumference*; and #23 waist circ*; #24 total fat mass; #25 adipose tissue; #26 anthropometric measur*; #27 obesity; #28 type 2 diabetes, according to the following combinations: (((#1) OR (#2) OR (#3)) AND ((#4) OR (#5) OR (#6) OR (#7) OR (#8) OR (#9) OR (#10) OR (#11) OR (#12) OR (#13) OR (#14) OR (#15) OR (#16) OR (#17) OR (#18) OR (#19) OR (#20) OR (#21) OR (#22) OR (#23) OR (#24) OR (#25) OR (#26) OR (#27) OR (#28))). 

In addition, a manual search was carried out to retrieve other articles that had not been identified via the initial search strategy. The publication date was not considered an exclusion criterion for the purposes of this systematic review. 

####  2.3. Study Selection and Quality and Risk-of-Bias Assessments

The two investigators involved in the systematic review independently screened the studies according to their method of conduct and whether they would be appropriate to be included. The quality of each study was determined according to the Jadad scale [31], which relies on three different criteria: randomization (two points), blinding (two points) and a description of dropouts (one point). Out of a total of five points, a score ≥ 3 is indicative that the trial is of good quality [31]. Moreover, the included studies underwent a risk-of-bias assessment to determine whether the standards of reporting for RCTs were satisfied [32] according to the following items: the randomization method, allocation sequence concealment, participant blinding, outcome assessor blinding, outcome measurement, interventionist training and clustering, as well as withdrawals, intent-to-treat analyses, and baseline characteristics. Each study was assigned a “yes” for each criterion it satisfied, and a “no” for each it did not, while “not reported” was used where information for evaluation was insufficient or unavailable. Any disagreement was resolved by consensus discussion between both the reviewers and the principal investigator (PI) in order to take a final decision [33].

####  2.4. Data Collection Process and Data Items and Synthesis

Firstly, both the title and abstract of each paper that had been identified through the electronic or manual search strategies were assessed by two independent authors involved in the conduct of the systematic review for language suitability and topic matter relevance. In a second step, the remaining papers were evaluated for their appropriateness in terms of the inclusion criteria and quality of method. The studies that met the inclusion criteria were presented as a narrative synthesis.

##  3\. Results

A total of 1379 papers were retrieved from the initial search, and 355 were immediately eliminated due to being duplicates, with 1024 screened reports remaining. In the first round of screening (titles and abstracts), 996 papers were excluded on the following grounds: the study was (i) written in a language other from English, (ii) was not conducted on humans, (iii) was not identified as an RCT or (iv) was an RCT but did not involve TZP, or people with T2D or obesity. In the second round of the screening of the remaining 28 articles, the full-text papers were assessed for eligibility. Among these, 22 were removed on the following bases: (i) 14 because the participants were on medications other than TZP that might interfere with body weight and BC [20,21,34,35,36,37,38,39,40,41,42,43,44,45]; (ii) two due to the short duration of the TZP treatment [46,47]; (iii) one because it had an open-label lead-in period [48]; and (iv) five for not reporting data related to WC [49,50,51,52,53] (Figure 1).

At the end, six RCTs were available for systematic review and included in the narrative synthesis [22,54,55,56,57,58]. The first author, year of publication, study design, country of conduct, study sample (stratified also by intervention arm), mean baseline BMI and age, follow-up duration, BC assessment method and BC outcomes of each work are reported in Table 1. The Jadad scale checklist indicated that the RCTs (n = 6) were of a high quality (mean score 4.67 points) and had a very low risk of bias (Table 2). 

####  Narrative Synthsesis

Yabe et al. [55] conducted the SURPASS J-mono study in Japan, which included 48 participants with T2D that were randomized to receive TZP at 5, 10 or 15 mg or dulaglutide at 0.75 mg once a week, over a follow-up period of 52 weeks. The baseline mean age and BMI were 58.6 ± 7.5 years and 27.5 ± 3.5 kg/m2 respectively. After 52 weeks of treatment, the total FM decreased in all TZP groups compared to the baseline (−4.1 kg, p < 0.05; −6.8 kg, p < 0.001; and −6.6 kg, p < 0.001 in the 5, 10 and 15 mg TZP groups, respectively). Moreover, the 10 and 15 mg TZP groups showed a superior effect in the reduction of total FM, exceeding that derived from the dulaglutide (−6.6 kg, p < 0.001 and −6.4 kg, p < 0.01, respectively). On the other hand, after 52 weeks of treatment, the FFM dropped significantly in the 10 mg and 15 mg TZP groups from the baseline to week 52 (−1.9 kg, p < 0.01; and −2.3 kg, p < 0.01, respectively), but only in the 15 mg TZP group was it significantly higher than that in the dulaglutide group at week 52 (−2.0 kg, p < 0.05) (Table 1).

Jastreboff et al. [58] performed a multicenter, international RCT that included a total of 2539 individuals with overweight or obesity that were randomized to receive TZP (5, 10 or 15 mg) or a placebo once a week, over a follow-up period of 72 weeks. All the participants were assessed for WC, and at week 72, TZP at any dosage resulted in a greater reduction in WC than the placebo: −14.0 (−14.9 to −13.1) cm, −17.7 (−18.7 to −16.8) cm, −18.5 (−19.3 to −17.6) cm and −4.0 (−5.1 to −2.8) cm in the 5 mg, 10 mg, 15 mg TZP and placebo groups, respectively. In the same study, 255 participants also underwent DXA to assess BC, but DXA data were only available for 160 of those patients at 72 weeks of follow-up [58]. The change in total FM from the baseline to week 72 was −33.9% in the TZP groups, compared with −8.2% in the placebo group, with an estimated treatment difference between TZP and the placebo of 25.7%. Furthermore, the total FFM change from the baseline was −10.9% in the TZP groups, in comparison to −2.6% in the placebo group, with an estimated treatment difference between TZP and the placebo of 8.3%. The total FM-to-FFM ratio decreased in the TZP group from 0.93 (baseline) to 0.70 (at week 72) and from 0.95 (baseline) to 0.88 (at week 72) in the placebo group (Table 1).

Gastaldelli et al. [22] conducted a sub-study of the SURPASS-3 trial that included 296 participants with T2D randomized to receive TZP (5, 10, 15 mg) once a week or titrated insulin degludec once per day, with a follow-up period that lasted for 52 weeks. The mean age was 56.2 ± 9.8 years, and the mean BMI was 33.5 ± 4.8 kg/m2. All the participants underwent an MRI scan at baseline and at week 52 to assess VAT and abdominal subcutaneous adipose tissue (ASAT). Only 246 out of 296 participants had a post-baseline MRI scan. The VAT decreased significantly with 5 mg (−1.10 ± 0.19 L, p < 0.0001), 10 mg (−1.53 ± 0.18 L, p < 0.0001) and 15 mg TZP (−1.65 ± 0.18 L, p < 0.0001), and significantly increased with insulin degludec (0.38 ± 0.18 L, p = 0.04). In addition, ASAT dropped significantly in the TZP groups (−1.4 ± 0.25 L, p < 0.0001; −2.25 ± 0.24 L, p < 0.0001; and −2.05 ± 0.23 L, p < 0.0001 in the 5 mg, 10 mg and 15 mg groups, respectively). A significant increase was found in the insulin degludec group (0.63 ± 0.24 L, p = 0.0092). Moreover, the VAT-to-ASAT ratio percentage declined in the TZP groups (−2 ± 0.62%, p = 0.0014; −4.96 ± 0.56%, and p < 0.0001; −4.36 ± 0.56%, p < 0.0001 in the 5 mg, 10 mg and 15 mg groups, respectively), whereas no significant change was observed in the insulin degludec group (1.06 ± 0.57%, p = 0.065) (Table 1).

In 2023, Heise et al. [54] conducted a sub-analysis of an RCT on the effect of TZP on BC in patients with T2D, in which 117 participants were randomized to receive 15 mg TZP, 1 mg semaglutide or a placebo once a week, over a follow-up period of 28 weeks. Each patient underwent a plethysmography (using the BOD POD) to assess the FM and the FFM at baseline and after 28 weeks of treatment. Only the participants taking weekly TZP or semaglutide exhibited a significant reduction in total FM (36.8 ± 11.5 kg at baseline and 26.9 ± 0.85 kg at week 28 in the TZP group; 35.3 ± 8.0 kg at baseline and 30.7 ± 0.83 kg at week 28 in the semaglutide group; 38.6 ± 10.7 kg at baseline and 36.6 ± 1.11 kg at week 28 in the placebo group) and FFM (57.7 ± 9.3 kg at baseline and 55.8 ± 0.25 kg at week 28 in the TZP group; 56.3 ± 10.3 kg at baseline and 56.7 ± 0.24 kg at week 28 in the semaglutide group; 59.1 ± 10.3 kg at baseline and 57.3 ± 0.32 kg at week 28 in the placebo group) from the baseline. Furthermore, the FM% loss was significantly higher in the group taking TZP versus those receiving semaglutide (−3.1% [4.9, 1.2]; p =0.001), as was the decrease in FFM (−0.8 vs. 1.6 kg; p = 0.018) (Table 1).

Wadden et al. [56] conducted an 84-week (12 + 72 weeks) multicenter, international, randomized, parallel-arm, double-blind, placebo-controlled, phase 3 trial to assess the efficacy of TZP in adults with obesity or overweight who successfully lost ≥5% of their baseline weight during a 12-week lead-in period with an intensive lifestyle intervention. Subsequently, 579 participants were then randomized to receive TZP at the maximum tolerated dose (10 or 15 mg) or a placebo once a week. In the TZP group, 86.4% of participants reached a maximum tolerated dose of 15 mg. At week 72, the change in WC in the TZP group was greater than in the placebo one (−14.6 ± 0.7 cm in the TZP group, +0.2 ± 1.0 cm in the placebo group) (Table 1).

In 2024, Zhao et al. [57] conducted an RCT in China known as the SURMOUNT-CN trial among individuals with overweight or obesity. A total of 210 participants were randomly assigned to receive subcutaneous 10 mg or 15 mg TZP or a placebo once a week, plus a lifestyle intervention, for 52 weeks. The mean age was 36.1 ± 9.1 years, and the mean BMI was 32.3 ± 3.8 kg/m2. At the end of the study, the participants on TZP exhibited a consistent body weight reduction compared to the placebo group, associated, along the same line, with a more pronounced decrease in WC that was dose-dependent on TZP (difference between TZP 10 mg and the placebo, −8.7 cm [95% CI, −11.2 cm to −6.2 cm; p < 0.001]; difference between TZP 15 mg and the placebo, −11.8 cm [95% CI, −14.4 cm to −9.3 cm; p < 0.001]) (Table 1).

##  4\. Discussion

The aim of this paper was to provide preliminary data on the effects of TZP in terms of changes in BC patterns, as well as to compare its impact with that of other anti-obesity medications on these outcomes. The systematic review included six studies that were objectively judged to be mainly of high quality with a very low risk of bias, and it yielded two main findings.

####  4.1. Main Findings

The first was that TZP is associated with a significant reduction in total FM with respect to the baseline over short (i.e., ≤28 weeks) [54] and intermediate (i.e., 52 and 72 weeks) follow-up periods [55,58]. Moreover, the impact of TZP on the decrease in the total FM seems to exceed that of the other anti-obesity drugs (i.e., dulaglutide and semaglutide) and the placebo (lifestyle modification), but this apparently occurs at higher doses of TZP (i.e., 10 and 15 mg) [54,55,58]. Secondly, TZP at any dose appears to determine a significant decrement in VAT with respect to the baseline over the intermediate follow-up period (i.e., 52 weeks), and its effect seemingly exceeds insulin over the same follow-up duration [22]. To support this finding, data deriving from studies on changes in WC—an anthropometric measure widely accepted as a basic method of assessing body composition, specifically representing a surrogate indirect expression of visceral adiposity (i.e., VAT) [59]—reported a significant reduction exceeding that determined by the placebo over the intermediate follow-up periods (i.e., 52 and 72 weeks) [56,57,58]. Therefore, in the bigger picture, TZP may be considered an effective treatment, which determines a significant drop in FM and can improve its distribution, as its effect also seems to be significantly larger when compared to other anti-obesity or anti-diabetes medications used over a similar follow-up duration.

In this systematic review, we are not in a position to explain the exact mechanism behind the additional beneficial impact of TZP on FM and its distribution, since this is still unclear and not fully understood [60]. However, we can speculate that the dual action of the receptor agonist of GLP-1/GIP of TZP, which can act synergically, may at least in part explain its effect on BC compartments. On a general scale, GLP-1RA reduces fat synthesis and deposition through the regulation of adipose tissue (AT) (lipolysis, fatty acid oxidation and adipocyte differentiation) [61], and this specifically seems to determine a decrease in VAT that is more pronounced in comparison to the reduction in SAT [62]. In addition, GLP-1RA is involved in a relevant process defined as the browning of white adipose tissue (WAT), and it also appears that GLP-1RA activates brown adipose tissue (BAT) [63]. On the other hand, the GIP RA reduces WAT storage expansion, as well as the lipid spillover from the latter to ectopic sites in various organs [64]. This may also explain the greater effect of TZP in reducing BF compared to GLP-1RA alone. This is in line with previous studies that have reported the superiority of TZP with respect to only GLP-1RA on other health outcomes, such as a recent systematic review that showed TZP had a more pronounced effect on HbA1c and weight reduction compared with semaglutide in people with TZP [65].

####  4.2. Clinical Implications

Our systematic review has some clinical implications. Primarily, awareness should be raised among health professionals dealing with obesity and its management through anti-obesity drugs strategies about the effect of TZP on BC compartments from a personalized medicine perspective, especially in terms of body fat and beyond weight loss, and this should be openly discussed with patients.

####  4.3. Strength and Limitations

This study has several strengths. For instance, it is the first systematic review to be conducted on the effect of TZP on BC in patients affected by overweight or obesity with or without T2D and that rigorously adhered to the PRISMA guideline standards; this made its methodology robust, to support the validity of the conclusions related to the findings on body fat compartments. In fact, the studies included in this systematic review were well designed, namely, with suitable randomized samples and appropriate control groups. In other words, the current systematic review was conducted on RCTs that are considered the gold standard in clinical research to assess treatment effectiveness (e.g., medications) [66]. Last but not least, the tools used in the majority of the included studies in this systematic review to assess the BC outcomes (DXA, ADP and MRI) have been widely validated within both clinical and research settings in this population [67].

On the other hand, the findings of this systematic review should be interpreted with caution since it does have some limitations, the foremost being those related to FFM, leading to difficulties in relation to drawing a clear understanding and firm conclusions with regard to the impact of TZP and FFM. In detail, the findings on FFM derived from small-sampled trials, specifically three [54,55,58]. In one study, the findings reported on FFM at different times (i.e., 32 vs. 52 weeks) appear to be inconsistent and do not seem reasonable. In fact, certain methodological limitations can be identified in this study, as the sample size did not exceed 10 participants in each TZP arm, and this may have had an impact on the power of the analysis, as well as the results and conclusions [55]. In addition, in the same study the BIA has been used to measure lean mass (i.e., FFM), while the use of this technique for this aim (i.e., FFM assessment) in people with obesity remains highly debatable [68], especially during weight loss periods, where alterations in hydration status are usually noticed, as reported by the authors themselves in this study [55]. In the second study, despite the fact that the patients on TZP displayed a higher FFM reduction compared to those on semaglutide by only 0.8 kg, the authors considered only the effect of TZP at 15 mg, with no data available on lower TZP doses (i.e., 5 mg and 10 mg), which potentially may have had a more protective effect on lean mass [54]. Similarly, in the last trial, the patients received different doses of TZP, and the analysis was conducted collectively on the entire sample. It was therefore difficult to rule out any potential difference in FFM reduction at different doses [58]. Moreover, on a general scale in our systematic review, we were not able to perform a meta-analysis due to the lack of homogeneity in the BC assessment methods and outcome reporting, which differed widely between the included studies. Finally, the lack of data on adolescents and a longer follow-up duration in adults (i.e., >1–1.5 years) limits the ability to generalize the findings of this systematic review across to the entire population affected by overweight or obesity [69].

####  4.4. New Directions for Future Research

Future works are still necessary on several areas in this topic. Firstly, further investigations that replicate and confirm the findings regarding the beneficial effect of TZP on FM compartments and distribution are vitally needed, since to date the available number of studies is not large, and the majority of them have been conducted in research settings (RCTs), not in real-world clinical ones.

Secondly, regarding FFM, the findings are still inconclusive; therefore, no firm deduction can be made on the matter. In other words, it is still unknown whether TZP may have an adverse or a beneficial impact on FFM during weight loss treatment, from the baseline to follow-up endpoints, or whether TZP can determine a smaller or larger reduction in FFM in comparison to other anti-obesity drugs. On the one hand, TZP seems to determine a higher reduction/deterioration in FFM compared to that of other medications (dulaglutide and semaglutide) by nearly 0.8–2 kg, which appears to occur at the highest dose of TZP (i.e., 15 mg) [54,55]. On the other, TZP apparently causes a greater reduction in fat over lean mass loss by approximately three times [58], which is a similar outcome to what happens during traditional diet-induced weight loss in individuals with obesity, that also accounts for one third (i.e., 20–30%) of FFM [70]. Therefore, the decrease in FFM is an unavoidable phenomenon with TZP, as well as in any other drug or weight loss strategy (i.e., diet, bariatric surgery, etc.). However, we speculate that TZP may have the potential to attenuate the FFM loss in comparison to other anti-obesity drugs due to some novel potential mechanisms that have been recently described in mainly preclinical studies. This includes the impact of GLP-1RA, which appears to increase vascular blood flow and activate glucose delivery into skeletal muscle via the AMP-activated protein kinase (AMPK), thereby promoting muscle synthesis and reducing muscle breakdown [71,72]. In addition, GIP RA was found to suppress intramuscular adipose tissue accumulation [73]. Therefore, it should be expected that TZP could potentially attenuate greater FFM loss and ameliorate sarcopenia. However, this hypothesis should be properly studied in order for it to be confirmed or disproved in clinical settings, due to the importance of this topic. Finally, a better understanding remains necessary of the mechanism of action of TZP, as well as the consequences on health outcomes relating to the BC changes determined by this drug, regardless of the generic effect of weight loss.

##  5\. Conclusions

TZP is a new anti-obesity drug, which has been demonstrated to be effective in terms of weight loss, as well as determining significant improvements in obesity comorbidities. After a careful systematic review of the current evidence, TZP can be recommended because of its beneficial impact on BC compartments, specifically through reducing body fat and central obesity. However, future studies are still needed to investigate the impact of TZP on FFM (i.e., muscle and bone mass).

## Author Contributions

Conceptualization, M.E.G. and V.R.; methodology, M.E.G. and L.I.; investigation, S.B., F.C., L.D.V. and E.Z.; writing—original draft preparation, M.E.G., S.B., F.C., L.D.V., E.Z. and L.I.; writing—review and editing, V.R. and C.G. All authors have read and agreed to the published version of the manuscript.

## Funding

This research received no external funding.

## Conflicts of Interest

The authors declare no conflicts of interest.

## References

  1. Tiwari, A.; Balasundaram, P. Public Health Considerations Regarding Obesity. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2024. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Public+Health+Considerations+Regarding+Obesity&author=Tiwari,+A.&author=Balasundaram,+P.&publication_year=2024)]
  2. El Ghoch, M.; Fakhoury, R. Challenges and New Directions in Obesity Management: Lifestyle Modification Programmes, Pharmacotherapy and Bariatric Surgery. J. Popul. Ther. Clin. Pharmacol. **2019** , 26, e1–e4. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Challenges+and+New+Directions+in+Obesity+Management:+Lifestyle+Modification+Programmes,+Pharmacotherapy+and+Bariatric+Surgery&author=El+Ghoch,+M.&author=Fakhoury,+R.&publication_year=2019&journal=J.+Popul.+Ther.+Clin.+Pharmacol.&volume=26&pages=e1%E2%80%93e4&doi=10.15586/jptcp.v26i2.599&pmid=31577079)] [[CrossRef](https://doi.org/10.15586/jptcp.v26i2.599)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/31577079)]
  3. Abdelaal, M.; le Roux, C.W.; Docherty, N.G. Morbidity and mortality associated with obesity. Ann. Transl. Med. **2017** , 5, 161. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Morbidity+and+mortality+associated+with+obesity&author=Abdelaal,+M.&author=le+Roux,+C.W.&author=Docherty,+N.G.&publication_year=2017&journal=Ann.+Transl.+Med.&volume=5&pages=161&doi=10.21037/atm.2017.03.107&pmid=28480197)] [[CrossRef](https://doi.org/10.21037/atm.2017.03.107)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/28480197)]
  4. Muscogiuri, G.; El Ghoch, M.; Colao, A.; Hassapidou, M.; Yumuk, V.; Busetto, L. Obesity Management Task Force (OMTF) of the European Association for the Study of Obesity (EASO). European Guidelines for Obesity Management in Adults with a Very Low-Calorie Ketogenic Diet: A Systematic Review and Meta-Analysis. Obes. Facts **2021** , 14, 222–245. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Obesity+Management+Task+Force+\(OMTF\)+of+the+European+Association+for+the+Study+of+Obesity+\(EASO\).+European+Guidelines+for+Obesity+Management+in+Adults+with+a+Very+Low-Calorie+Ketogenic+Diet:+A+Systematic+Review+and+Meta-Analysis&author=Muscogiuri,+G.&author=El+Ghoch,+M.&author=Colao,+A.&author=Hassapidou,+M.&author=Yumuk,+V.&author=Busetto,+L.&publication_year=2021&journal=Obes.+Facts&volume=14&pages=222%E2%80%93245&doi=10.1159/000515381&pmid=33882506)] [[CrossRef](https://doi.org/10.1159/000515381)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/33882506)]
  5. Hassapidou, M.; Vlassopoulos, A.; Kalliostra, M.; Govers, E.; Mulrooney, H.; Ells, L.; Salas, X.R.; Muscogiuri, G.; Darleska, T.H.; Busetto, L.; et al. European Association for the Study of Obesity Position Statement on Medical Nutrition Therapy for the Management of Overweight and Obesity in Adults Developed in Collaboration with the European Federation of the Associations of Dietitians. Obes. Facts **2023** , 16, 11–28. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=European+Association+for+the+Study+of+Obesity+Position+Statement+on+Medical+Nutrition+Therapy+for+the+Management+of+Overweight+and+Obesity+in+Adults+Developed+in+Collaboration+with+the+European+Federation+of+the+Associations+of+Dietitians&author=Hassapidou,+M.&author=Vlassopoulos,+A.&author=Kalliostra,+M.&author=Govers,+E.&author=Mulrooney,+H.&author=Ells,+L.&author=Salas,+X.R.&author=Muscogiuri,+G.&author=Darleska,+T.H.&author=Busetto,+L.&publication_year=2023&journal=Obes.+Facts&volume=16&pages=11%E2%80%9328&doi=10.1159/000528083)] [[CrossRef](https://doi.org/10.1159/000528083)]
  6. Yumuk, V.; Tsigos, C.; Fried, M.; Schindler, K.; Busetto, L.; Micic, D.; Toplak, H. Obesity Management Task Force of the European Association for the Study of Obesity. European Guidelines for Obesity Management in Adults. Obes. Facts **2015** , 8, 402–424. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Obesity+Management+Task+Force+of+the+European+Association+for+the+Study+of+Obesity.+European+Guidelines+for+Obesity+Management+in+Adults&author=Yumuk,+V.&author=Tsigos,+C.&author=Fried,+M.&author=Schindler,+K.&author=Busetto,+L.&author=Micic,+D.&author=Toplak,+H.&publication_year=2015&journal=Obes.+Facts&volume=8&pages=402%E2%80%93424&doi=10.1159/000442721&pmid=26641646)] [[CrossRef](https://doi.org/10.1159/000442721)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/26641646)]
  7. Durrer Schutz, D.; Busetto, L.; Dicker, D.; Farpour-Lambert, N.; Pryke, R.; Toplak, H.; Widmer, D.; Yumuk, V.; Schutz, Y. European Practical and Patient-Centred Guidelines for Adult Obesity Management in Primary Care. Obes. Facts **2019** , 12, 40–66. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=European+Practical+and+Patient-Centred+Guidelines+for+Adult+Obesity+Management+in+Primary+Care&author=Durrer+Schutz,+D.&author=Busetto,+L.&author=Dicker,+D.&author=Farpour-Lambert,+N.&author=Pryke,+R.&author=Toplak,+H.&author=Widmer,+D.&author=Yumuk,+V.&author=Schutz,+Y.&publication_year=2019&journal=Obes.+Facts&volume=12&pages=40%E2%80%9366&doi=10.1159/000496183)] [[CrossRef](https://doi.org/10.1159/000496183)]
  8. Kreidieh, D.; Fakhoury, R.; El Ghoch, M. Exploring the effectiveness of a 1.5-Year weight management intervention for adults with obesity. Clin. Nutr. ESPEN **2021** , 42, 215–220. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Exploring+the+effectiveness+of+a+1.5-Year+weight+management+intervention+for+adults+with+obesity&author=Kreidieh,+D.&author=Fakhoury,+R.&author=El+Ghoch,+M.&publication_year=2021&journal=Clin.+Nutr.+ESPEN&volume=42&pages=215%E2%80%93220&doi=10.1016/j.clnesp.2021.01.036)] [[CrossRef](https://doi.org/10.1016/j.clnesp.2021.01.036)]
  9. Wadden, T.A.; Tronieri, J.S.; Butryn, M. Lifestyle modification approaches for the treatment of obesity in adults. Am. Psychol. **2020** , 75, 235–251. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Lifestyle+modification+approaches+for+the+treatment+of+obesity+in+adults&author=Wadden,+T.A.&author=Tronieri,+J.S.&author=Butryn,+M.&publication_year=2020&journal=Am.+Psychol.&volume=75&pages=235%E2%80%93251&doi=10.1037/amp0000517)] [[CrossRef](https://doi.org/10.1037/amp0000517)]
  10. Gostoli, S.; Raimondi, G.; Popa, A.P.; Giovannini, M.; Benasi, G.; Rafanelli, C. Behavioral Lifestyle Interventions for Weight Loss in Overweight or Obese Patients with Type 2 Diabetes: A Systematic Review of the Literature. Curr. Obes. Rep. **2024** , 13, 224–241. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Behavioral+Lifestyle+Interventions+for+Weight+Loss+in+Overweight+or+Obese+Patients+with+Type+2+Diabetes:+A+Systematic+Review+of+the+Literature&author=Gostoli,+S.&author=Raimondi,+G.&author=Popa,+A.P.&author=Giovannini,+M.&author=Benasi,+G.&author=Rafanelli,+C.&publication_year=2024&journal=Curr.+Obes.+Rep.&volume=13&pages=224%E2%80%93241&doi=10.1007/s13679-024-00552-5)] [[CrossRef](https://doi.org/10.1007/s13679-024-00552-5)]
  11. Cosentino, C.; Marchetti, C.; Monami, M.; Mannucci, E.; Cresci, B. Efficacy and effects of bariatric surgery in the treatment of obesity: Network meta-analysis of randomized controlled trials. Nutr. Metab. Cardiovasc. Dis. **2021** , 31, 2815–2824. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+and+effects+of+bariatric+surgery+in+the+treatment+of+obesity:+Network+meta-analysis+of+randomized+controlled+trials&author=Cosentino,+C.&author=Marchetti,+C.&author=Monami,+M.&author=Mannucci,+E.&author=Cresci,+B.&publication_year=2021&journal=Nutr.+Metab.+Cardiovasc.+Dis.&volume=31&pages=2815%E2%80%932824&doi=10.1016/j.numecd.2021.06.018)] [[CrossRef](https://doi.org/10.1016/j.numecd.2021.06.018)]
  12. Pentin, P.L.; Nashelsky, J. What are the indications for bariatric surgery? J. Fam. Pract. **2005** , 54, 633–634. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=What+are+the+indications+for+bariatric+surgery?&author=Pentin,+P.L.&author=Nashelsky,+J.&publication_year=2005&journal=J.+Fam.+Pract.&volume=54&pages=633%E2%80%93634&pmid=16009096)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/16009096)]
  13. Collazo-Clavell, M.L.; Shah, M. Common and Rare Complications of Bariatric Surgery. Endocrinol. Metab. Clin. N. Am. **2020** , 49, 329–346. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Common+and+Rare+Complications+of+Bariatric+Surgery&author=Collazo-Clavell,+M.L.&author=Shah,+M.&publication_year=2020&journal=Endocrinol.+Metab.+Clin.+N.+Am.&volume=49&pages=329%E2%80%93346&doi=10.1016/j.ecl.2020.02.003)] [[CrossRef](https://doi.org/10.1016/j.ecl.2020.02.003)]
  14. Pucher, P.H.; Lord, A.C.; Sodergren, M.H.; Ahmed, A.R.; Darzi, A.; Purkayastha, S. Reversal to normal anatomy after failed gastric bypass: Systematic review of indications, techniques, and outcomes. Surg. Obes. Relat. Dis. **2016** , 12, 1351–1356. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Reversal+to+normal+anatomy+after+failed+gastric+bypass:+Systematic+review+of+indications,+techniques,+and+outcomes&author=Pucher,+P.H.&author=Lord,+A.C.&author=Sodergren,+M.H.&author=Ahmed,+A.R.&author=Darzi,+A.&author=Purkayastha,+S.&publication_year=2016&journal=Surg.+Obes.+Relat.+Dis.&volume=12&pages=1351%E2%80%931356&doi=10.1016/j.soard.2016.01.030)] [[CrossRef](https://doi.org/10.1016/j.soard.2016.01.030)]
  15. O’Brien, P. Controversies in bariatric surgery. Br. J. Surg. **2015** , 102, 611–618. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Controversies+in+bariatric+surgery&author=O%E2%80%99Brien,+P.&publication_year=2015&journal=Br.+J.+Surg.&volume=102&pages=611%E2%80%93618&doi=10.1002/bjs.9760)] [[CrossRef](https://doi.org/10.1002/bjs.9760)]
  16. Gulliford, M.C.; Charlton, J.; Prevost, T.; Booth, H.; Fildes, A.; Ashworth, M.; Littlejohns, P.; Reddy, M.; Khan, O.; Rudisill, C. Costs and Outcomes of Increasing Access to Bariatric Surgery: Cohort Study and Cost-Effectiveness Analysis Using Electronic Health Records. Value Health **2017** , 20, 85–92. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Costs+and+Outcomes+of+Increasing+Access+to+Bariatric+Surgery:+Cohort+Study+and+Cost-Effectiveness+Analysis+Using+Electronic+Health+Records&author=Gulliford,+M.C.&author=Charlton,+J.&author=Prevost,+T.&author=Booth,+H.&author=Fildes,+A.&author=Ashworth,+M.&author=Littlejohns,+P.&author=Reddy,+M.&author=Khan,+O.&author=Rudisill,+C.&publication_year=2017&journal=Value+Health&volume=20&pages=85%E2%80%9392&doi=10.1016/j.jval.2016.08.734&pmid=28212974)] [[CrossRef](https://doi.org/10.1016/j.jval.2016.08.734)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/28212974)]
  17. Jones, B.J.; Bloom, S. The New Era of Drug Therapy for Obesity: The Evidence and the Expectations. Drugs **2015** , 75, 935–945. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=The+New+Era+of+Drug+Therapy+for+Obesity:+The+Evidence+and+the+Expectations&author=Jones,+B.J.&author=Bloom,+S.&publication_year=2015&journal=Drugs&volume=75&pages=935%E2%80%93945&doi=10.1007/s40265-015-0410-1&pmid=25985865)] [[CrossRef](https://doi.org/10.1007/s40265-015-0410-1)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/25985865)]
  18. Cai, W.; Zhang, R.; Yao, Y.; Wu, Q.; Zhang, J. Tirzepatide as a novel effective and safe strategy for treating obesity: A systematic review and meta-analysis of randomized controlled trials. Front. Public Health **2024** , 12, 1277113. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+as+a+novel+effective+and+safe+strategy+for+treating+obesity:+A+systematic+review+and+meta-analysis+of+randomized+controlled+trials&author=Cai,+W.&author=Zhang,+R.&author=Yao,+Y.&author=Wu,+Q.&author=Zhang,+J.&publication_year=2024&journal=Front.+Public+Health&volume=12&pages=1277113&doi=10.3389/fpubh.2024.1277113)] [[CrossRef](https://doi.org/10.3389/fpubh.2024.1277113)]
  19. Guglielmi, V.; Bettini, S.; Sbraccia, P.; Busetto, L.; Pellegrini, M.; Yumuk, V.; Colao, A.M.; El Ghoch, M.; Muscogiuri, G. Beyond Weight Loss: Added Benefits Could Guide the Choice of Anti-Obesity Medications. Curr. Obes. Rep. **2023** , 12, 127–146. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Beyond+Weight+Loss:+Added+Benefits+Could+Guide+the+Choice+of+Anti-Obesity+Medications&author=Guglielmi,+V.&author=Bettini,+S.&author=Sbraccia,+P.&author=Busetto,+L.&author=Pellegrini,+M.&author=Yumuk,+V.&author=Colao,+A.M.&author=El+Ghoch,+M.&author=Muscogiuri,+G.&publication_year=2023&journal=Curr.+Obes.+Rep.&volume=12&pages=127%E2%80%93146&doi=10.1007/s13679-023-00502-7)] [[CrossRef](https://doi.org/10.1007/s13679-023-00502-7)]
  20. Frias, J.P.; Nauck, M.A.; Van, J.; Kutner, M.E.; Cui, X.; Benson, C.; Urva, S.; Gimeno, R.E.; Milicevic, Z.; Robins, D.; et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: A randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet **2018** , 392, 2180–2193. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+and+safety+of+LY3298176,+a+novel+dual+GIP+and+GLP-1+receptor+agonist,+in+patients+with+type+2+diabetes:+A+randomised,+placebo-controlled+and+active+comparator-controlled+phase+2+trial&author=Frias,+J.P.&author=Nauck,+M.A.&author=Van,+J.&author=Kutner,+M.E.&author=Cui,+X.&author=Benson,+C.&author=Urva,+S.&author=Gimeno,+R.E.&author=Milicevic,+Z.&author=Robins,+D.&publication_year=2018&journal=Lancet&volume=392&pages=2180%E2%80%932193&doi=10.1016/S0140-6736\(18\)32260-8)] [[CrossRef](https://doi.org/10.1016/S0140-6736\(18\)32260-8)]
  21. Dahl, D.; Onishi, Y.; Norwood, P.; Huh, R.; Bray, R.; Patel, H.; Rodríguez, Á. Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial. JAMA **2022** , 327, 534–545. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+Subcutaneous+Tirzepatide+vs+Placebo+Added+to+Titrated+Insulin+Glargine+on+Glycemic+Control+in+Patients+With+Type+2+Diabetes:+The+SURPASS-5+Randomized+Clinical+Trial&author=Dahl,+D.&author=Onishi,+Y.&author=Norwood,+P.&author=Huh,+R.&author=Bray,+R.&author=Patel,+H.&author=Rodr%C3%ADguez,+%C3%81.&publication_year=2022&journal=JAMA&volume=327&pages=534%E2%80%93545&doi=10.1001/jama.2022.0078)] [[CrossRef](https://doi.org/10.1001/jama.2022.0078)]
  22. Gastaldelli, A.; Cusi, K.; Landó, L.F.; Bray, R.; Brouwers, B.; Rodríguez, A. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): A substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. **2022** , 10, 393–406. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+tirzepatide+versus+insulin+degludec+on+liver+fat+content+and+abdominal+adipose+tissue+in+people+with+type+2+diabetes+\(SURPASS-3+MRI\):+A+substudy+of+the+randomised,+open-label,+parallel-group,+phase+3+SURPASS-3+trial&author=Gastaldelli,+A.&author=Cusi,+K.&author=Land%C3%B3,+L.F.&author=Bray,+R.&author=Brouwers,+B.&author=Rodr%C3%ADguez,+A.&publication_year=2022&journal=Lancet+Diabetes+Endocrinol.&volume=10&pages=393%E2%80%93406&doi=10.1016/S2213-8587\(22\)00070-5)] [[CrossRef](https://doi.org/10.1016/S2213-8587\(22\)00070-5)]
  23. Malhotra, A.; Bednarik, J.; Chakladar, S.; Dunn, J.P.; Weaver, T.; Grunstein, R.; Fietze, I.; Redline, S.; Azarbarzin, A.; Sands, S.A.; et al. Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial. Contemp. Clin. Trials **2024** , 141, 107516. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+for+the+treatment+of+obstructive+sleep+apnea:+Rationale,+design,+and+sample+baseline+characteristics+of+the+SURMOUNT+-OSA+phase+3+trial&author=Malhotra,+A.&author=Bednarik,+J.&author=Chakladar,+S.&author=Dunn,+J.P.&author=Weaver,+T.&author=Grunstein,+R.&author=Fietze,+I.&author=Redline,+S.&author=Azarbarzin,+A.&author=Sands,+S.A.&publication_year=2024&journal=Contemp.+Clin.+Trials&volume=141&pages=107516&doi=10.1016/j.cct.2024.107516&pmid=38547961)] [[CrossRef](https://doi.org/10.1016/j.cct.2024.107516)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/38547961)]
  24. Mishra, R.; Raj, R.; Elshimy, G.; Zapata, I.; Kannan, L.; Majety, P.; Edem, D.; Correa, R. Adverse Events Related to Tirzepatide. J. Endocr. Soc. **2023** , 7, bvad016. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Adverse+Events+Related+to+Tirzepatide&author=Mishra,+R.&author=Raj,+R.&author=Elshimy,+G.&author=Zapata,+I.&author=Kannan,+L.&author=Majety,+P.&author=Edem,+D.&author=Correa,+R.&publication_year=2023&journal=J.+Endocr.+Soc.&volume=7&pages=bvad016&doi=10.1210/jendso/bvad016&pmid=36789109)] [[CrossRef](https://doi.org/10.1210/jendso/bvad016)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/36789109)]
  25. Baker, D.E.; Walley, K.; Levien, T.L. Tirzepatide. Hosp. Pharm. **2023** , 58, 227–243. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide&author=Baker,+D.E.&author=Walley,+K.&author=Levien,+T.L.&publication_year=2023&journal=Hosp.+Pharm.&volume=58&pages=227%E2%80%93243&doi=10.1177/00185787221125724&pmid=37216078)] [[CrossRef](https://doi.org/10.1177/00185787221125724)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/37216078)]
  26. Busetto, L.; Dicker, D.; Frühbeck, G.; Halford, J.C.G.; Sbraccia, P.; Yumuk, V.; Goossens, G. A new framework for the diagnosis, staging and management of obesity in adults. Nat. Med. **2024**. online ahead of print. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=A+new+framework+for+the+diagnosis,+staging+and+management+of+obesity+in+adults&author=Busetto,+L.&author=Dicker,+D.&author=Fr%C3%BChbeck,+G.&author=Halford,+J.C.G.&author=Sbraccia,+P.&author=Yumuk,+V.&author=Goossens,+G.&publication_year=2024&journal=Nat.+Med.)]
  27. El Ghoch, M.; Pellegrini, M. Why should sarcopenic obesity be included in a routine assessment during weight-management programmes? Front. Endocrinol. **2022** , 13, 962895. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Why+should+sarcopenic+obesity+be+included+in+a+routine+assessment+during+weight-management+programmes?&author=El+Ghoch,+M.&author=Pellegrini,+M.&publication_year=2022&journal=Front.+Endocrinol.&volume=13&pages=962895&doi=10.3389/fendo.2022.962895&pmid=35937807)] [[CrossRef](https://doi.org/10.3389/fendo.2022.962895)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/35937807)]
  28. Jensen, T.L.; Brønden, A.; Karstoft, K.; Sonne, D.P.; Christensen, M. The Body weight Reducing Effects of Tirzepatide in People with and without Type 2 Diabetes: A Review on Efficacy and Adverse Effects. Patient Prefer Adherence. Patient Prefer. Adherence **2024** , 18, 373–382. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=The+Body+weight+Reducing+Effects+of+Tirzepatide+in+People+with+and+without+Type+2+Diabetes:+A+Review+on+Efficacy+and+Adverse+Effects.+Patient+Prefer+Adherence&author=Jensen,+T.L.&author=Br%C3%B8nden,+A.&author=Karstoft,+K.&author=Sonne,+D.P.&author=Christensen,+M.&publication_year=2024&journal=Patient+Prefer.+Adherence&volume=18&pages=373%E2%80%93382&doi=10.2147/PPA.S419304)] [[CrossRef](https://doi.org/10.2147/PPA.S419304)]
  29. Richardson, W.S.; Wilson, M.C.; Nishikawa, J.; Hayward, R.S. The well-built clinical question: A key to evidence-based decisions. ACP J. Club **1995** , 123, A12–A13. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=The+well-built+clinical+question:+A+key+to+evidence-based+decisions&author=Richardson,+W.S.&author=Wilson,+M.C.&author=Nishikawa,+J.&author=Hayward,+R.S.&publication_year=1995&journal=ACP+J.+Club&volume=123&pages=A12%E2%80%93A13&doi=10.7326/ACPJC-1995-123-3-A12)] [[CrossRef](https://doi.org/10.7326/ACPJC-1995-123-3-A12)]
  30. Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gotzsche, P.C.; Ioannidis, J.P.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. Ann. Intern. Med. **2009** , 151, W65–W94. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=The+PRISMA+statement+for+reporting+systematic+reviews+and+meta-analyses+of+studies+that+evaluate+health+care+interventions:+Explanation+and+elaboration&author=Liberati,+A.&author=Altman,+D.G.&author=Tetzlaff,+J.&author=Mulrow,+C.&author=Gotzsche,+P.C.&author=Ioannidis,+J.P.&author=Clarke,+M.&author=Devereaux,+P.J.&author=Kleijnen,+J.&author=Moher,+D.&publication_year=2009&journal=Ann.+Intern.+Med.&volume=151&pages=W65%E2%80%93W94&doi=10.7326/0003-4819-151-4-200908180-00136)] [[CrossRef](https://doi.org/10.7326/0003-4819-151-4-200908180-00136)]
  31. Clark, H.D.; Wells, G.A.; Huet, C.; McAlister, F.A.; Salmi, L.R.; Fergusson, D.; Laupacis, A. Assessing the quality of randomized trials: Reliability of the Jadad scale. Control Clin. Trials **1999** , 20, 448–452. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Assessing+the+quality+of+randomized+trials:+Reliability+of+the+Jadad+scale&author=Clark,+H.D.&author=Wells,+G.A.&author=Huet,+C.&author=McAlister,+F.A.&author=Salmi,+L.R.&author=Fergusson,+D.&author=Laupacis,+A.&publication_year=1999&journal=Control+Clin.+Trials&volume=20&pages=448%E2%80%93452&doi=10.1016/S0197-2456\(99\)00026-4)] [[CrossRef](https://doi.org/10.1016/S0197-2456\(99\)00026-4)]
  32. Kiehna, E.N.; Starke, R.M.; Pouratian, N.; Dumont, A.S. Standards for reporting randomized controlled trials in neurosurgery. J. Neurosurg. **2011** , 114, 280–285. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Standards+for+reporting+randomized+controlled+trials+in+neurosurgery&author=Kiehna,+E.N.&author=Starke,+R.M.&author=Pouratian,+N.&author=Dumont,+A.S.&publication_year=2011&journal=J.+Neurosurg.&volume=114&pages=280%E2%80%93285&doi=10.3171/2010.8.JNS091770)] [[CrossRef](https://doi.org/10.3171/2010.8.JNS091770)]
  33. Chess, L.E.; Gagnier, J. Risk of bias of randomized controlled trials published in orthopaedic journals. BMC Med. Res. Methodol. **2013** , 13, 76. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Risk+of+bias+of+randomized+controlled+trials+published+in+orthopaedic+journals&author=Chess,+L.E.&author=Gagnier,+J.&publication_year=2013&journal=BMC+Med.+Res.+Methodol.&volume=13&pages=76&doi=10.1186/1471-2288-13-76&pmid=23758875)] [[CrossRef](https://doi.org/10.1186/1471-2288-13-76)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/23758875)]
  34. Inagaki, N.; Takeuchi, M.; Oura, T.; Imaoka, T.; Seino, Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): A double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol. **2022** , 10, 623–633. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+and+safety+of+tirzepatide+monotherapy+compared+with+dulaglutide+in+Japanese+patients+with+type+2+diabetes+\(SURPASS+J-mono\):+A+double-blind,+multicentre,+randomised,+phase+3+trial&author=Inagaki,+N.&author=Takeuchi,+M.&author=Oura,+T.&author=Imaoka,+T.&author=Seino,+Y.&publication_year=2022&journal=Lancet+Diabetes+Endocrinol.&volume=10&pages=623%E2%80%93633&doi=10.1016/S2213-8587\(22\)00188-7)] [[CrossRef](https://doi.org/10.1016/S2213-8587\(22\)00188-7)]
  35. Rosenstock, J.; Frías, J.P.; Rodbard, H.W.; Tofé, S.; Sears, E.; Huh, R.; Fernández Landó, L.; Patel, H. Tirzepatide vs Insulin Lispro Added to Basal Insulin in Type 2 Diabetes: The SURPASS-6 Randomized Clinical Trial. JAMA **2023** , 330, 1631–1640. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+vs+Insulin+Lispro+Added+to+Basal+Insulin+in+Type+2+Diabetes:+The+SURPASS-6+Randomized+Clinical+Trial&author=Rosenstock,+J.&author=Fr%C3%ADas,+J.P.&author=Rodbard,+H.W.&author=Tof%C3%A9,+S.&author=Sears,+E.&author=Huh,+R.&author=Fern%C3%A1ndez+Land%C3%B3,+L.&author=Patel,+H.&publication_year=2023&journal=JAMA&volume=330&pages=1631%E2%80%931640&doi=10.1001/jama.2023.20294&pmid=37786396)] [[CrossRef](https://doi.org/10.1001/jama.2023.20294)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/37786396)]
  36. Garvey, W.T.; Frias, J.P.; Jastreboff, A.M.; le Roux, C.W.; Sattar, N.; Aizenberg, D.; Mao, H.; Zhang, S.; Ahmad, N.N.; Bunck, M.C.; et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet **2023** , 402, 613–626. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+once+weekly+for+the+treatment+of+obesity+in+people+with+type+2+diabetes+\(SURMOUNT-2\):+A+double-blind,+randomised,+multicentre,+placebo-controlled,+phase+3+trial&author=Garvey,+W.T.&author=Frias,+J.P.&author=Jastreboff,+A.M.&author=le+Roux,+C.W.&author=Sattar,+N.&author=Aizenberg,+D.&author=Mao,+H.&author=Zhang,+S.&author=Ahmad,+N.N.&author=Bunck,+M.C.&publication_year=2023&journal=Lancet&volume=402&pages=613%E2%80%93626&doi=10.1016/S0140-6736\(23\)01200-X)] [[CrossRef](https://doi.org/10.1016/S0140-6736\(23\)01200-X)]
  37. Gao, L.; Lee, B.W.; Chawla, M.; Kim, J.; Huo, L.; Du, L.; Huang, Y.; Ji, L. Tirzepatide versus insulin glargine as second-line or third-line therapy in type 2 diabetes in the Asia-Pacific region: The SURPASS-AP-Combo trial. Nat. Med. **2023** , 29, 1500–1510. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+versus+insulin+glargine+as+second-line+or+third-line+therapy+in+type+2+diabetes+in+the+Asia-Pacific+region:+The+SURPASS-AP-Combo+trial&author=Gao,+L.&author=Lee,+B.W.&author=Chawla,+M.&author=Kim,+J.&author=Huo,+L.&author=Du,+L.&author=Huang,+Y.&author=Ji,+L.&publication_year=2023&journal=Nat.+Med.&volume=29&pages=1500%E2%80%931510&doi=10.1038/s41591-023-02344-1&pmid=37231074)] [[CrossRef](https://doi.org/10.1038/s41591-023-02344-1)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/37231074)]
  38. Kadowaki, T.; Chin, R.; Ozeki, A.; Imaoka, T.; Ogawa, Y. Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): A multicentre, randomised, open-label, parallel-group, phase 3 trial. Lancet Diabetes Endocrinol. **2022** , 10, 634–644. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Safety+and+efficacy+of+tirzepatide+as+an+add-on+to+single+oral+antihyperglycaemic+medication+in+patients+with+type+2+diabetes+in+Japan+\(SURPASS+J-combo\):+A+multicentre,+randomised,+open-label,+parallel-group,+phase+3+trial&author=Kadowaki,+T.&author=Chin,+R.&author=Ozeki,+A.&author=Imaoka,+T.&author=Ogawa,+Y.&publication_year=2022&journal=Lancet+Diabetes+Endocrinol.&volume=10&pages=634%E2%80%93644&doi=10.1016/S2213-8587\(22\)00187-5)] [[CrossRef](https://doi.org/10.1016/S2213-8587\(22\)00187-5)]
  39. Heise, T.; Mari, A.; DeVries, J.H.; Urva, S.; Li, J.; Pratt, E.J.; Coskun, T.; Thomas, M.K.; Mather, K.J.; Haupt, A.; et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: A multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. **2022** , 10, 418–429. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Effects+of+subcutaneous+tirzepatide+versus+placebo+or+semaglutide+on+pancreatic+islet+function+and+insulin+sensitivity+in+adults+with+type+2+diabetes:+A+multicentre,+randomised,+double-blind,+parallel-arm,+phase+1+clinical+trial&author=Heise,+T.&author=Mari,+A.&author=DeVries,+J.H.&author=Urva,+S.&author=Li,+J.&author=Pratt,+E.J.&author=Coskun,+T.&author=Thomas,+M.K.&author=Mather,+K.J.&author=Haupt,+A.&publication_year=2022&journal=Lancet+Diabetes+Endocrinol.&volume=10&pages=418%E2%80%93429&doi=10.1016/S2213-8587\(22\)00085-7)] [[CrossRef](https://doi.org/10.1016/S2213-8587\(22\)00085-7)]
  40. Del Prato, S.; Kahn, S.E.; Pavo, I.; Weerakkody, G.J.; Yang, Z.; Doupis, J.; Aizenberg, D.; Wynne, A.G.; Riesmeyer, J.S.; Heine, R.J.; et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet **2021** , 398, 1811–1824. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+versus+insulin+glargine+in+type+2+diabetes+and+increased+cardiovascular+risk+\(SURPASS-4\):+A+randomised,+open-label,+parallel-group,+multicentre,+phase+3+trial&author=Del+Prato,+S.&author=Kahn,+S.E.&author=Pavo,+I.&author=Weerakkody,+G.J.&author=Yang,+Z.&author=Doupis,+J.&author=Aizenberg,+D.&author=Wynne,+A.G.&author=Riesmeyer,+J.S.&author=Heine,+R.J.&publication_year=2021&journal=Lancet&volume=398&pages=1811%E2%80%931824&doi=10.1016/S0140-6736\(21\)02188-7)] [[CrossRef](https://doi.org/10.1016/S0140-6736\(21\)02188-7)]
  41. Ludvik, B.; Giorgino, F.; Jódar, E.; Frias, J.P.; Landó, L.F.; Brown, K.; Bray, R.; Rodríguez, A. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): A randomised, open-label, parallel-group, phase 3 trial. Lancet **2021** , 398, 583–598. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Once-weekly+tirzepatide+versus+once-daily+insulin+degludec+as+add-on+to+metformin+with+or+without+SGLT2+inhibitors+in+patients+with+type+2+diabetes+\(SURPASS-3\):+A+randomised,+open-label,+parallel-group,+phase+3+trial&author=Ludvik,+B.&author=Giorgino,+F.&author=J%C3%B3dar,+E.&author=Frias,+J.P.&author=Land%C3%B3,+L.F.&author=Brown,+K.&author=Bray,+R.&author=Rodr%C3%ADguez,+A.&publication_year=2021&journal=Lancet&volume=398&pages=583%E2%80%93598&doi=10.1016/S0140-6736\(21\)01443-4)] [[CrossRef](https://doi.org/10.1016/S0140-6736\(21\)01443-4)]
  42. Rosenstock, J.; Wysham, C.; Frías, J.P.; Kaneko, S.; Lee, C.J.; Fernández Landó, L.; Mao, H.; Cui, X.; Karanikas, C.A.; Thieu, V. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet **2021** , 398, 143–155. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+and+safety+of+a+novel+dual+GIP+and+GLP-1+receptor+agonist+tirzepatide+in+patients+with+type+2+diabetes+\(SURPASS-1\):+A+double-blind,+randomised,+phase+3+trial&author=Rosenstock,+J.&author=Wysham,+C.&author=Fr%C3%ADas,+J.P.&author=Kaneko,+S.&author=Lee,+C.J.&author=Fern%C3%A1ndez+Land%C3%B3,+L.&author=Mao,+H.&author=Cui,+X.&author=Karanikas,+C.A.&author=Thieu,+V.&publication_year=2021&journal=Lancet&volume=398&pages=143%E2%80%93155&doi=10.1016/S0140-6736\(21\)01324-6)] [[CrossRef](https://doi.org/10.1016/S0140-6736\(21\)01324-6)]
  43. Frías, J.P.; Davies, M.J.; Rosenstock, J.; Pérez Manghi, F.C.; Fernández Landó, L.; Bergman, B.K.; Liu, B.; Cui, X.; Brown, K. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N. Engl. J. Med. **2021** , 385, 503–515. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+versus+Semaglutide+Once+Weekly+in+Patients+with+Type+2+Diabetes&author=Fr%C3%ADas,+J.P.&author=Davies,+M.J.&author=Rosenstock,+J.&author=P%C3%A9rez+Manghi,+F.C.&author=Fern%C3%A1ndez+Land%C3%B3,+L.&author=Bergman,+B.K.&author=Liu,+B.&author=Cui,+X.&author=Brown,+K.&publication_year=2021&journal=N.+Engl.+J.+Med.&volume=385&pages=503%E2%80%93515&doi=10.1056/NEJMoa2107519&pmid=34170647)] [[CrossRef](https://doi.org/10.1056/NEJMoa2107519)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/34170647)]
  44. Frias, J.P.; Nauck, M.A.; Van, J.; Benson, C.; Bray, R.; Cui, X.; Milicevic, Z.; Urva, S.; Haupt, A. Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens. Diabetes Obes. Metab. **2020** , 22, 938–946. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+and+tolerability+of+tirzepatide,+a+dual+glucose-dependent+insulinotropic+peptide+and+glucagon-like+peptide-1+receptor+agonist+in+patients+with+type+2+diabetes:+A+12-week,+randomized,+double-blind,+placebo-controlled+study+to+evaluate+different+dose-escalation+regimens&author=Frias,+J.P.&author=Nauck,+M.A.&author=Van,+J.&author=Benson,+C.&author=Bray,+R.&author=Cui,+X.&author=Milicevic,+Z.&author=Urva,+S.&author=Haupt,+A.&publication_year=2020&journal=Diabetes+Obes.+Metab.&volume=22&pages=938%E2%80%93946)]
  45. Mather, K.J.; Mari, A.; Heise, T.; DeVries, J.H.; Hua, M.; Urva, S.; Coskun, T.; Haupt, A.; Heine, R.J.; Pratt, E.; et al. Effects of Tirzepatide vs Semaglutide on β-cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test. J. Clin. Endocrinol. Metab. **2024**. online ahead of print. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Effects+of+Tirzepatide+vs+Semaglutide+on+%CE%B2-cell+Function,+Insulin+Sensitivity,+and+Glucose+Control+During+a+Meal+Test&author=Mather,+K.J.&author=Mari,+A.&author=Heise,+T.&author=DeVries,+J.H.&author=Hua,+M.&author=Urva,+S.&author=Coskun,+T.&author=Haupt,+A.&author=Heine,+R.J.&author=Pratt,+E.&publication_year=2024&journal=J.+Clin.+Endocrinol.+Metab.)]
  46. Jabbour, S.; Paik, J.S.; Aleppo, G.; Sharma, P.; Valderas, E.G.; Benneyworth, B. Switching to Tirzepatide 5 mg From Glucagon-Like Peptide-1 Receptor Agonists: Clinical Expectations in the First 12 Weeks of Treatment. Endocr. Pract. **2024**. online ahead of print. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Switching+to+Tirzepatide+5+mg+From+Glucagon-Like+Peptide-1+Receptor+Agonists:+Clinical+Expectations+in+the+First+12+Weeks+of+Treatment&author=Jabbour,+S.&author=Paik,+J.S.&author=Aleppo,+G.&author=Sharma,+P.&author=Valderas,+E.G.&author=Benneyworth,+B.&publication_year=2024&journal=Endocr.+Pract.)]
  47. Bagherzadeh-Rahmani, B.; Marzetti, E.; Karami, E.; Campbell, B.I.; Fakourian, A.; Haghighi, A.H.; Mousavi, S.H.; Heinrich, K.M.; Brazzi, L.; Jung, F.; et al. Tirzepatide and exercise training in obesity. Clin. Hemorheol. Microcirc. **2024**. online ahead of print. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+and+exercise+training+in+obesity&author=Bagherzadeh-Rahmani,+B.&author=Marzetti,+E.&author=Karami,+E.&author=Campbell,+B.I.&author=Fakourian,+A.&author=Haghighi,+A.H.&author=Mousavi,+S.H.&author=Heinrich,+K.M.&author=Brazzi,+L.&author=Jung,+F.&publication_year=2024&journal=Clin.+Hemorheol.+Microcirc.)]
  48. Aronne, L.J.; Sattar, N.; Horn, D.B.; Bays, H.E.; Wharton, S.; Lin, W.Y.; Ahmad, N.N.; Zhang, S.; Liao, R.; Bunck, M.C.; et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA **2024** , 331, 38–48. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Continued+Treatment+With+Tirzepatide+for+Maintenance+of+Weight+Reduction+in+Adults+With+Obesity:+The+SURMOUNT-4+Randomized+Clinical+Trial&author=Aronne,+L.J.&author=Sattar,+N.&author=Horn,+D.B.&author=Bays,+H.E.&author=Wharton,+S.&author=Lin,+W.Y.&author=Ahmad,+N.N.&author=Zhang,+S.&author=Liao,+R.&author=Bunck,+M.C.&publication_year=2024&journal=JAMA&volume=331&pages=38%E2%80%9348&doi=10.1001/jama.2023.24945&pmid=38078870)] [[CrossRef](https://doi.org/10.1001/jama.2023.24945)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/38078870)]
  49. Malhotra, A.; Grunstein, R.R.; Fietze, I.; Weaver, T.E.; Redline, S.; Azarbarzin, A.; Sands, S.A.; Schwab, R.J.; Dunn, J.P.; Chakladar, S.; et al. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N. Engl. J. Med. **2024**. online ahead of print. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+for+the+Treatment+of+Obstructive+Sleep+Apnea+and+Obesity&author=Malhotra,+A.&author=Grunstein,+R.R.&author=Fietze,+I.&author=Weaver,+T.E.&author=Redline,+S.&author=Azarbarzin,+A.&author=Sands,+S.A.&author=Schwab,+R.J.&author=Dunn,+J.P.&author=Chakladar,+S.&publication_year=2024&journal=N.+Engl.+J.+Med.)]
  50. Loomba, R.; Hartman, M.L.; Lawitz, E.J.; Vuppalanchi, R.; Boursier, J.; Bugianesi, E.; Yoneda, M.; Behling, C.; Cummings, O.W.; Tang, Y.; et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N. Engl. J. Med. **2024**. online ahead of print. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+for+Metabolic+Dysfunction-Associated+Steatohepatitis+with+Liver+Fibrosis&author=Loomba,+R.&author=Hartman,+M.L.&author=Lawitz,+E.J.&author=Vuppalanchi,+R.&author=Boursier,+J.&author=Bugianesi,+E.&author=Yoneda,+M.&author=Behling,+C.&author=Cummings,+O.W.&author=Tang,+Y.&publication_year=2024&journal=N.+Engl.+J.+Med.)]
  51. Feng, P.; Sheng, X.; Ji, Y.; Urva, S.; Wang, F.; Miller, S.; Qian, C.; An, Z.; Cui, Y. A Phase 1 Multiple Dose Study of Tirzepatide in Chinese Patients with Type 2 Diabetes. Adv. Ther. **2023** , 40, 3434–3445. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=A+Phase+1+Multiple+Dose+Study+of+Tirzepatide+in+Chinese+Patients+with+Type+2+Diabetes&author=Feng,+P.&author=Sheng,+X.&author=Ji,+Y.&author=Urva,+S.&author=Wang,+F.&author=Miller,+S.&author=Qian,+C.&author=An,+Z.&author=Cui,+Y.&publication_year=2023&journal=Adv.+Ther.&volume=40&pages=3434%E2%80%933445&doi=10.1007/s12325-023-02536-8&pmid=37285081)] [[CrossRef](https://doi.org/10.1007/s12325-023-02536-8)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/37285081)]
  52. Battelino, T.; Bergenstal, R.M.; Rodríguez, A.; Fernández Landó, L.; Bray, R.; Tong, Z.; Brown, K. Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): A substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. **2022** , 10, 407–417. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Efficacy+of+once-weekly+tirzepatide+versus+once-daily+insulin+degludec+on+glycaemic+control+measured+by+continuous+glucose+monitoring+in+adults+with+type+2+diabetes+\(SURPASS-3+CGM\):+A+substudy+of+the+randomised,+open-label,+parallel-group,+phase+3+SURPASS-3+trial&author=Battelino,+T.&author=Bergenstal,+R.M.&author=Rodr%C3%ADguez,+A.&author=Fern%C3%A1ndez+Land%C3%B3,+L.&author=Bray,+R.&author=Tong,+Z.&author=Brown,+K.&publication_year=2022&journal=Lancet+Diabetes+Endocrinol.&volume=10&pages=407%E2%80%93417)]
  53. Furihata, K.; Mimura, H.; Urva, S.; Oura, T.; Ohwaki, K.; Imaoka, T. A phase 1 multiple-ascending dose study of tirzepatide in Japanese participants with type 2 diabetes. Diabetes Obes. Metab. **2022** , 24, 239–246. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=A+phase+1+multiple-ascending+dose+study+of+tirzepatide+in+Japanese+participants+with+type+2+diabetes&author=Furihata,+K.&author=Mimura,+H.&author=Urva,+S.&author=Oura,+T.&author=Ohwaki,+K.&author=Imaoka,+T.&publication_year=2022&journal=Diabetes+Obes.+Metab.&volume=24&pages=239%E2%80%93246&doi=10.1111/dom.14572&pmid=34647404)] [[CrossRef](https://doi.org/10.1111/dom.14572)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/34647404)]
  54. Heise, T.; DeVries, J.H.; Urva, S.; Li, J.; Pratt, E.J.; Thomas, M.K.; Mather, K.J.; Karanikas, C.A.; Dunn, J.; Haupt, A.; et al. Tirzepatide Reduces Appetite, Energy Intake, and Fat Mass in People With Type 2 Diabetes. Diabetes Care **2023** , 46, 998–1004. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+Reduces+Appetite,+Energy+Intake,+and+Fat+Mass+in+People+With+Type+2+Diabetes&author=Heise,+T.&author=DeVries,+J.H.&author=Urva,+S.&author=Li,+J.&author=Pratt,+E.J.&author=Thomas,+M.K.&author=Mather,+K.J.&author=Karanikas,+C.A.&author=Dunn,+J.&author=Haupt,+A.&publication_year=2023&journal=Diabetes+Care&volume=46&pages=998%E2%80%931004&doi=10.2337/dc22-1710)] [[CrossRef](https://doi.org/10.2337/dc22-1710)]
  55. Yabe, D.; Kawamori, D.; Seino, Y.; Oura, T.; Takeuchi, M.F. Change in pharmacodynamic variables following once-weekly tirzepatide treatment versus dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono substudy). Diabetes Obes. Metab. **2023** , 25, 398–406. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Change+in+pharmacodynamic+variables+following+once-weekly+tirzepatide+treatment+versus+dulaglutide+in+Japanese+patients+with+type+2+diabetes+\(SURPASS+J-mono+substudy\)&author=Yabe,+D.&author=Kawamori,+D.&author=Seino,+Y.&author=Oura,+T.&author=Takeuchi,+M.F.&publication_year=2023&journal=Diabetes+Obes.+Metab.&volume=25&pages=398%E2%80%93406&doi=10.1111/dom.14882)] [[CrossRef](https://doi.org/10.1111/dom.14882)]
  56. Wadden, T.A.; Chao, A.M.; Machineni, S.; Kushner, R.; Ard, J.; Srivastava, G.; Halpern, B.; Zhang, S.; Chen, J.; Bunck, M.C.; et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: The SURMOUNT-3 phase 3 trial. Nat. Med. **2023** , 29, 2909–2918. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+after+intensive+lifestyle+intervention+in+adults+with+overweight+or+obesity:+The+SURMOUNT-3+phase+3+trial&author=Wadden,+T.A.&author=Chao,+A.M.&author=Machineni,+S.&author=Kushner,+R.&author=Ard,+J.&author=Srivastava,+G.&author=Halpern,+B.&author=Zhang,+S.&author=Chen,+J.&author=Bunck,+M.C.&publication_year=2023&journal=Nat.+Med.&volume=29&pages=2909%E2%80%932918&doi=10.1038/s41591-023-02597-w)] [[CrossRef](https://doi.org/10.1038/s41591-023-02597-w)]
  57. Zhao, L.; Cheng, Z.; Lu, Y.; Liu, M.; Chen, H.; Zhang, M.; Wang, R.; Yuan, Y.; Li, X. Tirzepatide for Weight Reduction in Chinese Adults With Obesity: The SURMOUNT-CN Randomized Clinical Trial. JAMA **2024**. online ahead of print. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+for+Weight+Reduction+in+Chinese+Adults+With+Obesity:+The+SURMOUNT-CN+Randomized+Clinical+Trial&author=Zhao,+L.&author=Cheng,+Z.&author=Lu,+Y.&author=Liu,+M.&author=Chen,+H.&author=Zhang,+M.&author=Wang,+R.&author=Yuan,+Y.&author=Li,+X.&publication_year=2024&journal=JAMA)]
  58. Jastreboff, A.M.; Aronne, L.J.; Ahmad, N.N.; Wharton, S.; Connery, L.; Alves, B.; Kiyosue, A.; Zhang, S.; Liu, B.; Bunck, M.C.; et al. Tirzepatide Once Weekly for the Treatment of Obesity. N. Engl. J. Med. **2022** , 387, 205–216. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide+Once+Weekly+for+the+Treatment+of+Obesity&author=Jastreboff,+A.M.&author=Aronne,+L.J.&author=Ahmad,+N.N.&author=Wharton,+S.&author=Connery,+L.&author=Alves,+B.&author=Kiyosue,+A.&author=Zhang,+S.&author=Liu,+B.&author=Bunck,+M.C.&publication_year=2022&journal=N.+Engl.+J.+Med.&volume=387&pages=205%E2%80%93216&doi=10.1056/NEJMoa2206038)] [[CrossRef](https://doi.org/10.1056/NEJMoa2206038)]
  59. Duren, D.L.; Sherwood, R.J.; Czerwinski, S.A.; Lee, M.; Choh, A.C.; Siervogel, R.M.; Cameron Chumlea, W. Body composition methods: Comparisons and interpretation. J. Diabetes Sci. Technol. **2008** , 2, 1139–1146. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Body+composition+methods:+Comparisons+and+interpretation&author=Duren,+D.L.&author=Sherwood,+R.J.&author=Czerwinski,+S.A.&author=Lee,+M.&author=Choh,+A.C.&author=Siervogel,+R.M.&author=Cameron+Chumlea,+W.&publication_year=2008&journal=J.+Diabetes+Sci.+Technol.&volume=2&pages=1139%E2%80%931146&doi=10.1177/193229680800200623)] [[CrossRef](https://doi.org/10.1177/193229680800200623)]
  60. Dutta, P.; Kumar, Y.; Babu, A.T.; Giri Ravindran, S.; Salam, A.; Rai, B.; Baskar, A.; Dhawan, A.; Jomy, M. Tirzepatide: A Promising Drug for Type 2 Diabetes and Beyond. Cureus **2023** , 15, e38379. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Tirzepatide:+A+Promising+Drug+for+Type+2+Diabetes+and+Beyond&author=Dutta,+P.&author=Kumar,+Y.&author=Babu,+A.T.&author=Giri+Ravindran,+S.&author=Salam,+A.&author=Rai,+B.&author=Baskar,+A.&author=Dhawan,+A.&author=Jomy,+M.&publication_year=2023&journal=Cureus&volume=15&pages=e38379&doi=10.7759/cureus.38379&pmid=37265914)] [[CrossRef](https://doi.org/10.7759/cureus.38379)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/37265914)]
  61. Bu, T.; Sun, Z.; Pan, Y.; Deng, X.; Yuan, G. Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism. Diabetes Metab. J. **2024** , 48, 354–372. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Glucagon-Like+Peptide-1:+New+Regulator+in+Lipid+Metabolism&author=Bu,+T.&author=Sun,+Z.&author=Pan,+Y.&author=Deng,+X.&author=Yuan,+G.&publication_year=2024&journal=Diabetes+Metab.+J.&volume=48&pages=354%E2%80%93372&doi=10.4093/dmj.2023.0277)] [[CrossRef](https://doi.org/10.4093/dmj.2023.0277)]
  62. Duan, K.; Yan, X.; Gao, Z.; Hou, Y.; Lv, X.; Song, G. Effect of glucagon-like peptide-1 receptor agonists on fat distribution in patients with type 2 diabetes: A systematic review and meta-analysis. J. Diabetes Investig. **2022** , 13, 1149–1160. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Effect+of+glucagon-like+peptide-1+receptor+agonists+on+fat+distribution+in+patients+with+type%E2%80%892+diabetes:+A+systematic+review+and+meta-analysis&author=Duan,+K.&author=Yan,+X.&author=Gao,+Z.&author=Hou,+Y.&author=Lv,+X.&author=Song,+G.&publication_year=2022&journal=J.+Diabetes+Investig.&volume=13&pages=1149%E2%80%931160&doi=10.1111/jdi.13775)] [[CrossRef](https://doi.org/10.1111/jdi.13775)]
  63. Müller, T.D.; Finan, B.; Bloom, S.R.; D’Alessio, D.; Drucker, D.J.; Flatt, P.R.; Fritsche, A.; Gribble, F.; Grill, H.J.; Habener, J.F.; et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. **2019** , 30, 72–130. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Glucagon-like+peptide+1+\(GLP-1\)&author=M%C3%BCller,+T.D.&author=Finan,+B.&author=Bloom,+S.R.&author=D%E2%80%99Alessio,+D.&author=Drucker,+D.J.&author=Flatt,+P.R.&author=Fritsche,+A.&author=Gribble,+F.&author=Grill,+H.J.&author=Habener,+J.F.&publication_year=2019&journal=Mol.+Metab.&volume=30&pages=72%E2%80%93130&pmid=31767182)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/31767182)]
  64. Andraos, J.; Muhar, H.; Smith, S. Beyond glycemia: Comparing tirzepatide to GLP-1 analogues. Rev. Endocr. Metab. Disord. **2023** , 24, 1089–1101. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Beyond+glycemia:+Comparing+tirzepatide+to+GLP-1+analogues&author=Andraos,+J.&author=Muhar,+H.&author=Smith,+S.&publication_year=2023&journal=Rev.+Endocr.+Metab.+Disord.&volume=24&pages=1089%E2%80%931101&doi=10.1007/s11154-023-09825-1&pmid=37526853)] [[CrossRef](https://doi.org/10.1007/s11154-023-09825-1)] [[PubMed](https://www.ncbi.nlm.nih.gov/pubmed/37526853)]
  65. Karagiannis, T.; Malandris, K.; Avgerinos, I.; Stamati, A.; Kakotrichi, P.; Liakos, A.; Vasilakou, D.; Kakaletsis, N.; Tsapas, A.; Bekiari, E. Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: A systematic review and network meta-analysis of randomised controlled trials. Diabetologia **2024** , 67, 1206–1222. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Subcutaneously+administered+tirzepatide+vs+semaglutide+for+adults+with+type+2+diabetes:+A+systematic+review+and+network+meta-analysis+of+randomised+controlled+trials&author=Karagiannis,+T.&author=Malandris,+K.&author=Avgerinos,+I.&author=Stamati,+A.&author=Kakotrichi,+P.&author=Liakos,+A.&author=Vasilakou,+D.&author=Kakaletsis,+N.&author=Tsapas,+A.&author=Bekiari,+E.&publication_year=2024&journal=Diabetologia&volume=67&pages=1206%E2%80%931222&doi=10.1007/s00125-024-06144-1)] [[CrossRef](https://doi.org/10.1007/s00125-024-06144-1)]
  66. Hariton, E.; Locascio, J. Randomised controlled trials—The gold standard for effectiveness research: Study design: Randomised controlled trials. BJOG **2018** , 125, 1716. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Randomised+controlled+trials%E2%80%94The+gold+standard+for+effectiveness+research:+Study+design:+Randomised+controlled+trials&author=Hariton,+E.&author=Locascio,+J.&publication_year=2018&journal=BJOG&volume=125&pages=1716&doi=10.1111/1471-0528.15199)] [[CrossRef](https://doi.org/10.1111/1471-0528.15199)]
  67. Kuriyan, R. Body composition techniques. Indian J. Med. Res. **2018** , 148, 648–658. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Body+composition+techniques&author=Kuriyan,+R.&publication_year=2018&journal=Indian+J.+Med.+Res.&volume=148&pages=648%E2%80%93658&doi=10.4103/ijmr.IJMR_1777_18)] [[CrossRef](https://doi.org/10.4103/ijmr.IJMR_1777_18)]
  68. Ballesteros-Pomar, M.D.; González-Arnáiz, E.; Pintor-de-la Maza, B.; Barajas-Galindo, D.; Ariadel-Cobo, D.; González-Roza, L.; Cano-Rodríguez, I. Bioelectrical impedance analysis as an alternative to dual-energy x-ray absorptiometry in the assessment of fat mass and appendicular lean mass in patients with obesity. Nutrition **2022** , 93, 111442. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Bioelectrical+impedance+analysis+as+an+alternative+to+dual-energy+x-ray+absorptiometry+in+the+assessment+of+fat+mass+and+appendicular+lean+mass+in+patients+with+obesity&author=Ballesteros-Pomar,+M.D.&author=Gonz%C3%A1lez-Arn%C3%A1iz,+E.&author=Pintor-de-la+Maza,+B.&author=Barajas-Galindo,+D.&author=Ariadel-Cobo,+D.&author=Gonz%C3%A1lez-Roza,+L.&author=Cano-Rodr%C3%ADguez,+I.&publication_year=2022&journal=Nutrition&volume=93&pages=111442&doi=10.1016/j.nut.2021.111442)] [[CrossRef](https://doi.org/10.1016/j.nut.2021.111442)]
  69. Susukida, R.; Crum, R.M.; Ebnesajjad, C.; Stuart, E.A.; Mojtabai, R. Generalizability of findings from randomized controlled trials: Application to the National Institute of Drug Abuse Clinical Trials Network. Addiction **2017** , 112, 1210–1219. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Generalizability+of+findings+from+randomized+controlled+trials:+Application+to+the+National+Institute+of+Drug+Abuse+Clinical+Trials+Network&author=Susukida,+R.&author=Crum,+R.M.&author=Ebnesajjad,+C.&author=Stuart,+E.A.&author=Mojtabai,+R.&publication_year=2017&journal=Addiction&volume=112&pages=1210%E2%80%931219&doi=10.1111/add.13789)] [[CrossRef](https://doi.org/10.1111/add.13789)]
  70. Cava, E.; Yeat, N.C.; Mittendorfer, B. Preserving Healthy Muscle during Weight Loss. Adv. Nutr. **2017** , 8, 511–519. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Preserving+Healthy+Muscle+during+Weight+Loss&author=Cava,+E.&author=Yeat,+N.C.&author=Mittendorfer,+B.&publication_year=2017&journal=Adv.+Nutr.&volume=8&pages=511%E2%80%93519&doi=10.3945/an.116.014506)] [[CrossRef](https://doi.org/10.3945/an.116.014506)]
  71. Abdulla, H.; Phillips, B.; Smith, K.; Wilkinson, D.; Atherton, P.J.; Idris, I. Physiological mechanisms of action of incretin and insulin in regulating skeletal muscle metabolism. Curr. Diabetes Rev. **2014** , 10, 327–335. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Physiological+mechanisms+of+action+of+incretin+and+insulin+in+regulating+skeletal+muscle+metabolism&author=Abdulla,+H.&author=Phillips,+B.&author=Smith,+K.&author=Wilkinson,+D.&author=Atherton,+P.J.&author=Idris,+I.&publication_year=2014&journal=Curr.+Diabetes+Rev.&volume=10&pages=327%E2%80%93335&doi=10.2174/1573399810666141017153749)] [[CrossRef](https://doi.org/10.2174/1573399810666141017153749)]
  72. Andreozzi, F.; Raciti, G.A.; Nigro, C.; Mannino, G.C.; Procopio, T.; Davalli, A.M.; Beguinot, F.; Sesti, G.; Miele, C.; Folli, F. The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. J. Transl. Med. **2016** , 14, 229. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=The+GLP-1+receptor+agonists+exenatide+and+liraglutide+activate+Glucose+transport+by+an+AMPK-dependent+mechanism&author=Andreozzi,+F.&author=Raciti,+G.A.&author=Nigro,+C.&author=Mannino,+G.C.&author=Procopio,+T.&author=Davalli,+A.M.&author=Beguinot,+F.&author=Sesti,+G.&author=Miele,+C.&author=Folli,+F.&publication_year=2016&journal=J.+Transl.+Med.&volume=14&pages=229&doi=10.1186/s12967-016-0985-7)] [[CrossRef](https://doi.org/10.1186/s12967-016-0985-7)]
  73. Takahashi, Y.; Fujita, H.; Seino, Y.; Hattori, S.; Hidaka, S.; Miyakawa, T.; Suzuki, A.; Waki, H.; Yabe, D.; Seino, Y.; et al. Gastric inhibitory polypeptide receptor antagonism suppresses intramuscular adipose tissue accumulation and ameliorates sarcopenia. J. Cachexia Sarcopenia Muscle **2023** , 14, 2703–2718. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=Gastric+inhibitory+polypeptide+receptor+antagonism+suppresses+intramuscular+adipose+tissue+accumulation+and+ameliorates+sarcopenia&author=Takahashi,+Y.&author=Fujita,+H.&author=Seino,+Y.&author=Hattori,+S.&author=Hidaka,+S.&author=Miyakawa,+T.&author=Suzuki,+A.&author=Waki,+H.&author=Yabe,+D.&author=Seino,+Y.&publication_year=2023&journal=J.+Cachexia+Sarcopenia+Muscle&volume=14&pages=2703%E2%80%932718&doi=10.1002/jcsm.13346)] [[CrossRef](https://doi.org/10.1002/jcsm.13346)]



**Figure 1.** The flowchart summarizing the study selection procedure. 

**Figure 1.** The flowchart summarizing the study selection procedure.

**Table 1.** The RCTs included in the systematic review. 

**Table 1.** The RCTs included in the systematic review.

Author and Study Design| Country| Sample| Mean Baseline BMI and Age| Follow-Up   
Duration| Body Composition Assessment| Body Composition Outcomes ¥  
---|---|---|---|---|---|---  
Yabe et al.,  
2023 [55]  
Multicenter,  
double-blind  
RCT| Japan| Total sample: n = 48 (M/F)  


➢
    By intervention arm:
•
    TZP 5 mg (n = 9)
•
    TZP 10 mg (n = 11) 
•
    TZP 15 mg (n = 9)
•
    Dulaglutide 0.75 mg (n = 19)
| BMI = 27.5 ± 3.5 kg/m2  
Age = 58.6 ± 7.5 years| 52 weeks| BIA| FM change at week 52  


  * TZP 5 mg: −4.1 (1.7) kg
  * TZP 10 mg: −6.8 (1.5) kg
  * TZP 15 mg: −6.6 (1.6) kg
  * Dulaglutide 0.75 mg: −0.2 (1.1)

FFM change at week 52 
  * TZP 5 mg: −1.2 (0.8) kg
  * TZP 10 mg: −1.9 (0.7) kg
  * TZP 15 mg: −2.3 (0.7) kg
  * Dulaglutide 0.75 mg: −0.3 (0.5)

  
Jastreboff et al., 2022 [58]  
Multicenter,  
double-blind  
RCT| USA, Mexico,   
Russia, Japan, China, Taiwan,   
India, South America| Total sample: n = 160 (M/F)  


➢
    By intervention arm:
•
    Nr
| Nr| 72 weeks| DXA| FM change at week 72  


  * TZP: −33.9% (pooled 5 mg, 10 mg and 15 mg groups)
  * Placebo: −8.2%
  * FFM change at week 72
  * TZP: −10.9% (pooled 5 mg, 10 mg and 15 mg groups)
  * Placebo: −2.6%

FM/FFM at baseline vs. week 72  


  * TZP 0.93 vs. 0.70 (pooled 5 mg, 10 mg and 15 mg groups)
  * Placebo 0.95 vs. 0.88

  
Continued  
Jastreboff et al., 2022 [58]  
Multicenter,  
double-blind  
RCT| USA, Mexico,   
Russia, Japan, China, Taiwan,   
India, South America| Total sample: n = 2539 (M/F)  


➢
    By intervention arm:
•
    TZP 5 mg (n = 630)
•
    TZP 10 mg (n = 636)
•
    TZP 15 mg (n = 630)
•
    Placebo (n = 643)
| BMI = 38.0 ± 6.8 kg/m2  
Age = 44.9 ± 12.5 years|  | WC| Change in WC at week 72  


  * TZP 5 mg: −14.0 (−14.9 to −13.1) cm
  * TZP 10 mg: −17.7 (−18.7 to −16.8) cm
  * TZP 15 mg: −18.5 (−19.3 to −17.6) cm
  * Placebo: −4.0 (−5.1 to −2.8) cm

  
Gastaldelli et al., 2022 [22]  
Multicenter,  
double-blind  
RCT| USA, Europe,   
Argentina| Total sample: n= 246 (M/F)  


➢
    By intervention arm:
•
    TZP 5 mg (n = 71)
•
    TZP 10 mg (n = 79)
•
    TZP 15 mg (n = 72)
•
    Insulin degludec (n = 74)
| BMI = 33.5 ± 4.8 kg/m2  
Age = 56.2 ± 9.8 years| 52 weeks| MRI| VAT volume change at week 52  


  * TZP 5 mg: −1.10 L (0.19)
  * TZP 10 mg: −1.53 L (0.18)
  * TZP 15 mg: −1.65 L (0.18)
  * Insulin degludec: +0.38 L (0.18)

ASAT volume change at week 52  


  * TZP 5 mg: −1.40 L (0.25)
  * TZP 10 mg: −2.25 L (0.24)
  * TZP 15 mg: −2.05 L (0.23)
  * Insulin degludec: + 0.63 L (0.24)

  
Heise et al.,  
2023 [54]  
Double-blind  
RCT| Germany| Total sample: n = 117 (M/F)  


➢
    By intervention arms:
•
    TZP 15 mg (n = 45)
•
    Semaglutide 1 mg (n = 44)
•
    Placebo (n = 28)
| Nr| 28 weeks| Bod Pod| FM at baseline  


  * TZP 15 mg: 36.8 ±11.5 kg
  * Semaglutide 1 mg: 35.3 ± 8.0 kg
  * Placebo: 38.6 ± 10.7 kg

FM after 28 weeks  


  * TZP 15 mg: 26.9 (0.85) kg
  * Semaglutide 1 mg: 30.7 (0.83) kg
  * Placebo: 36.6 (1.11) kg

FFM at baseline  


  * TZP 15 mg: 57.7 ± 9.3 kg
  * Semaglutide 1 mg: 56.3 ± 10.3 kg
  * Placebo: 59.1 ± 10.3 kg

FFM after 28 weeks  


  * TZP 15 mg: 55.8 (0.25) kg
  * Semaglutide 1 mg: 56.7 (0.24) kg
  * Placebo: 57.3 (0.32) kg

  
Wadden et al., 2023 [56]  
Multicenter,  
double-blind  
RCT| USA,   
South America| Total sample: n = 579 (M/F)  


➢
    By intervention arm:
•
    TZP 10 mg (n = 39)
•
    TZP15 mg (n = 248)
•
    Placebo (n = 292)
| BMI = 35.9 ± 6.3 kg/m2  
Age = 45.6 ± 12.2 years| 72 weeks| WC| Mean WC absolute change at week 72  


  * TZP: −14.6 (0.7) cm (maximum tolerated dose, 10 or 15 mg)
  * Placebo: +0.2 (1.0) cm

  
Zhao et al.,  
2024 [57]  
Multicenter,  
double-blind  
RCT| China| Total sample: n = 210 (M/F)  
By intervention arm:  


➢
    TZP 10 mg (n = 70)
•
    TZP 15 mg (n = 71)
•
    Placebo (n = 69)
| BMI = 32.3 ± 3.8 kg/m2  
Age = 36.1 ± 9.1 years| 52 weeks| WC| Change in WC at week 52  


  * TZP 10 mg: −11.4 cm (−13.2 to −9.6)
  * TZP 15 mg: −14.5 cm (−16.3 to −12.6)
  * Placebo: −2.6 cm (−4.4 to −0.9)

  
  
Abbreviations: USA = United States of America; BIA = bioelectrical impedance analysis; WC = waist circumference; M = males; F = females; SD = standard deviation; BMI = body mass index; MRI = magnetic resonance imaging; DXA = dual-energy X-ray absorptiometry; Nr = not reported; FM = fat mass; FFM = fat-free mass; VAT = visceral adipose tissue, ASAT = abdominal subcutaneous adipose tissue, TZP = Tirzepatide. ¥ Values are expressed as least squared mean (LSM) standard error (SE) or LSM (95% CI) or mean ± SD.

**Table 2.** Risk-of-bias criteria and Jadad scale. 

**Table 2.** Risk-of-bias criteria and Jadad scale.

Author| Yabe et al., 2022   
[55]| Jastreboff et al., 2022 [58]| Gastaldelli et al., 2022 [22]| Wadden et al., 2023   
[56]| Heise et al., 2023   
[54]| Zhao et al., 2024  
[57]  
---|---|---|---|---|---|---  
Risk of bias  
Was the method of randomization to groups appropriate?| +| +| +| +| +| +  
Was the allocation sequence concealed from those assigning patients to groups?| +| +| −| +| +| +  
Was the outcome measurement performed in the same manner with similar intensity in all groups being compared?| +| +| +| +| +| +  
Were similarly trained individuals administering the intervention across groups?| +| +| +| +| +| +  
Were all the withdrawals described?| +| +| +| +| +| +  
Were all originally randomized participants analyzed in the groups they were assigned to (i.e., an intention-to-treat analysis)?| +| +| +| +| +| +  
Was clustering at the group level accounted for in the analyses? Were the groups similar at baseline?| +| +| +| +| +| +  
Jadad Scale  
Randomization| 2| 2| 2| 2| 2| 2  
Blinding| 2| 2| 0| 2| 2| 2  
Account of all patients| 1| 1| 1| 1| 1| 1  
Total Score| 5| 5| 3| 5| 5| 5  
  
Risk-of-bias reporting: Yes: +; no: −; not reported: nr. Jadad scale reporting randomized controlled trials. It evaluates three different items: randomization (0–2), blinding (0–2), and account of all patients (0–1); studies with scores > 3 were considered as good quality.

| **Disclaimer/Publisher’s Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.  
---|---  
  
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<https://creativecommons.org/licenses/by/4.0/>).

## Share and Cite


**MDPI and ACS Style**

Rochira, V.; Greco, C.; Boni, S.; Costantino, F.; Dalla Valentina, L.; Zanni, E.; Itani, L.; El Ghoch, M. The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies. _Diseases_ **2024** , _12_ , 204. https://doi.org/10.3390/diseases12090204 

**AMA Style**  


Rochira V, Greco C, Boni S, Costantino F, Dalla Valentina L, Zanni E, Itani L, El Ghoch M. The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies. _Diseases_. 2024; 12(9):204. https://doi.org/10.3390/diseases12090204 

**Chicago/Turabian Style**  


Rochira, Vincenzo, Carla Greco, Stefano Boni, Francesco Costantino, Leonardo Dalla Valentina, Eleonora Zanni, Leila Itani, and Marwan El Ghoch. 2024\. "The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies" _Diseases_ 12, no. 9: 204. https://doi.org/10.3390/diseases12090204 

**APA Style**  


Rochira, V., Greco, C., Boni, S., Costantino, F., Dalla Valentina, L., Zanni, E., Itani, L., & El Ghoch, M. (2024). The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies. _Diseases_ , _12_(9), 204. https://doi.org/10.3390/diseases12090204 

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details [here](https://www.mdpi.com/about/announcements/784). 

## Article Metrics

No

No

### Article Access Statistics

For more information on the journal statistics, click [here](/journal/diseases/stats). 

Multiple requests from the same IP address are counted as one view. 

Zoom | Orient  | As Lines  | As Sticks  | As Cartoon  | As Surface  | Previous Scene | Next Scene

## Cite

Export citation file: [BibTeX](javascript:window.document.forms\['export-bibtex'\].submit\(\)) | [EndNote](javascript:window.document.forms\['export-endnote'\].submit\(\)) | [RIS](javascript:window.document.forms\['export-ris'\].submit\(\))

**MDPI and ACS Style**

Rochira, V.; Greco, C.; Boni, S.; Costantino, F.; Dalla Valentina, L.; Zanni, E.; Itani, L.; El Ghoch, M. The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies. _Diseases_ **2024** , _12_ , 204. https://doi.org/10.3390/diseases12090204 

**AMA Style**  


Rochira V, Greco C, Boni S, Costantino F, Dalla Valentina L, Zanni E, Itani L, El Ghoch M. The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies. _Diseases_. 2024; 12(9):204. https://doi.org/10.3390/diseases12090204 

**Chicago/Turabian Style**  


Rochira, Vincenzo, Carla Greco, Stefano Boni, Francesco Costantino, Leonardo Dalla Valentina, Eleonora Zanni, Leila Itani, and Marwan El Ghoch. 2024\. "The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies" _Diseases_ 12, no. 9: 204. https://doi.org/10.3390/diseases12090204 

**APA Style**  


Rochira, V., Greco, C., Boni, S., Costantino, F., Dalla Valentina, L., Zanni, E., Itani, L., & El Ghoch, M. (2024). The Effect of Tirzepatide on Body Composition in People with Overweight and Obesity: A Systematic Review of Randomized, Controlled Studies. _Diseases_ , _12_(9), 204. https://doi.org/10.3390/diseases12090204 

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details [here](https://www.mdpi.com/about/announcements/784). 

_clear_

_[Diseases](/journal/diseases)_ , EISSN 2079-9721, Published by MDPI 

[RSS](/rss/journal/diseases) [Content Alert](/journal/diseases/toc-alert)

###  Further Information 

[ Article Processing Charges ](/apc) [ Pay an Invoice ](/about/payment) [ Open Access Policy ](/openaccess) [ Contact MDPI ](/about/contact) [ Jobs at MDPI ](https://careers.mdpi.com)

###  Guidelines 

[ For Authors ](/authors) [ For Reviewers ](/reviewers) [ For Editors ](/editors) [ For Librarians ](/librarians) [ For Publishers ](/publishing_services) [ For Societies ](/societies) [ For Conference Organizers ](/conference_organizers)

###  MDPI Initiatives 

[ Sciforum ](https://sciforum.net) [ MDPI Books ](https://www.mdpi.com/books) [ Preprints.org ](https://www.preprints.org) [ Scilit ](https://www.scilit.com) [ SciProfiles ](https://sciprofiles.com?utm_source=mpdi.com&utm_medium=bottom_menu&utm_campaign=initiative) [ Encyclopedia ](https://encyclopedia.pub) [ JAMS ](https://jams.pub) [ Proceedings Series ](/about/proceedings)

###  Follow MDPI 

[ LinkedIn ](https://www.linkedin.com/company/mdpi) [ Facebook ](https://www.facebook.com/MDPIOpenAccessPublishing) [ Twitter ](https://twitter.com/MDPIOpenAccess)

![MDPI](https://pub.mdpi-res.com/img/design/mdpi-pub-logo-white-small.png?71d18e5f805839ab?1740558760)

Subscribe to receive issue release notifications and newsletters from MDPI journals 

Acoustics Acta Microbiologica Hellenica Actuators Adhesives Administrative Sciences Adolescents Advances in Respiratory Medicine Aerobiology Aerospace Agriculture AgriEngineering Agrochemicals Agronomy AI AI Sensors Air Algorithms Allergies Alloys Analytica Analytics Anatomia Anesthesia Research Animals Antibiotics Antibodies Antioxidants Applied Biosciences Applied Mechanics Applied Microbiology Applied Nano Applied Sciences Applied System Innovation AppliedChem AppliedMath Aquaculture Journal Architecture Arthropoda Arts Astronomy Atmosphere Atoms Audiology Research Automation Axioms Bacteria Batteries Behavioral Sciences Beverages Big Data and Cognitive Computing BioChem Bioengineering Biologics Biology Biology and Life Sciences Forum Biomass Biomechanics BioMed Biomedicines BioMedInformatics Biomimetics Biomolecules Biophysica Biosensors Biosphere BioTech Birds Blockchains Brain Sciences Buildings Businesses C Cancers Cardiogenetics Catalysts Cells Ceramics Challenges ChemEngineering Chemistry Chemistry Proceedings Chemosensors Children Chips CivilEng Clean Technologies Climate Clinical and Translational Neuroscience Clinical Bioenergetics Clinics and Practice Clocks & Sleep Coasts Coatings Colloids and Interfaces Colorants Commodities Complexities Complications Compounds Computation Computer Sciences & Mathematics Forum Computers Condensed Matter Conservation Construction Materials Corrosion and Materials Degradation Cosmetics COVID Craniomaxillofacial Trauma & Reconstruction Crops Cryo Cryptography Crystals Current Issues in Molecular Biology Current Oncology Dairy Data Dentistry Journal Dermato Dermatopathology Designs Diabetology Diagnostics Dietetics Digital Disabilities Diseases Diversity DNA Drones Drugs and Drug Candidates Dynamics Earth Ecologies Econometrics Economies Education Sciences Electricity Electrochem Electronic Materials Electronics Emergency Care and Medicine Encyclopedia Endocrines Energies Energy Storage and Applications Eng Engineering Proceedings Entropy Environmental and Earth Sciences Proceedings Environments Epidemiologia Epigenomes European Burn Journal European Journal of Investigation in Health, Psychology and Education Fermentation Fibers FinTech Fire Fishes Fluids Foods Forecasting Forensic Sciences Forests Fossil Studies Foundations Fractal and Fractional Fuels Future Future Internet Future Pharmacology Future Transportation Galaxies Games Gases Gastroenterology Insights Gastrointestinal Disorders Gastronomy Gels Genealogy Genes Geographies GeoHazards Geomatics Geometry Geosciences Geotechnics Geriatrics Glacies Gout, Urate, and Crystal Deposition Disease Grasses Green Health Hardware Healthcare Hearts Hemato Hematology Reports Heritage Histories Horticulturae Hospitals Humanities Humans Hydrobiology Hydrogen Hydrology Hygiene Immuno Infectious Disease Reports Informatics Information Infrastructures Inorganics Insects Instruments Intelligent Infrastructure and Construction International Journal of Environmental Research and Public Health International Journal of Financial Studies International Journal of Molecular Sciences International Journal of Neonatal Screening International Journal of Orofacial Myology and Myofunctional Therapy International Journal of Plant Biology International Journal of Topology International Journal of Translational Medicine International Journal of Turbomachinery, Propulsion and Power International Medical Education Inventions IoT ISPRS International Journal of Geo-Information J Journal of Ageing and Longevity Journal of Cardiovascular Development and Disease Journal of Clinical & Translational Ophthalmology Journal of Clinical Medicine Journal of Composites Science Journal of Cybersecurity and Privacy Journal of Dementia and Alzheimer's Disease Journal of Developmental Biology Journal of Experimental and Theoretical Analyses Journal of Eye Movement Research Journal of Functional Biomaterials Journal of Functional Morphology and Kinesiology Journal of Fungi Journal of Imaging Journal of Intelligence Journal of Low Power Electronics and Applications Journal of Manufacturing and Materials Processing Journal of Marine Science and Engineering Journal of Market Access & Health Policy Journal of Mind and Medical Sciences Journal of Molecular Pathology Journal of Nanotheranostics Journal of Nuclear Engineering Journal of Otorhinolaryngology, Hearing and Balance Medicine Journal of Parks Journal of Personalized Medicine Journal of Pharmaceutical and BioTech Industry Journal of Respiration Journal of Risk and Financial Management Journal of Sensor and Actuator Networks Journal of the Oman Medical Association Journal of Theoretical and Applied Electronic Commerce Research Journal of Vascular Diseases Journal of Xenobiotics Journal of Zoological and Botanical Gardens Journalism and Media Kidney and Dialysis Kinases and Phosphatases Knowledge LabMed Laboratories Land Languages Laws Life Limnological Review Lipidology Liquids Literature Livers Logics Logistics Lubricants Lymphatics Machine Learning and Knowledge Extraction Machines Macromol Magnetism Magnetochemistry Marine Drugs Materials Materials Proceedings Mathematical and Computational Applications Mathematics Medical Sciences Medical Sciences Forum Medicina Medicines Membranes Merits Metabolites Metals Meteorology Methane Methods and Protocols Metrics Metrology Micro Microbiology Research Micromachines Microorganisms Microplastics Microwave Minerals Mining Modelling Modern Mathematical Physics Molbank Molecules Multimedia Multimodal Technologies and Interaction Muscles Nanoenergy Advances Nanomanufacturing Nanomaterials NDT Network Neuroglia Neurology International NeuroSci Nitrogen Non-Coding RNA Nursing Reports Nutraceuticals Nutrients Obesities Oceans Onco Optics Oral Organics Organoids Osteology Oxygen Parasitologia Particles Pathogens Pathophysiology Pediatric Reports Pets Pharmaceuticals Pharmaceutics Pharmacoepidemiology Pharmacy Philosophies Photochem Photonics Phycology Physchem Physical Sciences Forum Physics Physiologia Plants Plasma Platforms Pollutants Polymers Polysaccharides Populations Poultry Powders Proceedings Processes Prosthesis Proteomes Psychiatry International Psychoactives Psychology International Publications Purification Quantum Beam Science Quantum Reports Quaternary Radiation Reactions Real Estate Receptors Recycling Regional Science and Environmental Economics Religions Remote Sensing Reports Reproductive Medicine Resources Rheumato Risks Robotics Ruminants Safety Sci Scientia Pharmaceutica Sclerosis Seeds Sensors Separations Sexes Signals Sinusitis Smart Cities Social Sciences Société Internationale d’Urologie Journal Societies Software Soil Systems Solar Solids Spectroscopy Journal Sports Standards Stats Stresses Surfaces Surgeries Surgical Techniques Development Sustainability Sustainable Chemistry Symmetry SynBio Systems Targets Taxonomy Technologies Telecom Textiles Thalassemia Reports Therapeutics Thermo Time and Space Tomography Tourism and Hospitality Toxics Toxins Transplantology Trauma Care Trends in Higher Education Tropical Medicine and Infectious Disease Universe Urban Science Uro Vaccines Vehicles Venereology Veterinary Sciences Vibration Virtual Worlds Viruses Vision Waste Water Wild Wind Women World World Electric Vehicle Journal Youth Zoonotic Diseases Subscribe

© 1996-2025 MDPI (Basel, Switzerland) unless otherwise stated 

Disclaimer 

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. 

[ Terms and Conditions ](/about/terms-and-conditions) [ Privacy Policy ](/about/privacy)

We use cookies on our website to ensure you get the best experience.  
Read more about our cookies [here](/about/privacy). 

[Accept](/accept_cookies)

## Share Link


Copy

_clear_

## Share

https://www.mdpi.com/2943284

_clear_

Back to TopTop


