# documents

title: How Creatine Interacts with Weight Loss Medications | Curex
scrape_date: 2025-02-28T15:04:58.890304
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# How Creatine Interacts with Weight Loss Medications

Discover how creatine interacts with weight loss medications, its effects, benefits, and potential risks to optimize your fitness journey.

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Carbohydrates

### 

gr.

Sugar

### 

gr.

Fats

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gr.

Proteins

### 

Calories

![](https://cdn.prod.website-files.com/61bbbbd3e287ff6cf9bcbda8/676e7edb270d10dd80abd4af_curex2.webp)

### 

 

**Understanding Creatine**

 

  * Creatine is a popular supplement primarily used by athletes to improve muscle strength and enhance exercise performance.

 

  * It is naturally found in muscle cells and helps produce energy during high-intensity exercise or heavy lifting.



 

**Weight Loss Medications Overview**

 

  * Weight loss medications, also known as anti-obesity drugs, are prescribed to aid individuals in losing weight, especially when exercise and diet alone have not been sufficient.

 

  * These medications often work by suppressing appetite, increasing feelings of fullness, or inhibiting fat absorption.



 

**How Creatine Interacts with Weight Loss Medications**

 

  * **Energy and Metabolism:** Creatine aids in ATP production, potentially offsetting the reduction in energy levels some may experience from weight loss medications. This compensatory effect might help maintain exercise routines.

 

  * **Fluid Retention:** Creatine supplementation is often associated with fluid retention, which may counteract the weight loss effects of these medications in terms of visible weight on the scale, even if fat loss is occurring.

 

  * **Muscle Preservation:** Weight loss often leads to a reduction in muscle mass. Creatine may help preserve lean muscle during caloric deficits induced by weight loss medications, enhancing fat loss outcomes.

 

  * **Possible Gastric Interaction:** Some weight loss drugs can cause gastric side effects. Creatine should be consumed with adequate water to avoid potential digestive distress, ensuring compatibility with these medications.



 

**Considerations and Recommendations**

 

  * Consult a healthcare professional before combining creatine with weight loss medications to ensure personalized advice and monitoring.

 

  * Stay hydrated as both creatine and weight loss pills can impact fluid balance and hydration status.

 

  * Observe any changes in side effects when beginning creatine supplementation alongside weight loss medications for early intervention if necessary.



 

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### 

gr.

Carbohydrates

### 

gr.

Sugar

### 

gr.

Fats

### 

gr.

Proteins

### 

Calories

![](https://cdn.prod.website-files.com/61bbbbd3e287ff6cf9bcbda8/67bc788a8c8b6ce3a9036d53_1000_F_79808551_352ySE4vd4K0g31YyeeHRDNZbuH2qb9j.jpg)

### 

 

**Understanding Creatine**

 

  * Creatine is a popular supplement primarily used by athletes to improve muscle strength and enhance exercise performance.

 

  * It is naturally found in muscle cells and helps produce energy during high-intensity exercise or heavy lifting.



 

**Weight Loss Medications Overview**

 

  * Weight loss medications, also known as anti-obesity drugs, are prescribed to aid individuals in losing weight, especially when exercise and diet alone have not been sufficient.

 

  * These medications often work by suppressing appetite, increasing feelings of fullness, or inhibiting fat absorption.



 

**How Creatine Interacts with Weight Loss Medications**

 

  * **Energy and Metabolism:** Creatine aids in ATP production, potentially offsetting the reduction in energy levels some may experience from weight loss medications. This compensatory effect might help maintain exercise routines.

 

  * **Fluid Retention:** Creatine supplementation is often associated with fluid retention, which may counteract the weight loss effects of these medications in terms of visible weight on the scale, even if fat loss is occurring.

 

  * **Muscle Preservation:** Weight loss often leads to a reduction in muscle mass. Creatine may help preserve lean muscle during caloric deficits induced by weight loss medications, enhancing fat loss outcomes.

 

  * **Possible Gastric Interaction:** Some weight loss drugs can cause gastric side effects. Creatine should be consumed with adequate water to avoid potential digestive distress, ensuring compatibility with these medications.



 

**Considerations and Recommendations**

 

  * Consult a healthcare professional before combining creatine with weight loss medications to ensure personalized advice and monitoring.

 

  * Stay hydrated as both creatine and weight loss pills can impact fluid balance and hydration status.

 

  * Observe any changes in side effects when beginning creatine supplementation alongside weight loss medications for early intervention if necessary.



 

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How Creatine Interacts with Weight Loss Medications

 

**Understanding Creatine**

 

  * Creatine is a popular supplement primarily used by athletes to improve muscle strength and enhance exercise performance.

 

  * It is naturally found in muscle cells and helps produce energy during high-intensity exercise or heavy lifting.



 

**Weight Loss Medications Overview**

 

  * Weight loss medications, also known as anti-obesity drugs, are prescribed to aid individuals in losing weight, especially when exercise and diet alone have not been sufficient.

 

  * These medications often work by suppressing appetite, increasing feelings of fullness, or inhibiting fat absorption.



 

**How Creatine Interacts with Weight Loss Medications**

 

  * **Energy and Metabolism:** Creatine aids in ATP production, potentially offsetting the reduction in energy levels some may experience from weight loss medications. This compensatory effect might help maintain exercise routines.

 

  * **Fluid Retention:** Creatine supplementation is often associated with fluid retention, which may counteract the weight loss effects of these medications in terms of visible weight on the scale, even if fat loss is occurring.

 

  * **Muscle Preservation:** Weight loss often leads to a reduction in muscle mass. Creatine may help preserve lean muscle during caloric deficits induced by weight loss medications, enhancing fat loss outcomes.

 

  * **Possible Gastric Interaction:** Some weight loss drugs can cause gastric side effects. Creatine should be consumed with adequate water to avoid potential digestive distress, ensuring compatibility with these medications.



 

**Considerations and Recommendations**

 

  * Consult a healthcare professional before combining creatine with weight loss medications to ensure personalized advice and monitoring.

 

  * Stay hydrated as both creatine and weight loss pills can impact fluid balance and hydration status.

 

  * Observe any changes in side effects when beginning creatine supplementation alongside weight loss medications for early intervention if necessary.



 

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## Premium Medication you can trust

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### Initial Dosage

Your initial medication and dosage are carefully determined by doctors, taking into account your unique health profile. This ensures a personalized and safe treatment plan tailored to your specific needs.

### Titration

We gradually adjust your dosage to reach the optimal therapeutic level, ensuring maximum effectiveness while minimizing potential side effects.

### Additional Treatments

Our providers may also recommend medications such as metformin or supplements such as vitamin B12. We recognize the importance of managing side effects, so your care plan may include medication to alleviate them.

## Got questions? We have answers.

Do your plans include prescriptions and medications?

Curex plans cover everything from reviewing your medical intake to providing prescription medications, with free shipping included. There are no extra or hidden charges. Prescriptions are issued only after a medical provider reviews your information to confirm that the medication is suitable for you. Our service includes continuous support and regular follow-ups to ensure your treatment stays on track.

Our clinicians may order labs and additional medications for you, which would not be covered by the plan but for which you can use your insurance.

Please note: Compounded medications are tailored to individual needs or used in case of shortages, but they are not FDA-approved for safety or effectiveness. A prescription is required. Results may vary from person to person.

What medications do your providers prescribe?

We prioritize a personalized approach to your health. If your medical provider prescribes medication, options may include GLP-1 treatments such as compounded semaglutide (the active ingredient in Wegovy®* and Ozempic®*). Our providers prescribe only combination treatments not available at your local pharmacy that may include vitamin B12, etc. to help you achieve your goals faster.

Depending on your treatment goals, other medications such as metformin may also be considered. We recognize the importance of managing side effects, so your care plan might include medication to ease symptoms like nausea. Your well-being is always our top priority!

Please note that compounded medications are customized to meet individual patient needs and are not FDA-approved for safety or effectiveness. A prescription is necessary. Results may vary from person to person.

Curex and its pharmacy partners do not have any association with Novo Nordisk.

Will I be prescribed semaglutide if I sign up?

Your health journey is unique, and we tailor our care to match. Any prescriptions, including semaglutide, will be based on the expert assessment of the medical provider matched with you through our platform. You can trust that your treatment plan will be personalized to fit your specific needs. And if semaglutide is not prescribed, we will provide a full refund.

What is compounded medication?

Compounding involves creating customized medications to meet the specific needs of individual patients. For instance, a patient may require a liquid version of a medication that is only available in tablet form. Pharmacies can also compound medications using FDA-approved drugs that are on the FDA’s shortage list.

These compounded medications are made by state-licensed pharmacies that follow both federal and state regulations, including quality standards. However, when compounded in accordance with these laws, these medications are not subject to FDA approval and are not evaluated for safety or effectiveness.

Is compounded medication the same as generic medication?

Compounded medications differ from generic drugs. Generics require FDA approval by demonstrating bio-equivalence to the brand-name drug. In contrast, compounded medications are not FDA-approved. They are made based on a personalized prescription that may not be commercially available elsewhere or when a drug appears on the FDA’s shortage list. Compounding pharmacies must have the proper licensed facilities and comply with state and federal regulations before dispensing these medications.

Is insurance required?

No, Curex doesn’t require insurance. We offer clear and simple pricing, along with affordable medication options, making it easy and accessible to take care of your health.

Can I pay with an FSA or HSA card?

Yes! You can pay with your HSA or FSA card.

How much does treatment cost?

Semaglutide:

Prices for semaglutide start at only $149 per month for weekly doses of 0.25mg and 0.5mg. You can cancel anytime. Some people experience weight loss at these doses and higher doses aren't advisable due to a higher risk of side effects. If you need a higher dose to achieve your weight loss goals, we offer higher-dose plans for 1 mg, 1.7 mg and 2.4 mg of semaglutide for an additional $50 per month for each plan. 

Tirzepatide:

Prices for tirzepatide start at only $249 per month for weekly doses of 2.5 mg and 5 mg of tirzepatide.You can cancel anytime. Some people experience weight loss at these doses and higher doses aren't advisable due to a higher risk of side effects. If you need a higher dose to achieve your weight loss goals, we offer higher-dose plans for 7.5mg, 10 mg and 12.5 mg of tirzepatide for an additional $100 per month for each plan.

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Can you prescribe Ozempic®* or Wegovy®*?

Our providers focus on personalized medications and dosages that aren’t commercially available at your local pharmacy. While we don’t prescribe Ozempic®* or Wegovy®* directly, we may prescribe treatments containing the same active ingredient. These medications are specially compounded for you by a licensed pharmacy to meet your specific needs.

Are video visits with a provider required?

Our providers will review your information 100% online. Depending on where you live and the specifics of your medical history, our providers may require you to have a video visit or asynchronous visit via text message. If prescribed, you’ll get unlimited online access to message your provider as needed for follow-ups, adjustments, and answers to your questions.

What states do you serve?

Currently, we do not serve Arkansas, Connecticut, and New Mexico. However, we are always working to expand our reach, so stay in touch with us at [hi@getcurex.com](mailto:hi@curex.org?subject=Enquiry).

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[home](https://www.avivaplasticsurgery.com/) ■ [Blog](https://www.avivaplasticsurgery.com/blog/) ■ Optimize Your Weight Loss Journey with GLP-1 Medications, Exercise, and Nutrition

# Optimize Your Weight Loss Journey with GLP-1 Medications, Exercise, and Nutrition

At Aviva Plastic Surgery & Aesthetics, we strive to empower our clients with holistic wellness strategies that enhance weight loss results, improve overall health, and support sustainable lifestyle changes. For those on GLP-1 medications, such as semaglutide (Wegovy or Ozempic), incorporating weightlifting, creatine supplementation, and a high-protein diet can amplify results by preserving muscle mass, enhancing metabolism, and promoting satiety. This guide explores the science behind these strategies, offering actionable tips to optimize your weight loss journey and maximize long-term success.

## **1\. Why Weightlifting is Essential for Weight Loss**

**Preserving Muscle During Weight Loss**

When losing weight, especially with GLP-1 medications, the goal is to shed fat, not muscle. However, muscle loss can occur without proper exercise, slowing metabolism and reducing strength. Weightlifting helps preserve and even build muscle mass, ensuring that your body composition improves as you lose weight.

**Benefits of Weightlifting**

  * **Increased Metabolism:** Muscle tissue burns more calories at rest compared to fat, keeping your metabolism active.
  * **Enhanced Body Composition:** By retaining muscle, weight lifting ensures weight loss is primarily from fat.
  * **Bone and Joint Health:** Resistance training strengthens bones and stabilizes joints, reducing the risk of osteoporosis.



![Enhance Weight Loss with Weight Lifting, Creatine, and High-Protein Diet](data:image/svg+xml;base64,PHN2ZyB4bWxucz0iaHR0cDovL3d3dy53My5vcmcvMjAwMC9zdmciIHdpZHRoPSI2MDAiIGhlaWdodD0iNjAwIiB2aWV3Qm94PSIwIDAgNjAwIDYwMCI+PHJlY3Qgd2lkdGg9IjEwMCUiIGhlaWdodD0iMTAwJSIgc3R5bGU9ImZpbGw6I2NmY2ZjZjtmaWxsLW9wYWNpdHk6IDAuMDsiLz48L3N2Zz4=)![Enhance Weight Loss with Weight Lifting, Creatine, and High-Protein Diet](https://www.avivaplasticsurgery.com/wp-content/uploads/2024/11/weight-loss-journey.jpg)  
**How to Start**

  * Begin with **2–3 sessions per week** , focusing on major muscle groups like legs, back, chest, and shoulders.
  * Incorporate compound exercises such as **squats, deadlifts, and rows** to engage multiple muscles simultaneously.
  * Gradually increase weights and intensity to continually challenge your body.



## **2\. The Role of Creatine in Supporting Strength and Endurance**

**What is Creatine?**

Creatine is a naturally occurring compound that boosts muscle energy production, enhancing performance during resistance training and physical activity. It’s particularly beneficial during a calorie deficit, helping preserve muscle mass while improving strength.

**Benefits of Creatine Supplementation**

  * **Improved Strength and Stamina:** Creatine supports energy production, allowing for better gym performance and muscle growth.
  * **Enhanced Recovery:** Stronger muscles enable an active lifestyle, supporting weight loss.
  * **Cognitive Benefits:** Research shows creatine may improve brain health and cognitive function.



**Dosage Recommendations**

  * Take **3–5 grams of creatine monohydrate daily** , ideally mixed with water or a protein shake. Consistency is key for optimal results.



## 3\. Embracing a High-Protein Diet

**Why Protein is Critical**

Protein is vital for repairing muscle tissue post-exercise and promotes feelings of fullness, reducing hunger spikes and cravings. For those on GLP-1 medications, which regulate appetite, a high-protein diet complements their effects by supporting satiety and muscle preservation.

**How Much Protein is Enough?**

  * Aim for **1.2–1.6 grams of protein per kilogram of body weight** , or approximately **100–150 grams per day** for most individuals.
  * Adjust based on activity levels, weight loss goals, and age.



**Best Protein Sources**

  * **Lean meats, fish, eggs, tofu, Greek yogurt, and legumes** provide high-quality protein.
  * Consider **protein shakes or bars** to meet daily protein requirements, especially post-workout.



**Timing Your Protein Intake**

  * Spread protein consumption across meals to optimize absorption.
  * Consume a **protein-rich snack or meal post-workout** to maximize muscle repair and growth.



## **4\. Leveraging GLP-1 Medications for Weight Loss**

**How GLP-1 Medications Work**

GLP-1 medications, like semaglutide, mimic the body’s natural hormones to regulate insulin secretion and appetite. They reduce hunger and help control blood sugar, creating the perfect environment for effective weight loss.

**Combining GLP-1 Medications with Weightlifting and Nutrition**

  * **Weightlifting** helps ensure weight loss is fat-focused while preserving muscle.
  * **Creatine** supports exercise performance and recovery.
  * A **high-protein diet** complements GLP-1 by reducing hunger and supporting metabolic health.



**Building a Synergistic Approach**

By integrating exercise, supplementation, and diet, patients maximize the benefits of GLP-1 medications. This combined strategy accelerates weight loss while supporting long-term health and wellness.

## **5\. A Holistic Wellness Approach at Aviva Plastic Surgery & Aesthetics**

Beyond Weight Loss

At Aviva Plastic Surgery & Aesthetics, we believe in a comprehensive approach to health. Whether you are exploring GLP-1 medications, body contouring treatments, or wellness strategies, our goal is to help you achieve sustainable results.

Personalized Support

Our team works closely with patients to develop individualized plans that incorporate:

  * **Fitness routines tailored to your needs.**
  * **Supplement recommendations** to enhance your results.
  * **Nutritional guidance** for sustainable weight management.



**Additional Services**

We offer body contouring treatments that can enhance the results of your weight loss efforts. These services are designed to complement your hard work and help you look and feel your best.

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url: http://arxiv.org/abs/1711.00928v1
scrape_date: 2025-02-28T15:26:44.070117
content_type: markdown
hash: c321f7cad712ae6606596e17bbebe8edc05890c97900114cd5c50ca7227591e4
title:
[1711.00928v1] Physiological Tremor Increases when Skeletal Muscle is Shortened: Implications for Fusimotor Control

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# Quantitative Biology > Neurons and Cognition

**arXiv:1711.00928v1** (q-bio) 

[Submitted on 2 Nov 2017]

# Title:Physiological Tremor Increases when Skeletal Muscle is Shortened: Implications for Fusimotor Control

Authors:[Kian Jalaleddini](https://arxiv.org/search/q-bio?searchtype=author&query=Jalaleddini,+K), [Akira Nagamori](https://arxiv.org/search/q-bio?searchtype=author&query=Nagamori,+A), [Christopher M Laine](https://arxiv.org/search/q-bio?searchtype=author&query=Laine,+C+M), [Mahsa A. Golkar](https://arxiv.org/search/q-bio?searchtype=author&query=Golkar,+M+A), [RObert E. Kearney](https://arxiv.org/search/q-bio?searchtype=author&query=Kearney,+R+E), [Francisco J. Valero-Cuevas](https://arxiv.org/search/q-bio?searchtype=author&query=Valero-Cuevas,+F+J)

View a PDF of the paper titled Physiological Tremor Increases when Skeletal Muscle is Shortened: Implications for Fusimotor Control, by Kian Jalaleddini and 5 other authors

[View PDF](/pdf/1711.00928v1)

> Abstract:The involuntary force fluctuations associated with physiological (as distinct from pathological) tremor are an unavoidable component of human motor control. While the origins of the physiological tremor are known to depend on muscle afferentation, it is possible that the mechanical properties of muscle-tendon systems also affect its generation, amplification and maintenance. In this paper, we investigated the dependence of physiological tremor during tonic, isometric plantarflextion torque at 30% of maximum at three ankle angles. The amplitude of physiological tremor increased as calf muscles shortened in contrast to the stretch reflex whose amplitude decreases as muscle shortens. We used a closed-loop simulation model of afferented muscle to explore the mechanisms responsible for this behavior. We demonstrate that changing muscle lengths does not suffice to explain our experimental findings. Rather, the model consistently required the modulation of gamme-static fusimotor drive to produce increases in physiological tremor with muscle shortening--while successfully replicating the concomitant reduction in stretch reflex amplitude. This need to control gamma-static fusimotor drive explicitly as a function of muscle length has important implication. First, it permits the amplitudes of physiological tremor and stretch reflex to be decoupled. Second, it postulates neuromechanical interaction that require length-dependent gamma drive modulation to be independent from alpha drive to the parent muscle. Lastly, it suggests that physiological tremor can be used as a simple, non-invasive measure of the afferent mechanisms underlying healthy motor function, and their disruption in neurological conditions. 

Subjects: |  Neurons and Cognition (q-bio.NC)  
---|---  
Cite as: | [arXiv:1711.00928](https://arxiv.org/abs/1711.00928) [q-bio.NC]  
  | (or  [arXiv:1711.00928v1](https://arxiv.org/abs/1711.00928v1) [q-bio.NC] for this version)   
  |  <https://doi.org/10.48550/arXiv.1711.00928> Focus to learn more arXiv-issued DOI via DataCite  
Journal reference: | NCBI, 2017  
Related DOI:  | <https://doi.org/10.1113/JP274899> Focus to learn more DOI(s) linking to related resources   
  
## Submission history

From: Francisco Valero-Cuevas [[view email](/show-email/7f59f548/1711.00928)]   
**[v1]** Thu, 2 Nov 2017 20:45:07 UTC (3,197 KB)  


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Transforming Diabetes Care: The Molecular Pathways through Which GLP1-RAs Impact the Kidneys in Diabetic Kidney Disease

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#  Transforming Diabetes Care: The Molecular Pathways through Which GLP1-RAs Impact the Kidneys in Diabetic Kidney Disease 

by 

Merita Rroji

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Merita Rroji

[ SciProfiles ](https://sciprofiles.com/profile/630199?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name)[ Scilit ](https://scilit.com/scholars?q=Merita%20Rroji)[ Preprints.org ](https://www.preprints.org/search?search1=Merita%20Rroji&field1=authors)[ Google Scholar ](https://scholar.google.com/scholar?q=Merita%20Rroji)

Associate Professor Merita Rroji currently serves as a Lecturer at the University of Medicine, and a [...] 

Associate Professor Merita Rroji currently serves as a Lecturer at the University of Medicine, Tirana, and is a nephrologist at the University Hospital Center "Mother Tereza" in Tirana, Albania. She carried out her postgraduate studies and training in nephrology at the University Hospital of Tirana, Azienda Ospedaliero-Universitaria Policlinico Sant’Orsola Malpighi, Bologna and Gent University Hospital. She obtained her PhD in Internal Medicine, focusing on Nephrology, from the University of Medicine, Tirana. She was an “ISN Fellow” trained at Gent University. Following her PhD, she was appointed associate professor at the same university, the Department of Internal Medicine, Service of Nephrology. Professor Rroji's research interests center on Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), clinical aspects of nephrology, kidney transplantation, and haemodialysis and peritoneal dialysis techniques. 

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1,*[__](/cdn-cgi/l/email-protection#022d616c662f61656b2d6e2d676f636b6e2f72706d766761766b6d6c213232323a346633643236333b3261336433643230323532363066333632613237323032303631326732303232)[![](https://pub.mdpi-res.com/img/design/orcid.png?0465bc3812adeb52?1740558760)](https://orcid.org/0000-0003-1048-2579)and

Goce Spasovski

![](/bundles/mdpisciprofileslink/img/unknown-user.png)Goce Spasovski

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Prof. Dr. Goce Spasovski carried out his postgraduate studies and training in nephrology at the in a [...] 

Prof. Dr. Goce Spasovski carried out his postgraduate studies and training in nephrology at the University Hospital in Skopje, the University of Antwerp, Katowice, and the "Laiko“ University Hospital in Athens. His master's degree in medical science in nephrology was earned at the University of Skopje and his PhD at the Universities of Skopje and Antwerp. He is an active investigator in clinical trials related to anemia, hyperphosphatemia, and bone diseases in patients with chronic kidney disease, especially in bone biopsy-based studies. His academic career is supported by more than 330 published articles and book chapters in peer-reviewed and national journals, and lectures on topics related to chronic kidney disease, dialysis and mineral and bone disorders, and kidney transplantation. Also, he is a member of many professional societies, is an editor of the BANTAO Journal and Macedonian Medical Review, and is a member of the Editorial Board of several international nephrological journals. He finished his term as an ERA/EDTA Ordinary Council Member in 2009, but currently, he is a Chairman of the Committee for CME activities at ERA-EDTA. He is also a president of the Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs, a member of the ISN/COMGAN Central & East European Committee, EUTox group, ERBP board, and chairman of the ERBP hyponatremia group as well as of the Clinical workgroup at the COST initiative. 

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1

Department of Nephrology, Faculty of Medicine, University of Medicine Tirana, 1001 Tirana, Albania

2

University Clinic for Nephrology, Medical Faculty, University St. Cyril and Methodius, 1000 Skopje, North Macedonia

*

Author to whom correspondence should be addressed. 

_Biomedicines_ **2024** , _12_(3), 657; <https://doi.org/10.3390/biomedicines12030657>

Submission received: 15 February 2024 / Revised: 8 March 2024 / Accepted: 13 March 2024 / Published: 14 March 2024

(This article belongs to the Special Issue [Molecular Mechanisms and Novel Therapies for Chronic Kidney Disease: Focus on Diabetic Kidney Disease](        
    /journal/biomedicines/special_issues/96AAV80Q71
))  


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## Abstract

**:**

Diabetic kidney disease (DKD) is a substantial complication of type 2 diabetes (T2D), presenting challenges in chronic kidney disease (CKD) management. In addition to traditional and recent therapies, including angiotensin, converting enzyme (ACE) inhibitors, angiotensin receptor blockers, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists, the evolution of antihyperglycemic treatments has introduced a promising agent, glucagon-like peptide-1 receptor agonist (GLP-1RA) for the management of DKD. GLP-1RAs enhance insulin release and reduce glucagon release, offering a novel approach to DKD management. This review analyzes the molecular pathways through which GLP1-RAs confer renal protection in T2D and DKD, which are complex and multifaceted. They include modulation of renal hemodynamics, antioxidative and anti-inflammatory actions, metabolic regulation, and direct cellular effects. These mechanisms highlight GLP1-RA's potential as a therapeutic option for glycemic control and direct or indirect renal function protection in diabetic patients, emphasizing the potentiality of GLP-1RAs for dual therapy, with cardiovascular and renal protection as a holistic approach. Clinical evidence supports GLP-1RAs in reducing albuminuria and enhancing kidney outcomes, highlighting their value in a comprehensive DKD management strategy.

Keywords: 

[diabetic kidney disease](/search?q=diabetic+kidney+disease); [inflammation](/search?q=inflammation); [natriuresis](/search?q=natriuresis); [renal protection](/search?q=renal+protection)




##  1\. Introduction

Exploring glucagon-like peptide-1 receptor agonist (GLP1-RA) in renal protection, especially in diabetic kidney disease (DKD), reveals a refined molecular landscape. GLP-1 therapies show a wide range of beneficial effects on kidney health. These effects have been observed in both diabetic and non-diabetic models of chronic kidney disease (CKD) and acute kidney injury (AKI).

Both animal and clinical studies have demonstrated the effectiveness of GLP-1-based treatments in improving kidney function. We discuss several mechanisms that have been proposed to explain the renal effects of GLP-1RAs, including direct actions on renal hemodynamics, reduction of systemic and intraglomerular pressure, modulation of tubuloglomerular feedback, inhibition of the oxidative stress, inflammation, and fibrosis.

####  1.1. Multifaceted Roles of GLP-1 in Metabolic Regulation

Glucagon-like peptide-1 (GLP-1), a critical hormone pivotal in glucose regulation, plays diverse roles in its metabolism. It originates from the preproglucagon (PPG) precursor encoded by the glucagon (GCG) gene. This gene, exhibiting expression in various body regions such as the pancreas, intestines, and central nervous system (CNS), orchestrates the synthesis of GLP-1 and other related peptide hormones. The generation of GLP-1 predominantly occurs via the post-translational modification of proglucagon, facilitated by proprotein convertase subtilisin/kexin type 1 or 3 in L cells of the terminal ileum and colon, as well as neurons in the nucleus of the solitary tract [1].

Nutrients like glucose, amino acids, free fatty acids, and bile acids stimulate GLP-1 secretion. These stimulants influence the hormone’s release through intracellular calcium and cAMP pathways. The regulatory mechanisms of GLP-1 secretion are complex and must be fully elucidated. Despite its pancreatic production, GLP-1’s contribution to circulating levels and receptor-mediated actions external to the pancreas is minimal. The hormone exerts its effects through the GLP-1 receptor, a member of the class B G protein-coupled receptor family, which is widespread across various tissues, underscoring GLP-1’s extensive role in systemic homeostasis, including glucose metabolism [2].

GLP-1’s primary metabolic functions are centered around the glucose-responsive enhancement of insulin secretion and the suppression of glucagon release from the pancreas. Here, it augments the insulin secretion, encourages beta-cell proliferation, hinders apoptosis, and modulates the release of other hormones, such as somatostatin and glucagon [3,4,5].

Further, GLP-1 influences gastric emptying and intestinal motility, affecting postprandial blood glucose levels, satiety, and food intake potentially contributing to weight loss. Existing in two bioactive forms, GLP-1 undergoes rapid cleavage by dipeptidyl peptidase 4 (DPP4), an enzyme targeting not only incretins but also various molecules with implications of immune cell function. GLP-1 degradation products, however, do not regulate glucose homeostasis through GLP-1 receptors as they lack ligand properties for these receptors. Neutral endopeptidase also processes GLP-1, yielding variants that potentially affect glucose utilization in the liver. The active GLP-1 fraction reaching target organs is minimal before the enzymatic cleavage and metabolism, primarily in the kidneys [6,7].

The swift degradation of GLP-1 by DPP4, leading to a brief half-life, has driven the development of GLP-1 receptor agonists (GLP-1RAs) as an efficacious approach in diabetes management.

####  1.2. GLP-1RA Development

GLP-1RAs effectively mimic the actions of natural GLP-1, significantly impacting glucose metabolism and weight management. They amplify insulin secretion, attenuate glucagon release, support beta-cell functionality, and enhance insulin sensitivity. GLP-1RAs also slow the gastric emptying, that combined with their metabolic effects, contributes to decreased hemoglobin A1c (HbA1c) levels and reduced fasting glucose concentrations, which in turn facilitates weight loss through prolonged gastric emptying and increased satiety [8,9].

A pioneering approach in this realm involved using exendin-4, a compound sourced from the Gila monster’s saliva (Heloderma suspectum). Exendin-4 shares a structural similarity with GLP-1, sufficient to activate the GLP-1 receptor, yet exhibits resistance to degradation by DPP4. This discovery paved the way for pharmaceuticals like exenatide and lixisenatide. However, these exendin-4-based therapies are subject to renal elimination and necessitate regular administration due to their limited half-life [10].

Addressing this challenge, researchers have modified the human GLP-1 molecule to increase its resistance to DPP4 degradation and reduce renal clearance [1]. Innovative formulations have been developed, such as the covalent or noncovalent albumin binding found in albiglutide, semaglutide, and liraglutide or the attachment to antibody fragment crystallizable domains evident in dulaglutide.

The therapeutic impact of GLP-1RAs varies depending on their action duration. Short-acting agents like exenatide and lixisenatide intermittently activate GLP1 receptors, closely mirroring the physiological patterns of natural GLP1. This preserves their capacity to modulate gastric emptying and influence postprandial glucose levels. In contrast, long-acting GLP-1RAs, such as liraglutide, exenatide XR, albiglutide, dulaglutide, and liraglutide, ensure continuous receptor engagement. While superior in the management of fasting glucose and HbA1c levels, their persistent receptor stimulation may lead to tachyphylaxis, potentially diminishing their effectiveness in delaying gastric emptying. Nevertheless, both short- and long-acting GLP-1RAs demonstrate comparable efficacy in weight reduction [11].

Moreover, exenatide has been innovatively formulated into an extended-release microsphere, enabling slower release and less frequent dosing. This advancement has led to most GLP-1RAs requiring only weekly injections, except liraglutide, which is administered daily [12].

GLP-1RAs are now advised as the initial choice for injectable glucose-lowering treatments in type 2 diabetes due to their comparable or even better capacity to decrease HbA1c levels, coupled with the benefits of weight loss and a lack of inherent risk for hypoglycemic events, potentially even preceding the use of insulin. Additionally, it is possible to use GLP-1RAs in conjunction with basal insulin, available in separate and combined dosages. Notably, newer drugs such as semaglutide have demonstrated a superior effectiveness in reducing blood glucose levels aiding in weight loss [1,8].

A notable breakthrough in GLP-1RA therapy was the introduction of an orally administered version of the drug, specifically, oral semaglutide. Achieved by combining the medication with sodium N-(8-[2-hydroxybenzoyl]amino)caprylate(SNAC), this innovation elevates stomach pH levels and impedes pepsin activity, safeguarding the drug from degradation and enhancing its absorption [13].

####  1.3. Localization and Expression of Glucagon-like Peptide-1 Receptors in Renal Tissues

Identifying the glucagon-like peptide-1 receptor (GLP-1R) in 1992 has been pivotal in advancing the comprehension of its anatomical distribution, particularly within the renal system [14]. Various methodologies, such as RT-PCR and in situ hybridization, have been employed to detect GLP-1R mRNA in this way to indicate gene transcription. However, these techniques have limitations in confirming the presence of functional GLP-1Rs, as the correlation between mRNA and protein levels might be inconsistent [15].

Studies across humans, mouse, and rat models have confirmed the presence of GLP-1R transcripts in kidney tissues. However, the specificity of these findings at the cellular level has been constrained due to the utilization of homogenized kidney samples. Focused research has identified GLP-1R mRNA in rat glomeruli and proximal convoluted tubules, as well as in the mouse glomerular capillaries and renal arteries [16].

An alternative method, employing radioactively labeled GLP-1, detected GLP-1R in human renal arteries but not within the tubular system. Initial studies using commercially available polyclonal antibodies indicated the presence of GLP-1R in various kidney regions, including the glomeruli and renal arteries. However, these antibodies were later identified as having low specificity [17].

A monoclonal antibody specifically targeting the extracellular domain of the GLP-1R was developed to enhance precision in detecting these receptors. This antibody showed increased specificity, selectively staining cells transfected with GLP-1R, facilitating a more accurate localization of these receptors. Immunohistochemistry studies leveraging this antibody have revealed that GLP-1R is predominantly located in smooth muscle cells within the renal vasculature rather than in tubular segments or endothelial cells, underscoring its specific distribution in these areas [18]. Further research utilizing this extensively validated monoclonal antibody has provided novel insights into GLP-1R localization, indicating its exclusive expression in both monkeys’ and humans’ preglomerular vascular smooth muscle cells and juxtaglomerular cells [19]. However, the precise intracellular localization of GLP-1R remains to be fully elucidated [18,19]. Additionally, GLP-1R has been identified as not being uniformly distributed within the vascular system [20,21]. Techniques such as in vivo autoradiography, immunohistochemistry, and in situ hybridization have identified GLP-1R in the arterial VSMCs of the kidneys in rats, mice, and monkeys, but only within a limited group of cells [18].

There is a significant gap in our understanding of how these receptors behave in live organisms compared to cell cultures [22,23]. Jensen et al. [24] discovered that GLP-1R is located in the renal microcirculation, i.e., in afferent arterioles. The experiments on rodents showed specific receptor binding, and in rats, GLP-1 infusion has led to an increased blood pressure, renal blood flow, and urine flow. Furthermore, it was found that GLP-1 and exendin-4, a GLP-1 analog, impacted afferent arterioles’ responses to pressure changes in isolated mouse kidneys, indicating a role in modulating renal blood flow [6].

GLP-1R activation in vascular smooth muscle cells increases cyclic AMP (cAMP), which in turn activates the activation of protein kinase A (PKA) and Exchange protein directly Activated by cAMP (EPAC). These pathways cause vasodilation by activating various potassium channels at the same time increasing the calcium release from the sarcoplasmic reticulum. This process is similar to GLP-1R’s function in pancreatic cells. The mechanisms by which GLP-1R activation influences renal vasodilation still need to be fully understood despite its observed effects on different arterial systems [15].

The inconsistent detection of GLP-1R in renal blood vessels, particularly in VSMCs, complicates our understanding of GLP-1’s role in kidney function, i.e., the body’s handling of albumin, water, and salt, either directly or through the kidneys and other mechanisms. Thus, the exact role of GLP-1 in both vascular and kidney health remains a topic that needs further study and clarification.

##  2\. The Role of GLP-1 Receptor Agonists in Renal Protection and Diabetic Kidney Disease Management

GLP-1RAs have attracted considerable interest for their potential effects on renal hemodynamics and their role in reducing glomerular hyperfiltration. These pharmaceutical agents successfully inhibited hyperfiltration and ameliorated albuminuria while concurrently attenuating renal inflammation and oxidative stress. Furthermore, they played a pivotal role in preserving the glomerular filtration rate (GFR) exhibiting significant reduction in the histopathological manifestations associated with diabetic nephropathy [5].

####  2.1. Understanding the Complex Pathophysiology of Diabetic Kidney Disease: Identifying Molecular Sites for Therapeutic Interventions

DKD is a common and severe complication in individuals with diabetes, affecting about one-third of those diagnosed. The presence of pathological levels of albuminuria, diabetic glomerular lesions, and a decline in GFR characterizes it. The pathophysiology of DKD progression is complex and involves multiple molecular pathways. These pathways, including inflammatory processes, oxidative stress, structural changes within the kidneys, alterations in blood flow dynamics, and metabolic disorders, trigger harmful physiological events [25].

High glucose levels stimulate the production of growth factors, such as transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF), which are the key mediators in mesangial cell proliferation and matrix expansion. These growth factors activate mesangial cells to produce excessive extracellular matrix components, leading to glomerulosclerosis, a hallmark of DKD characterized by thickening of the glomerular basement membrane and expansion of the mesangial matrix. This proliferation disrupts the typical architecture and function of the glomerulus and impairs filtration, contributing to the progressive decline in renal function seen in DKD [26].

Hyperglycemia plays a significant role in the pathogenesis of DKD, triggering a complex network of mechanisms leading to renal damage. The process begins with the formation of advanced glycation end products (AGEs) and the activation of their receptor (RAGE), initiating a cascade of signaling events, including the upregulation of protein kinase C, nuclear factor-kappa B, and transforming growth factor-β (TGF-β). This chain of events leads to the increased production of reactive oxygen species (ROS) and a chronic inflammatory response, pivotal in the development and progression of DKD [27].

RAGE activation further contributes to renal damage by promoting glomerular matrix production and oxidative stress through mitochondrial superoxide production. It also induces the epithelial–mesenchymal transition of renal tubular cells, leading to interstitial fibrosis. Experimental studies highlight RAGE-mediated mitochondrial dysfunction, often via NAD(P)H oxidase activation, as an early indicator of DKD, preceding clinical manifestations such as albuminuria and histological changes. Despite these insights, clinical trials focusing on oxidative stress and inflammation have not yet confirmed the effectiveness of targeted therapies, underscoring the importance of strict glucose control [28].

In the early stages of diabetes, there is a notable increase in intraglomerular pressure coupled with hyperfiltration, which is pivotal in the genesis and exacerbation of DKD. This hyperfiltration phenomenon can be partly attributed to anomalies in tubuloglomerular feedback mechanisms [28,29]. Abnormalities in the feedback mechanisms between different kidney parts can partially explain this increased filtration. During hyperglycemia, glucose filtration increases, leading to more glucose and sodium reabsorbing in the early part of the kidney’s tubules. This alteration reduces the amount of sodium reaching the distal tubular macula densa, decreasing afferent arteriolar resistance and raising intraglomerular pressure. Furthermore, the imbalance in vasoactive substances such as angiotensin II and endothelin-1 play a significant role in this dysregulation [30].

Glomerular hypertension exerts substantial mechanical stress on the capillary walls, being a precursor to glomerulosclerosis and the depletion of peritubular capillaries. Moreover, it facilitates increased protein filtration into the tubular lumen, which triggers the synthesis of proinflammatory and profibrotic factors with accelerated kidney damage [31].

In addition, diabetes and hyperglycemia increase the energy that cells in the kidney tubules need to enhance glucose reabsorption and increase filtration. At the same time, the oxygen supply to the kidneys is reduced in DKD due to the loss of peritubular capillaries and development of fibrosis (scarring) in the kidney’s tissue. This mismatch between oxygen demand and supply leads to hypoxia that worsens kidney damage by promoting inflammation, oxidative stress, impairment of cellular waste removal processes (autophagy), and further fibrosis. DKD animal models have demonstrated that interventions to decrease hypoxia can improve renal function [32].

Recent studies have also highlighted the importance of autophagy, a critical cellular process for maintaining balance within cells by breaking down large molecules and organelles. Impaired autophagy, especially in podocytes, exacerbates kidney damage under diabetic conditions. Additionally, epigenetics, which refers to changes in gene expression that occur without alterations in the DNA sequence, has gained attention in understanding DKD. This genetic memory leads to a continued expression of genes and phenotypes associated with high blood sugar levels, even after blood sugar normalization, indicating the complex and enduring impact of diabetes on kidney health and DKD progression [33,34].

Recently, researchers have been investigating how medications known as GLP-1RAs, primarily used in treating type 2 diabetes, might influence the kidneys and affect DKD progression [35]. The use of GLP-1RAs has been associated with improved kidney outcomes, including reduced albuminuria and preservation of the filtration rate. These findings have sparked interest in the potential kidney-protective benefits of GLP-1RAs for patients with DKD [36,37].

####  2.2. Impact of Glycemic Control and GLP-1 Receptor Agonists on CKD Progression: Mitigating Hyperfiltration and Albuminuria in Diabetes

Hyperfiltration, identified as an initial marker of DKD, is intricately linked to hyperglycemia [38]. The pathophysiological bridge between hyperglycemia and hyperfiltration predominantly involves the upregulation of sodium reabsorption via the SGLT-2 cotransporters, leading to adjustments in tubuloglomerular feedback and subsequently modulating the blood flow within the glomerular afferent arterioles. The efficacy of strict glucose regulation in mitigating the incidence of microalbuminuria and macroalbuminuria underscores its significance as a cornerstone in managing early CKD stages.

Intensive glycemic management reverses hyperfiltration, particularly in type 1 diabetes mellitus (T1DM) with insulin therapy and well controlled blood glucose levels. In addition to the improvement in hyperfiltration state, the therapy significantly reduces the risk and progression of albuminuria as a critical marker of nephropathy. Namely, the risk of microalbuminuria and albuminuria appearance has been reduced by 39 and 54 percent, respectively [39].

Furthermore, the intensive glycemic control has delayed the onset and progression of an early stage of diabetic microvascular complications in Japanese patients with T2D and the progression of nephropathy [40]. The discussion extends to the potential benefits of GLP-1RAs in the prevention of DKD going beyond glycemic control. Indeed, their mechanistic pathways of renal protection include improved metabolic control and modulated inflammatory response, retarding the progression to macroalbuminuria and thus, preserving kidney function.

Clinical trials have shown the safety and efficacy of GLP-1RAs in patients with moderate to severe kidney dysfunction, improving blood sugar control and reducing body weight. Studies like HARMONY 8 [41], LIRA-RENAL [42], AWARD-7 [43], and PIONEER 5 [44] compared GLP-1RAs to other treatments such as sitagliptin, placebo, or insulin glargine, demonstrating GLP-1RAs’ superiority or comparable efficacy in controlling glycemia. Although these trials indicated positive outcomes on surrogate kidney markers like albuminuria with no harmful effects on kidney function, they were not designed to conclusively determine the impact on significant kidney outcomes due to their short duration and limited power. GLP-1RAs, such as liraglutide [42] and semaglutide [45], have been shown to significantly reduce the progression of macroalbuminuria among diabetic patients, indicating a potential protective effect on kidney function without markedly altering the eGFR. This observation suggests that while GLP-1RAs effectively slow the progress to more severe stages of albuminuria, their impact on overall kidney disease progression in diabetic patients might be greater than changes in albuminuria levels. Indeed, further analysis and data suggest that GLP-1RAs offer broader renal protection by potentially reducing albuminuria (both macro- and microalbuminuria) and slowing the decline in kidney function over time [5,46].

####  2.3. Exploring the Influence of GLP-1 Receptor Agonists on Renal Hemodynamic

GLP-1RAs have attracted considerable scholarly interest for their prospective influence on renal hemodynamics. These agents attenuate glomerular hyperfiltration, a process facilitated by their capacity to increase diuresis and natriuresis.

####  2.3.1. Exploring the Dynamic Role of GLP-1R and GLP-1RA in Renal Natriuresis and Renal Hemodynamic: Acute and Chronic Perspectives

Exploring the dynamic role of GLP-1R and GLP-1RA unveils their significant impact on renal natriuresis and hemodynamics. In addition, the tubular effects of GLP-1R activation, acute and chronic responses, and the mechanisms driving these responses have been investigated.

Experimental and human studies have elucidated the crucial role of GLP-1 in modulating renal physiology, mainly through its tubular effects that induce natriuresis and diuresis. This mechanism primarily involves the inhibition of the Na+/H+ exchanger 3 (NHE3) in the proximal tubules, leading to decreased sodium reabsorption and enhanced natriuresis. GLP-1 exerts this effect by binding to its receptor, which activates PKA and results in the phosphorylation of NHE3, thereby diminishing sodium reabsorption. The observation that GLP-1 receptors are absent in proximal tubules suggests that the natriuretic responses to GLP-1-targeted therapies are likely mediated through indirect mechanisms rather than direct effects on these tubules. Additionally, GLP-1RAs have been shown to potentially increase renal blood flow and decrease vascular resistance, effects attributed to the stimulation of local nitric oxide production [15,24,47,48].

In research studies with anesthetized rats and various animal models, acute activation of GLP-1R reduces sodium reabsorption in the proximal tubules with a less marked effect in spontaneously hypertensive rats, suggesting these effects might also be due to GLP-1R located outside the kidney or other natriuretic mechanisms [49]. Data from human studies also present inconsistent results, indicating possible variations in the experimental setups [50,51]. Thus, the relationship between GLP-1RAs-induced natriuresis and its kidney-protective effects might be considered through the activation of tubuloglomerular feedback. This mechanism potentially reduces glomerular hyperfiltration and pressure stemming from increased distal sodium chloride delivery due to decreased NHE3 activity. Although this effect has been shown in standard rat models, clinical studies in patients with T2D, with or without DKD, have inconsistently shown an acute reduction in eGFR following GLP-1RA administration [51,52].

Nonetheless, a notable and consistent finding from these studies is a significant decrease in albuminuria, suggesting a connection between enhanced sodium transport to the distal nephron, increased afferent arteriolar resistance, reduced intraglomerular pressure, and the prevention of hyperfiltration, which is a common early feature of diabetic nephropathy [53,54].

Furthermore, GLP-1Rs have been identified within the renin-secreting cells of the juxtaglomerular apparatus, a critical area for blood pressure regulation. It is reported that when GLP-1 is infused into humans, it enhances natriuresis—the process by which the kidneys excrete sodium into the urine—without significantly impacting renin secretion [55]. This observation suggests that GLP-1 may contribute to lowering blood pressure through mechanisms that bypass the direct activation of the renin system [56].

Additionally, the role of extrarenal GLP-1Rs and a general increase in cAMP production following GLP-1R activation might contribute to natriuresis, paralleling the kidney’s response to glucagon. GLP-1R-expressing neurons in the brain are also considered to potentially influence water and salt balance [57,58].

Interestingly, GLP-1 infusion activates GLP-1R present in the walls of the renal pelvis and stimulates renal afferent nerves increasing renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR), mediating the diuretic and natriuretic effects of GLP-1 by the neural pathways. Furthermore, approaches like therapeutic renal denervation (T-RDN) and selective afferent renal denervation (A-RDN) were shown to enhance these effects while moderating the associated pressure and tachycardic responses [59].

These observations underscore a complex interaction of GLP-1 with renal nerves in regulating the sodium and water balance, essential for maintaining fluid balance and blood pressure stability. Additionally, the tubular effects of GLP-1R activation involve a blend of direct and indirect mechanisms, implicating the nervous system, renin–angiotensin system (RAS), and the regulation of atrial natriuretic peptide (ANP) [60,61].

Regarding chronic effects, GLP-1RA like lixisenatide was shown to reduce NHE3 activity in overweight T2D patients, leading to an increased natriuresis over eight weeks. Nevertheless, long-term GLP-1RA treatment has only slightly increased sodium excretion in people with type 2 diabetes, raising questions about the long-term impact of GLP-1R activation on the kidneys’ sodium handling and blood pressure control [15]. This has led to speculation about possible GLP-1R desensitization over time.

Although a direct link between GLP-1RA-induced natriuresis and kidney-protective effects is not well established, the presence of GLP-1R in the vascular smooth muscle cells of the afferent arteriole may be viewed as a key site for autoregulatory resistance changes. Thus, any direct renal vasodilatory effect of GLP-1 could impair renal autoregulation, negatively impacting renal function.

####  2.3.2. Effects on Renal Autoregulation

Renal autoregulation involves at least two main mechanisms: the myogenic response and tubuloglomerular feedback (TGF). Both mechanisms operate on the afferent arteriole and the distal part of radial arteries, contributing to the primary pressure drop in the kidneys. The myogenic response, intrinsic to vascular smooth muscle cells, causes constriction in response to increased intravascular pressure. The exact mechanism linking increased wall stress to constriction has yet to be fully understood. Presently, it is known that depolarization as a part of the process may be inhibited by antagonists of voltage-operated Ca2+ channels. Additionally, the transient receptor potential and epithelial Na+ channels are implicated in this depolarization [62,63,64].

TGF is a critical regulatory mechanism in the kidneys, initiated when the macula densa cells detect an increase in sodium chloride (NaCl) concentration in the filtrate at the junction of the loop of Henle and the distal convoluted tubule, indicating elevated GFR. In response, these cells release signaling molecules like adenosine and ATP, which cause the nearby afferent arteriole to constrict, thereby reducing blood flow into the glomerulus and decreasing GFR towards normal levels. Although primarily a local mechanism, the vasoconstriction effects of TGF can influence adjacent vascular structures and potentially synchronize responses across multiple nephrons through gap junctions. This interaction, along with the myogenic response—a separate mechanism that adjusts vessel tone in response to blood pressure changes—ensures stable renal perfusion and filtration rates, illustrating the intricate balance of renal regulatory processes to maintain systemic homeostasis [15].

The effect of GLP-1RA on renal function varies across different health conditions. Increased lithium clearance following GLP-1R activation in humans [56] and rodents [65,66] suggests enhanced outflow from the proximal tubule, indicating that TGF activation may counterbalance the increased tubular flow, potentially leading to a decrease in GFR. While acute GLP-1 treatment in animal studies appears to attenuate the myogenic response, leading to afferent arterioles’ dilatation, in type 2 diabetic patients with normal kidney function, the short-term treatment with GLP-1Ra did not significantly affect GFR, suggesting preservation of the myogenic response and renal autoregulation [67].

The effects of an extended GLP-1R activation on renal autoregulation in type 2 diabetes remain to be determined [68]. At an early stage of DKD, it is postulated that more significant sodium reabsorption through SGLT2 and unresponsiveness of TGF leads to hyperfiltration. Thus, a possible early effect of GLP-1 may attenuate this hyperfiltration by reducing sodium reabsorption in the proximal tubule. Hence, the stabilization or enhancement of GFR by GLP-1 treatment in the initial phases of renal impairment may be plausible. However, with the progression of kidney disease and increasing loss of nephrons that impaired GFR, the impact on reduction in proximal reabsorption by GLP-1R agonists may be questionable.

In placebo-controlled trials of type 2 diabetes patients with moderate to severe CKD, GLP-1R agonists significantly slowed the decline in eGFR. This could indicate that the vasodilatory aspects attained by the activation of GLP-1R could outweigh the TGF activation [43].

####  2.4. GLP-1RAs: Effect on Blood Pressure Control in Type 2 Diabetes

GLP-1RAs may help in the blood pressure control through multiple mechanisms, impacting the central nervous and peripheral systems. The GLP-1 receptor, found in essential brain areas like the hypothalamus and brainstem, regulates sympathetic nervous system activity, often enhanced in hypertension.

Along with central mechanisms, GLP-1Rs in the vascular system, such as those found in endothelial cells and vascular smooth muscle cells, help maintain the tone of the vascular system. It is primarily achieved through signaling pathways that enhance vasodilation, helping to lower blood pressure [69,70]. Specifically, GLP-1 signaling in the vascular system supports endothelium-mediated vasodilation [71], indicating an integral role in cardiovascular health [72].

Another critical aspect of GLP-1RAs’ effect on blood pressure is related to their action on renal function. Through the promotion of natriuresis, these agents assist in the regulation of the extracellular fluid volume, directly influencing blood pressure control that is confirmed in experimental studies [52]. In addition, GLP-1RAs influence blood pressure control through short- and long-term effects, impacting renal function, vascular tone, and insulin sensitivity. Acutely, GLP-1RAs induce diuresis and natriuresis in parallel with the increasing GFR and inhibition of the sodium reabsorption in the kidneys, thereby supporting a role in the maintenance of the sodium balance and prevention of volume expansion. Conversely, GLP-1R blockade leads to decreased GFR and increased sodium reabsorption, suggesting that endogenous GLP-1R signaling helps regulate physiological blood pressure homeostasis. Long-term, GLP-1R blockade raises blood pressure and worsens renal outcomes in hypertensive subjects, confirming GLP-1R activity in the modulation of renal sodium handling, the renin–angiotensin system (RAS), and insulin sensitivity [73].

Overall, GLP-1RAs may offer a multifaceted approach to hypertension management targeting the nervous system in reducing sympathetic activity, enhancing vascular function for better blood flow, and improving renal sodium handling to stabilize fluid balance. Additionally, their potential to counteract systems like the renin–angiotensin system (RAS) and the sympathetic nervous system (SNS), additionally underscores their role in mitigating hypertension. These combined actions make GLP-1RAs a promising therapeutic option for blood pressure control, particularly in metabolic disorders [52,74].

Recent meta-analysis suggests that semaglutide, a GLP-1 receptor agonist, significantly lowers systolic blood pressure (SBP) in individuals with T2D, independent of its blood glucose-lowering effects. Despite these known benefits, it remains unclear whether semaglutide can also regulate the dysregulation of blood pressure’s circadian rhythm, and what its long-term effects are [75].

Nevertheless, beyond glycemic and blood pressure control, other potential mechanisms for preserving renal function with a GLP-1R agonist treatment include anti-inflammatory actions, reduced fibrosis, and reduced glomerular sclerosis [15].

####  2.5. GLP-1 Receptor Agonists: Bridging Antioxidative and Anti-Inflammatory Mechanisms in Diabetes, Atherosclerosis, and Kidney Function

Recent evidence underscores the pivotal role of GLP-1RA in mitigating oxidative stress and inflammation, which is crucial in managing diabetes, particularly for DKD and CV health. GLP-1RA plays a significant role in glucose metabolism and significantly reduces oxidative stress markers through the receptor-mediated activation of pathways such as cAMP, PI3K, and PKC. This leads to the enhanced activation of Nrf-2 and strengthens the body’s antioxidant defenses, which is crucial in diabetes, where there is an increase in free radicals and a weakened antioxidant defense [76,77]. Specifically, GLP-1Ra therapies have been shown to reverse hepatic steatosis and improve insulin sensitivity in diabetic models, highlighting their antioxidative efficacy. These findings are supported by in vitro and in vivo studies demonstrating GLP-1’s protective action against oxidative damage and its essential role in preventing diabetes-related complications, such as cardiac remodeling and cardiovascular disease. Importantly, GLP-1 plays a crucial role in oxidative stress reduction within tissues, restoring mitochondrial functions, and preventing oxidative harm. Such beneficial impacts contribute to averting the loss of podocytes and dysfunction in mesangial and endothelial cells [5,15,78].

Recent studies underscore the beneficial effects of GLP-1RAs on oxidative stress mechanisms in diabetic nephropathy, potentially curbing CKD progression. Specifically, liraglutide has been shown to elevate levels of critical antioxidative enzymes, such as catalase and glutathione peroxidase-3, in Streptozotocin (STZ)-induced diabetic mice, indicating its protective role against tissue oxidative stress [79]. Likewise, lixisenatide enhanced renal tissue’s total antioxidant capacity and reduced oxidative stress markers, including Malondialdehyde (MDA), alongside the normalization of iNOS and COX-2 expressions in a high-fat diet mouse model [80]. Exendin-4’s role extends to inhibiting increases in TGFβ, type 1 collagen, and fibronectin mRNA in diabetic mice’s kidneys, markers indicative of DKD [81]. Furthermore, liraglutide reduced superoxide production and normalized NADPH oxidase complex components in STZ-induced diabetic animals, correlating with reduced albuminuria—a finding supported by in vitro studies on human mesangial cells [82]. Additionally, the combined treatment of exenatide and olmesartan in obese, insulin-resistant rats showed a significant decrease in Nox4 expression and increased antioxidative enzymes, effectively reducing albuminuria [83]. GLP-1RAs also counteract fibrosis and reduce extracellular vesicle secretion in tubular epithelial cells under high-glucose conditions, protecting against ischemia-reperfusion injury by mitigating oxidative stress and inflammation [84,85].

The interaction between the immune system and DKD has become increasingly evident, with kidney biopsies revealing accumulations of immune cells, notably macrophages and T-cells, and elevated levels of proinflammatory cytokines (TNF-alpha, MCP-1/CCL2, IL-6, IL-1β), orchestrated by NF-κβ [86]. This inflammatory cascade, fueled by high glucose levels and AGEs, activates pattern recognition receptors, leading to chronic inflammation and mitochondrial dysfunction, culminating in fibrosis and end-stage kidney disease [86]. GLP-1RAs have emerged as a significant counterforce, mimicking the effects of endogenous GLP-1 by activating GLP-1 receptors, which leads to a reduction in proinflammatory responses and direct beneficial impacts on kidney and vascular tissues. In DKD, GLP-1RAs like liraglutide mitigate renal inflammation by decreasing macrophage infiltration and inflammatory markers [5,15] while also demonstrating efficacy in non-diabetic kidney injury models and diseases characterized by inflammation, such as asthma and psoriasis [87].

The role of GLP-1RAs extends to vascular inflammation, where they reduce endothelial dysfunction and atherosclerosis by dampening the presentation of adhesion molecules and reducing oxidative stress through the AMPK and MAPK pathways [87], along with enhancing Sirtuin-6 expression, thereby modulating inflammatory responses in cardiovascular diseases [88]. Notably, GLP-1-based therapies have been shown to ameliorate cardiac dysfunction in disease models by inhibiting proinflammatory mediators [53,89]. Beyond their anti-inflammatory effects, these therapies improve insulin sensitivity and lipid metabolism, addressing critical aspects of diabetes management and reducing cardiovascular risk [90,91,92,93,94,95]. Liraglutide, in particular, has been highlighted for its atheroprotective effects, stabilizing plaques, improving endothelial function, and directly inhibiting atherosclerotic lesion development [96,97,98,99,100]. Table 1 summarizes the antioxidative and anti-inflammatory mechanisms of diabetes and its impact on atherosclerosis and kidney function.

####  2.6. Targeting Obesity-Induced CKD: The Multifaceted Role of GLP-1R Agonists in Metabolic and Renal Health

Obesity is a significant contributor to CKD, highlighting the importance of treating individuals with obesity and CKD to reduce its associated morbidity. The causal relationship between obesity and CKD has been validated through Mendelian randomization analyses, which utilize genetic risk scores to demonstrate the impact of BMI on CKD and arterial stiffness [103]. These genetic studies, including analyses from the UK Biobank, point to both central and general adiposity as significant, independent factors in CKD causation, with diabetes, blood pressure, and their correlates being significant explanatory variables [42]. This body of evidence highlights the importance of weight management in the primary prevention and control of CKD and subclinical vascular diseases, underlining obesity’s significant role across various kidney disorders and its largely independent effects on blood pressure and type 2 diabetes [104].

The pathophysiology behind obesity-related kidney disease is multifaceted, involving adipose tissue accumulation that affects kidney hemodynamics, leading to conditions such as glomerulomegaly and fibrosis. Adiposity impacts inflammatory adipokines, affecting renal function through mechanisms like leptin-induced hypertension and adiponectin-related podocyte dysfunction [105]. Furthermore, obesity’s influence on the renin–angiotensin–aldosterone system and the lipotoxic activity within the kidney underscores the complex interaction between obesity and renal health. The exacerbation of CKD by type 2 diabetes (T2D), an obesity complication, further complicates the picture. T2D accelerates kidney damage through insulin resistance, affecting podocyte function and promoting oxidative stress and fibrosis. Insulin resistance in T2D leads to increased insulin secretion, growth factor release, and dysregulation of the glomerular filtration barrier, culminating in the obesity-related glomerulopathy and further kidney injury [106,107].

This intricate web of associations between obesity, T2D, and CKD highlights the urgent need for integrated approaches for the management of these conditions. In this context, the therapeutic potential of GLP-1R agonists emerges as a beacon of hope [108]. Previous research has established that such agonists can significantly reduce food intake, body weight, and blood glucose levels in obese rats. Consistent with these findings, it was shown that GLP-1RA effectively reverses the metabolic disorders induced by a high-fat diet (HFD), including the alleviation of elevated body weight, hyperlipidemia, and impaired glucose tolerance [106]. Hence, GLP-1 receptor agonists could help fight obesity and its complications partially by increasing the number of fat cells and converting white fat to beige fat, which burns more calories. This increases energy use, aiding in weight control and metabolic health. Another significant mechanism is GLP-1RA’s capacity to mitigate tubular damage and inflammation within the kidneys. Research using the db/db mouse model, which simulates obesity, has shown increased levels of GLP1 can reduce histological signs of tubulointerstitial damage and decrease the renal expression of proinflammatory markers such as TNFα and Ccl5. This reduction in inflammation is accompanied by a decrease in the infiltration of CD3+ T cells and F4/80+ macrophages into the kidney [102]. Mice with elevated GLP1 expression also demonstrate a notable improvement in survival rates.

Furthermore, studies have identified that the absence of GLP1R can lead to spontaneous kidney damage, including albuminuria and glomerulosclerosis, conditions that worsen in the context of type-1 diabetes. However, treatment with liraglutide, a type of GLP-1RA, has been shown to enhance podocyte structure and reduce albuminuria and glomerulosclerosis [109]. Furthermore, GLP-1RA’s renal protective role is highlighted through its capacity to improve renal function, ameliorate histological injury, and diminish the expression of proinflammatory and profibrotic factors in the kidneys of HFD rats. The development of GLP1 analogs, inspired by the understanding of the metabolic roles of GLP1 and exendin-4 (exenatide), has led to the creation of advanced formulations for steady administration and a prolonged effect. Among these products, liraglutide (Victoza, Saxenda), dulaglutide (Trulicity), and semaglutide (Ozempic) have received approval from the FDA. Initially prescribed for T2D patients, liraglutide and semaglutide have also gained authorization for obesity management [108,110]. Moreover, semaglutide has been recently approved for lowering cardiovascular event risks in T2D patients with established cardiovascular disease [108]. Additionally, these medications have shown effectiveness in lowering renal dysfunction and fatty liver disease.

##  3\. Clinical Studies

In the treatment landscape for T2D with high cardiovascular risk, GLP1-RA have been the subject of numerous large-scale trials, underscoring their potential in kidney protection, including DKD. These trials have collectively contributed to a deeper understanding of the renal effects of GLP1-RA focused on the effects on albuminuria and eGFR.

The ELIXA Trial (Lixisenatide) was focused on T2D patients with recent acute coronary events. It was found that lixisenatide significantly reduced the urinary albumin-to-creatinine ratio (UACR) at 108 weeks. Despite this positive outcome, no significant change was observed in eGFR or other hard renal endpoints [111].

The LEADER and SUSTAIN-6 Trials with Liraglutide and Semaglutide, respectively, showed significant reductions in macroalbuminuria in individuals with a high cardiovascular risk profile. Importantly, these drugs also induced a slightly slower decline in eGFR compared to the placebo, an effect more pronounced in patients with moderate or severe renal impairment at baseline [112].

Weekly exenatide against placebo was examined in the EXCEL Trial (Exenatide), which studied T2D patients with a history of cardiovascular disease (CVD). The study reported a significant reduction in incident macroalbuminuria, although no other significant renal outcomes were affected. REWIND Trial with Dulaglutide treatment over 5.4 years was associated with a significant reduction in renal composite outcomes (new macroalbuminuria, a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy), although the absolute differences in eGFR by the end of the study were minor [113,114].

AWARD-7 Trial compared the effects of dulaglutide with insulin glargine in T2D patients with moderate to severe CKD. Dulaglutide led to a lower decline in eGFR and reduced UACR, particularly in patients with macroalbuminuria at baseline [115]. Importantly, the PIONEER-5 Trial, apart from the safety and efficacy of oral semaglutide in glycemic control, showed that this drug did not alter eGFR but effectively lowered UACR in T2D patients with eGFR between 30–59 mL/min/1.73 m2 [116].

In a comprehensive meta-analysis incorporating new data from the AMPLITUDE-O trial, researchers examined the efficacy of GLP-1RAs in the treatment of T2D patients. This study utilized a random effects model to analyze data from eight large-scale trials involving 60,080 patients to assess the impact of GLP-1RAs on major adverse cardiovascular events (MACE), all-cause mortality, hospital admissions for heart failure, and various kidney outcomes. The analysis revealed that GLP-1RAs reduced the risk of MACE by 14%, all-cause mortality by 12%, hospital admissions for heart failure by 11%, and composite kidney outcomes by 21%. These kidney outcomes included the development of macroalbuminuria, a significant decline in eGFR, the requirement for kidney replacement therapy, or death due to kidney disease. Additionally, the treatment showed a positive effect on worsening kidney function based on eGFR changes. Notably, these benefits were consistent across various subgroups, including patients with or without cardiovascular disease, different levels of baseline HbA1c, and varying eGFR. The study highlighted the consistent efficacy of GLP-1RAs in reducing cardiovascular and renal risks in T2D patients, irrespective of the drug’s structural homology to human GLP-1 or exendin-4. The safety profile of GLP-1RAs was favorable, with no increase in the risk of severe hypoglycemia, retinopathy, pancreatitis, or pancreatic cancer compared to the placebo. Thus, this analysis underscores the broad applicability and potential of GLP-1RAs in managing cardiovascular and renal outcomes in T2D patients [117].

Recently, the FLOW trial, with a primary focus on the renal outcomes with semaglutide in T2DM patients with CKD, was prematurely stopped due to compelling evidence of renal protection. This decision, announced by Novo Nordisk on 10 October 2023, was based on the recommendation of the independent Data Monitoring Committee after a pre-specified temporary analysis met the criteria for early termination due to the shown efficacy. Designed as a randomized, double-blind parallel-group, event-driven, phase 3b superiority trial, FLOW compared subcutaneous semaglutide 1.0 mg with a visually identical placebo alongside standard care in patients with T2DM and CKD. The trial included a dose-escalation regimen starting from 0.25 mg/week, increasing to 0.5 mg, and then to a maintenance dose of 1.0 mg/week. In total, 3534 patients were enrolled across 28 countries. The primary objective was to demonstrate a delay in the progression of CKD and a reduction in the risk of renal and cardiovascular mortality. The composite primary endpoint included the onset of kidney failure (defined as chronic kidney replacement therapy or persistent eGFR <15 mL/min/1.73 m2), death from kidney failure, cardiovascular death, and the onset of a persistent ≥50% reduction in eGFR from baseline. Key secondary endpoints encompassed the annual rate of change in eGFR, MACEs, and all-cause death [118].

The early cessation of the FLOW trial highlights the potential of semaglutide as a pharmacotherapy option for patients with T2DM and CKD to prevent clinically relevant renal outcomes. The results of this study are eagerly anticipated by the medical community, given their potential to change clinical practice in managing patients with T2DM and CKD.

Recently, there has been real-world evidence on the effects of GLP-1 receptor agonists (GLP-1RAs) and long-acting insulins (LAIs) on kidney health in type 2 diabetes patients who need intensive blood sugar control and have a high risk for CKD progression. Analyzing data from 7279 matched pairs from Taiwan’s National Health Insurance Research Database found that GLP-1RAs significantly reduced the risk of severe kidney outcomes, including renal failure and the need for dialysis, compared to LAIs. The findings suggest that GLP-1RAs offer superior kidney protection for these patients and indicate a more significant benefit for those with cardiovascular disease or good adherence to oral diabetes medications [119]. Table 2 outlines the impact of GLP-1 receptor agonists (GLP-1RAs) on reducing albumin in the urine and protecting kidney function in type 2 diabetes (T2D).

Finally, the ongoing GLP-1 receptor agonist (GLP-1RAs) trials are predicting a new era in the treatment of chronic kidney disease (CKD) and cardiovascular disease (CVD) in type 2 diabetes (T2D). The REMODEL study aims to explore how semaglutide affects kidney health, thereby enhancing CKD treatments with innovative mechanistic insights. Additionally, the SOUL trial like Flow is evaluating the effectiveness of semaglutide in reducing severe renal outcomes and cardiovascular mortality in T2D patients, potentially establishing GLP1-RAs as foundational in protecting both kidney and heart health. The SELECT trial is venturing into using semaglutide for patients with atherosclerotic cardiovascular disease (ASCVD) and obesity, suggesting a broader role for GLP1-RAs beyond diabetes management, extending into cardiovascular prevention [120,121]. Moreover, the SURPASS-CVOT [121,122] and TREASURE-CKD trials are investigating the benefits of tirzepatide, which provides dual GIP and GLP1 receptor activation, offering enhanced benefits in glycemic control, weight reduction, and organ protection compared to GLP1-RA monotherapy. These trials are expected to significantly inform new clinical guidelines, providing a robust evidence base for incorporating GLP1-RAs into treatment regimens for T2D, CKD, and CVD. This comprehensive research effort is crucial for understanding and applying GLP1-RAs in managing chronic conditions, potentially leading to improved patient outcomes and quality of life.

In summary, while GLP1-RA has demonstrated beneficial effects on kidney outcomes in patients with T2D, further studies are needed to fully elucidate their impact on severe kidney outcomes such as eGFR decline, progression to ESKD, and kidney-related death.

##  4\. Conclusions

The molecular pathways through which GLP1-RA confer renal protection in T2DM and DKD are complex and multifaceted. They include the modulation of renal hemodynamics, antioxidative and anti-inflammatory actions, metabolic regulation, and direct cellular effects. These mechanisms highlight GLP1-RA’s potential as a therapeutic option for glycemic control and direct and indirect renal function protection in diabetic patients. Ongoing research promises to enhance renal outcomes in T2DM and expand GLP1-RA’s therapeutic applications.

In conclusion, optimal glycemic control remains a critical strategy for slowing the progression of CKD in diabetes, with significant effects on reduction in hyperfiltration and albuminuria. Integrating GLP-1RAs into the therapeutic regimen offers a promising adjunctive approach, contributing to renal protective strategies against diabetes. The evolving evidence supports a multifaceted approach to managing DKD, highlighting the importance of both traditional and novel therapeutic modalities in preserving kidney health.

## Author Contributions

Conceptualization, M.R. and G.S.; writing—original draft preparation, M.R. and G.S.; editing, G.S.; visualization, M.R. 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.

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**Table 1.** GLP-1 receptor agonists: bridging antioxidative and anti-inflammatory mechanisms in diabetes, atherosclerosis, and kidney function. 

**Table 1.** GLP-1 receptor agonists: bridging antioxidative and anti-inflammatory mechanisms in diabetes, atherosclerosis, and kidney function.

Effects| Pathway| Outcome  
---|---|---  
Antioxidative  
Stress Mechanisms| GLP-1RAs activate receptor-mediated pathways (cAMP, PI3K, PKC), leading to the activation of Nrf-2.| Enhanced activity of antioxidant enzymes (superoxide dismutase, glutathione reductase, catalase), reduction in oxidative stress markers, and protection against oxidative damage in pancreatic cells, liver, and cardiac tissues [5,15,76,77,78].  
Anti-inflammatory Effects| GLP-1RAs modulate the immune system, reducing proinflammatory cytokine and chemokine levels (TNF-alpha, MCP-1/CCL2, IL-6, IL-1β), and decreasing macrophage infiltration in renal and vascular tissues.| Suppression of inflammation in diabetic nephropathy and atherosclerosis, protection against kidney and cardiovascular diseases [5,15,86,87,101,102].  
Renal Protection| Restoration of critical enzymes for oxidative stress protection (catalase, glutathione peroxidase-3), inhibition of superoxide generation and NADPH oxidase activity.| Decreased risk of CKD progression, protection against diabetic nephropathy [79,80,81,82,83,84,85].  
Insulin Sensitivity and Lipid Metabolism| GLP-1RAs improve lipid metabolism by reducing lipogenesis, inhibiting lipid peroxidation, and enhancing fatty acid β-oxidation. They also enhance insulin sensitivity by reducing the production of inflammatory cytokines in adipose tissue.| Reduced lipotoxicity and improved lipid homeostasis  
Improved lipid homeostasis, reduced insulin resistance, and therapeutic benefits extending beyond glycemic control [90,91,92,93,94,95].  
Cardiovascular Protection| Reduction in endothelial dysfunction, attenuation of microvascular permeability, and reduced expression of adhesion molecules. GLP-1RAs inhibit oxidative stress in endothelial cells and reduce atherosclerotic lesions through AMPK and MAPK-dependent mechanisms.| Lowered progression of atherosclerosis, reduced cardiovascular risks, and improved endothelial function [53,87,88,89,96,97,98,99,100].  
Direct Anti-Atherosclerotic Action| GLP-1RAs directly influence atherosclerotic plaque development and stability, reducing foam cell formation and carotid intima-media thickness, and affecting the formation and progression of early-stage atherosclerosis.| Stabilization of existing plaques, improved endothelial function, and reduced atherosclerosis progression [96,97,98,99,100].  
  
The table illustrates the effects of GLP-1 receptor agonists on atherosclerosis through several pathways. These include anti-inflammatory and antioxidant mechanisms, kidney and heart protection, and enhancements in lipid metabolism and insulin sensitivity. These effects contribute to the protection of the heart and kidneys. References are provided to support these findings.

**Table 2.** GLP-1 receptor agonists (GLP-1RAs) effect on albuminuria and GFR protection in type 2 diabetes (T2D). 

**Table 2.** GLP-1 receptor agonists (GLP-1RAs) effect on albuminuria and GFR protection in type 2 diabetes (T2D).

| GLP-1RA Used| Population Characteristics| Duration| Key Findings on Renal Outcomes  
---|---|---|---|---  
ELIXA| Lixisenatide| T2D patients with recent acute coronary events| 108 weeks| Significant reduction in UACR; no significant change in eGFR or other hard renal endpoints [111]  
LEADER| Liraglutide| Individuals with T2D and high cardiovascular risk| 3.8 years| Significant reductions in macroalbuminuria; slightly slower decline in eGFR compared to placebo, more pronounced in patients with moderate or severe renal impairment [112]  
SUSTAIN-6| Semaglutide| Individuals with T2D and high cardiovascular risk| 104 weeks| 58.6% of the UACR lowering effect independent of body weight and HbA1c; significant reductions in macroalbuminuria; slightly slower decline in eGFR compared to placebo [112]  
EXSCEL| Exenatide| T2D patients with a history of cardiovascular disease (CVD)| Mean 3.2 years| Reduced progression to microalbuminuria (p = 0.02);  
for the 40% eGFR decline + ESRD endpoint, the predicted and observed risk reductions were 11.0% (HR 0.89; 0.82–0.97) and 13.7% (HR 0.86, 0.72–1.04), respectively [113]  
REWIND| Dulaglutide| T2D patients, longer-term study| 5.4 years| Reduced albuminuria and surrogate renal endpoints; a ≥40% sustained eGFR decline occurred less frequently among participants assigned to DU than placebo (HR 0.72, 95% CI 0.58–0.88, p = 0.002); the mean annual decline in eGFR slope was significantly smaller for participants assigned to DU than placebo (−1.37 vs. −1.56 mL/min/1.73 m2/year, p < 0.001) [113,114]  
AWARD-7| Dulaglutide| T2D patients with moderate to severe CKD| 52 weeks| Significantly lower decline in eGFR; reduced UACR, particularly in patients with macroalbuminuria at baseline [115]  
PIONEER-5| Oral Semaglutide| T2D patients with eGFR between 30–59 mL/min/1.73 m2| 52 weeks| No alteration in eGFR; effective reduction in UACR [116]  
Meta-analysis including AMPLITUDE-O trial| Various GLP-1RAs| Large-scale trials involving 60,080 patients with T2D| Varied across studies| GLP-1RAs reduced the risk composite kidney outcomes by 21% [117].  
FLOW| Semaglutide| T2DM patients with CKD| (Trial halted early due to efficacy)| Early termination due to compelling evidence of renal protection; awaiting detailed results [118].  
  
Summary of GLP-1 receptor agonist (GLP-1RA) trials on renal outcomes in T2DM patients. References are provided to support these findings.

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Rroji M, Spasovski G. Transforming Diabetes Care: The Molecular Pathways through Which GLP1-RAs Impact the Kidneys in Diabetic Kidney Disease. _Biomedicines_. 2024; 12(3):657. https://doi.org/10.3390/biomedicines12030657 

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Rroji M, Spasovski G. Transforming Diabetes Care: The Molecular Pathways through Which GLP1-RAs Impact the Kidneys in Diabetic Kidney Disease. _Biomedicines_. 2024; 12(3):657. https://doi.org/10.3390/biomedicines12030657 

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Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials - PubMed

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Review

Ann Intern Med 

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. 2025 Feb;178(2):199-217.

doi: 10.7326/ANNALS-24-01590.  Epub 2025 Jan 7. 

#  Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials 

[Areesha Moiz](/?term=Moiz+A&cauthor_id=39761578)  1 , [Kristian B Filion](/?term=Filion+KB&cauthor_id=39761578)  2 , [Helia Toutounchi](/?term=Toutounchi+H&cauthor_id=39761578)  3 , [Michael A Tsoukas](/?term=Tsoukas+MA&cauthor_id=39761578)  4 , [Oriana H Y Yu](/?term=Yu+OHY&cauthor_id=39761578)  5 , [Tricia M Peters](/?term=Peters+TM&cauthor_id=39761578)  6 , [Mark J Eisenberg](/?term=Eisenberg+MJ&cauthor_id=39761578)  7 

Affiliations  Expand 

###  Affiliations 

  * 1 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, and Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada (A.M.).
  * 2 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; and Department of Medicine, McGill University, Montreal, Quebec, Canada (K.B.F.).
  * 3 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada (H.T.).
  * 4 Department of Medicine, McGill University, and Division of Endocrinology and Metabolism, McGill University, Montreal, Quebec, Canada (M.A.T.).
  * 5 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; Department of Medicine, McGill University; and Division of Endocrinology and Metabolism, McGill University, Montreal, Quebec, Canada (O.H.Y.Y.).
  * 6 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Division of Experimental Medicine, McGill University; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; Department of Medicine, McGill University; and Division of Endocrinology and Metabolism, McGill University, Montreal, Quebec, Canada (T.M.P.).
  * 7 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Division of Experimental Medicine, McGill University; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; Department of Medicine, McGill University; and Division of Cardiology, Jewish General Hospital/McGill University, Montreal, Quebec, Canada (M.J.E.).



  * PMID:  **39761578**
  * DOI:  [ 10.7326/ANNALS-24-01590 ](https://doi.org/10.7326/annals-24-01590)



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Review

#  Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials 

Areesha Moiz et al. Ann Intern Med. 2025 Feb.

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. 2025 Feb;178(2):199-217.

doi: 10.7326/ANNALS-24-01590.  Epub 2025 Jan 7. 

###  Authors 

[Areesha Moiz](/?term=Moiz+A&cauthor_id=39761578)  1 , [Kristian B Filion](/?term=Filion+KB&cauthor_id=39761578)  2 , [Helia Toutounchi](/?term=Toutounchi+H&cauthor_id=39761578)  3 , [Michael A Tsoukas](/?term=Tsoukas+MA&cauthor_id=39761578)  4 , [Oriana H Y Yu](/?term=Yu+OHY&cauthor_id=39761578)  5 , [Tricia M Peters](/?term=Peters+TM&cauthor_id=39761578)  6 , [Mark J Eisenberg](/?term=Eisenberg+MJ&cauthor_id=39761578)  7 

###  Affiliations 

  * 1 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, and Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada (A.M.).
  * 2 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; and Department of Medicine, McGill University, Montreal, Quebec, Canada (K.B.F.).
  * 3 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada (H.T.).
  * 4 Department of Medicine, McGill University, and Division of Endocrinology and Metabolism, McGill University, Montreal, Quebec, Canada (M.A.T.).
  * 5 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; Department of Medicine, McGill University; and Division of Endocrinology and Metabolism, McGill University, Montreal, Quebec, Canada (O.H.Y.Y.).
  * 6 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Division of Experimental Medicine, McGill University; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; Department of Medicine, McGill University; and Division of Endocrinology and Metabolism, McGill University, Montreal, Quebec, Canada (T.M.P.).
  * 7 Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital; Division of Experimental Medicine, McGill University; Department of Epidemiology, Biostatistics and Occupational Health, McGill University; Department of Medicine, McGill University; and Division of Cardiology, Jewish General Hospital/McGill University, Montreal, Quebec, Canada (M.J.E.).



  * PMID:  **39761578**
  * DOI:  [ 10.7326/ANNALS-24-01590 ](https://doi.org/10.7326/annals-24-01590)



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##  Abstract 

**Background:** Recent randomized controlled trials (RCTs) have investigated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual or triple co-agonists for weight loss among adults with overweight or obesity and without diabetes. 

**Purpose:** To assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes. 

**Data sources:** MEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024. 

**Study selection:** Placebo-controlled RCTs in otherwise healthy participants with overweight or obesity. 

**Data extraction:** The primary outcome was change in relative or absolute body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, serious adverse events (SAEs), any adverse events (AEs), and gastrointestinal AEs. 

**Data synthesis:** A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m2; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare. 

**Limitations:** No head-to-head RCTs were available. Heterogeneity prevented meta-analysis. 

**Conclusion:** GLP-1 RAs and co-agonists are efficacious for weight loss, with reported safety concerns predominantly gastrointestinal in nature, when used among adults with overweight or obesity and without diabetes. 

**Primary funding source:** None. (PROSPERO: CRD42024505558). 

[PubMed Disclaimer](/disclaimer/)

##  Conflict of interest statement 

Disclosures: Disclosure forms are available with the article online.

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  * Adult 

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url: https://www.ncbi.nlm.nih.gov/books/NBK551568/
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# Glucagon-Like Peptide-1 Receptor Agonists

Logan Collins; Ryan A. Costello.

Author Information and Affiliations

#### Authors

Logan Collins1; Ryan A. Costello.

#### Affiliations

1 St. Bernards Medical Center

Last Update: February 29, 2024.

## Continuing Education Activity

Glucagon-like peptide-1 (GLP-1) agonists are a class of medications utilized to treat type 2 diabetes mellitus (T2DM) and obesity. As a class of medications, they are among several pharmacological options for these endocrine diseases. The function of GLP-1 agonists is to lower serum glucose levels and thereby manage metabolism in affected patients. Participating clinicians gain an enhanced understanding of when to prescribe these agonists, consider specific patient populations, and seek consultations with specialists in the care of their patients. Recent recommendations regarding mixed formulations are also included in alignment with current research on this drug class. This activity will highlight the indications, mechanism of action, administration, adverse effect profile, and contraindications for these drugs. An interprofessional team of nurses, primary care clinicians, pharmacists, and endocrinologists remains pertinent to care for patients prescribed this class of medications.

**Objectives:**

  * Identify the mechanism of action of GLP-1 receptor agonists.

  * Assess the potential adverse effects of GLP-1 receptor agonists.

  * Differentiate the proper administration techniques for GLP-1 analogs and the clinical monitoring necessary for patients prescribed GLP-1 receptor agonists.

  * Implement effective collaboration among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from GLP-1 receptor agonists.


[Access free multiple choice questions on this topic.](https://www.statpearls.com/account/trialuserreg/?articleid=82078&utm_source=pubmed&utm_campaign=reviews&utm_content=82078)

## Indications

**FDA-Approved Indications**

GLP-1 agonists (also known as GLP-1 receptor agonists, incretin mimetics, or GLP-1 analogs) represent a class of medications used to treat T2DM and, in some cases, obesity. Examples of drugs in this class include Exenatide, Liraglutide, Dulaglutide, and Semaglutide. According to the American Diabetes Association (ADA), metformin remains the preferred first-line therapy for treating T2DM. However, the addition of a GLP-1 analog should be considered in patients with a contraindication or intolerance to metformin, in patients with a hemoglobin A1c greater than 1.5% over target, or in patients who do not reach their target A1c in 3 months, particularly in patients with atherosclerosis, heart failure, or chronic kidney disease.[1][2][3][4] Furthermore, Semaglutide and high-dose Liraglutide are FDA-approved as pharmacologic treatments for obesity or can be prescribed to overweight patients with comorbidities. The utilization of GLP-1 analogs is an area of research with favorable hemoglobin A1c results and weight loss results in patients with type-1 diabetes mellitus (T1DM). Of note, higher costs, as well as tolerability, remain significant barriers to prescribing these medications.[5][6][7][8]

As per the 2023 ADA guidelines, GLP-1 receptor agonists are recommended for mitigating cardiovascular risk. These agents not only lower the chances of cardiovascular events and hypoglycemia but also demonstrate potential in potentially decreasing the progression of chronic kidney disease (CKD). GLP-1 agonists are recommended for individuals with a history of clinical ASCVD (eg, prior myocardial infarction, stroke.[9][10] GLP-1 agonists, with proven cardiovascular benefits, include Liraglutide, subcutaneous Semaglutide, and Dulaglutide.[11]

Structurally, these agents fall into 2 broad categories: human GLP-1 backbone agents and exendin-4 backbone agents. Below are FDA-approved GLP-1 agonists.

Human GLP-1 backbone:

  * Dulaglutide



  * Albiglutide - discontinued



  * Liraglutide



  * Semaglutide




Exendin-4 backbone:

  * Exenatide (2 formulations)



  * Lixisenatide - discontinued



  * Tirzepatide is a GIP analog that activates both the GLP-1 and GIP receptors.




Liraglutide/insulin-degludec has obtained FDA approval, affirming their effectiveness and safety in diabetes management.[12][13] Because of safety concerns, research on another agent, taspoglutide, has been halted in phase III trials.[14] Recently, Orforglipron, a nonpeptide oral GLP-1 receptor agonist, has demonstrated promising results in phase 2 clinical trials.[15]

## Mechanism of Action

GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), both incretin hormones inactivated by dipeptidyl peptidase-4 (DPP-4), stimulate insulin secretion after an oral glucose load via the incretin effect.[16][17] In T2DM, this process can become blunted or absent; however, pharmacological levels of GLP-1 can revive insulin excretion. The benefits of this therapy to treat T2DM include delayed gastric emptying and inhibiting glucagon production from pancreatic α-cells if blood sugar levels are high. Furthermore, GLP-1 receptor agonists can decrease pancreatic β-cell apoptosis while promoting their proliferation.[18][19][20]

This class of medications promotes an average weight loss of 2.9 kg compared to placebo, in addition to lowering both systolic and diastolic blood pressure and total cholesterol. Regarding cardiovascular effects, GLP-1 agonists can improve left ventricular ejection fraction, myocardial contractility, coronary blood flow, cardiac output, and endothelial function while reducing infarction size and overall risks for a cardiovascular event.[21][22] Other functions of GLP-1 include increased glucose uptake in the muscles, decreased glucose production in the liver, neuroprotection, and increased satiety due to direct actions on the hypothalamus. GLP-1 analogs have also exhibited lower all-cause mortality and a hemoglobin A1c reduction of about 1% compared to control groups in patients with T2DM.[23][8] As per the ADA, strategies with higher efficacy are more likely to attain glycemic targets successfully. Specifically, the interventions regarded as highly effective for lowering glucose levels are high-dose Dulaglutide and Semaglutide, as well as Tripeptide, a combination of gastric inhibitory peptide (GIP) and GLP-1 receptor agonist, insulin therapy, oral combination therapy, and injectable combination therapy.[10]

**Pharmacokinetics**

**Absorption** : GLP-1 Receptor Agonists (RAs) like Exenatide, Liraglutide, and Semaglutide are administered subcutaneously, ensuring rapid absorption and achieving peak concentrations within hours. The novel oral formulation of Semaglutide is tailored for gastrointestinal (GI) absorption, with consideration for bioavailability. Factors such as first-pass metabolism and potential interactions with food and other medications bear relevance in determining effective dosing regimens for oral Semaglutide.

**Distribution** : Post-absorption, GLP-1 RAs (eg, Exenatide, Liraglutide, and Semaglutide) exhibit a low volume of distribution, predominantly remaining in the bloodstream. These agents selectively target GLP-1 receptors in various tissues involved in glucose regulation, with specific affinity for pancreatic cells and other metabolic control sites.

**Metabolism** : Exenatide undergoes primary metabolism in the kidneys and liver through hydrolysis, yielding smaller, inactive peptides subsequently excreted renally. Liraglutide follows a similar pathway involving proteolytic cleavage in various tissues, akin to the metabolism of large proteins. Enzymes like Dipeptidyl Peptidase-4 (DPP-4) and Neutral Endopeptidase (NEP) are likely involved, resulting in smaller, biologically inactive fragments subsequently eliminated. Semaglutide, a polypeptide, undergoes metabolic breakdown into individual amino acids facilitated by serum and tissue proteases.[24][25]

**Excretion** : Renal elimination primarily governs the clearance of GLP-1 RAs, including Exenatide, Liraglutide, and Semaglutide. The kidneys play a pivotal role in removing these compounds from the body. The rate of renal excretion impacts the duration of action and dosing frequency. Semaglutide, with its extended-release (ER) profile, exhibits a significantly prolonged half-life compared to short-acting formulations.

## Administration

**Available Dosage Forms, Strengths, and Adult Dosage**

Many formulations of GLP-1 agonists were historically injectable. GLP-1 agonists are generally administered subcutaneously due to poor oral bioavailability. Liraglutide is dosed daily. Dulaglutide and semaglutide dosing is weekly, and exenatide can be dosed twice daily or once weekly. Recently, the FDA approved an oral formulation of Semaglutide. Researchers have suspended trials investigating taspoglutide as a novel GLP-1 analog due to GI side effects and hypersensitivity reactions.[26][27][14]

Summary of dosing frequency for some commonly prescribed GLP-1 receptor agonists:

  * Dulaglutide - weekly



  * Liraglutide - daily



  * Semaglutide - weekly subcutaneously, daily orally



  * Exenatide BID - twice daily



  * Exenatide QW - weekly



  * Tirzepatide \- weekly



  * Albiglutide - weekly (withdrawn from the market)[28]




Depending on the drug prescribed, the medication may be available as a single- or multi-dose pen, and patients may need a separate prescription for needles with various needle gauge requirements. Patients have shown improved satisfaction with weekly exenatide compared to a twice-daily regimen, and studies have demonstrated their preferences for narrow needles. However, concerns regarding compliance with a weekly, as opposed to a daily regimen, have also been raised. GLP-1 analogs and long-acting insulin in a single injection have also been introduced to the pharmaceutical market.[29][8] This regimen potentially synergizes with insulin-lowering fasting, post-absorptive blood sugars, and GLP-1 agonists targeting postprandial blood sugars. This strategy may lower the risk of hypoglycemia due to less reliance on bolus and basal insulin and may offset potential weight gain experienced with insulin.[30][31] GLP-1 analogs are primarily excreted via renal pathways, and no dosage modifications are required for patients with mild renal or hepatic impairment. However, dose adjustment according to the product monograph should be considered, especially in older patients.[11] No recommendations are stated for specific populations, with limited data available for breastfeeding or pediatric patients. Moreover, use is contraindicated in patients who are pregnant.

## Adverse Effects

The most frequently exhibited side effects from GLP-1 agonists include nausea, vomiting, and diarrhea that could lead to an acute kidney injury due to volume contraction. Dizziness, mild tachycardia, infections, headaches, and dyspepsia may also occur. Patients should receive counseling that this class of drugs increases satiety, and transient, mild nausea may occur if they attempt to eat while feeling full. Increasing the dosage of these medications should occur slowly if nausea is present. Injection-site pruritus and erythema are also common, most notably with the longer-acting medications in this class.[16][32][18]

A low risk of minor episodes of hypoglycemia is evident; however, research has not described any major hypoglycemic episodes at this time. Patients can form antibodies to particular GLP-1 analogs that could affect the efficacy of these medications, particularly with exenatide. This immunogenicity could lead to injection site reactions and potential anaphylaxis. Studies have shown that these adverse effects typically lead to a low discontinuation rate of around 10%.[14][33][34] Anti-drug antibodies were more common, and titers were higher with the weekly dosed formulation of exenatide than with the twice-daily formulation of exenatide.[35] A meta-analysis revealed an association between the utilization of GLP-1 receptor agonists and an elevated likelihood of gallbladder or biliary disorders. This correlation was particularly notable in cases involving higher dosage and prolonged usage.[36]

Combination therapy with GLP-1 agonists and dipeptidyl peptidase-4 inhibitors is not a current recommendation due to statistically insignificant glycemic improvement and enhanced hypoglycemic effects. Depending on the glycemic control, adjust the insulin dosage by approximately 25% or reduce the sulfonylurea dosage to mitigate the risk of hypoglycemia.[8][37][11]

## Contraindications

**Boxed Warnings**

Contraindications to utilizing GLP-1 agonists include hypersensitivity and pregnancy as prohibitions to prescribing this class of medications. Some formulations of contraception are recommended with GLP-1 agonists in women of childbearing age. Patients with severe GI diseases such as gastroparesis and inflammatory bowel disease should also avoid GLP-1 analogs. Concern for long-term consequences on the thyroid gland using GLP-1 agonists has been a topic of investigation. Liraglutide stimulated calcitonin release in rodent models, leading to thyroid gland C-cell and tumor hyperplasia. The effects on humans remain unclear, with further investigations being necessary. Consequently, GLP-1 agonists are not recommended in patients with a personal or family history significant for multiple endocrine neoplasia 2A (MEN 2A), multiple endocrine neoplasia 2B (MEN 2B), or medullary thyroid cancer.[38][39][14][40]

While the mechanism remains largely unknown, acute pancreatitis, including potentially fatal hemorrhagic and necrotizing types, has been noted in users of GLP-1 analogs. Whether a causal relationship exists between GLP-1 analogs and pancreatitis or pancreatic cancer is still unknown. Nonetheless, GLP-1 agonists should not be prescribed in patients with a history of pancreatitis and should be discontinued in those who develop pancreatitis when taking this medication.[33][41][42]

**Warnings and Precautions**

The FDA has recently issued a cautionary statement regarding the compounding of Semaglutide formulations. Compounding involves customizing medications to individual patient needs by blending, altering, or combining various ingredients, including multiple drugs. It is critical to highlight the reported adverse events associated with compounded Semaglutide. Patients should be educated not to purchase compounded products, as the FDA does not assess compounded versions for safety, efficacy, or quality. Additionally, adverse effects are associated with cases where compounders salts of Semaglutide, such as Semaglutide sodium and Semaglutide acetate. In 3 recent cases, patients experienced adverse effects due to the incorrect administration of Semaglutide for weight loss. These incidents occurred after obtaining the medication from compounding pharmacies and an aesthetic spa. In 2 instances, patients self-administered doses 10 times higher than prescribed. All individuals reported experiencing significant symptoms such as nausea, vomiting, and prolonged abdominal discomfort lasting several days. Additionally, one patient mentioned experiencing a headache, reduced appetite, weakness, and fatigue. Notably, one patient sought medical evaluation and showed improvement after receiving antiemetic and intravenous fluids. Another patient, who obtained their medication from a compounding pharmacy, reported receiving a vial with syringes for self-administration but noted a lack of counseling on proper administration by the pharmacist. Compounded Semaglutide lacks the safety features in prefilled pens, potentially leading to dangerous overdoses. Using incorrect syringes adds to dosing variability and patient confusion. Stringent labeling, dispensing, and counseling practices are crucial to mitigate these risks. Healthcare professionals should actively advocate for the proper use and dispensing of compounded Semaglutide. These measures hold the potential to significantly decrease the risk of severe adverse events and unnecessary hospitalizations due to dosing errors.[43]

## Monitoring

GLP-1 analogs are principally renally eliminated. Dosing adjustments of GLP-1 agonists are unnecessary due to hepatic or mild renal impairment. Moderate renally impaired patients, on the other hand, should avoid weekly exenatide, and dosing escalations should be considered carefully in patients on twice-daily exenatide. Dosing increases of twice-daily exenatide for patients aged 70 years and older merit evaluation of the potential risks and benefits.

Patients with severe renal dysfunction should not take GLP-1 agonists. If a GLP-1 agonist is added to a regimen already consisting of a Sulfonylurea or long-acting insulin, patients require monitoring for hypoglycemia. A decrease in the insulin dose may become necessary, depending on the GLP-1 analog selected. Patients taking GLP-1 analogs should periodically have their hemoglobin A1c measured and their glycemic patterns examined. The clinician should follow the international normalized ratio (INR) in patients prescribed warfarin, as a GLP-1 agonist may alter the absorption of this medication by delaying gastric emptying. Clinicians should also monitor patients taking GLP-1 agonists for signs and symptoms consistent with pancreatitis. The FDA recommends not monitoring calcitonin levels for medullary thyroid cancer.[8][33][40]

Concerns have been raised about the potential for GLP-1 agonists to delay gastric emptying. This raises the risk of regurgitation and aspiration.[44] As a precaution for elective procedures, it is suggested that GLP-1 agonists be discontinued temporarily. This recommendation applies regardless of the indication for which the medication is prescribed. In cases where prolonged discontinuation of GLP-1 agonists may be necessary, consulting an endocrinologist for guidance on bridging antidiabetic therapy is advisable to prevent hyperglycemia. On the day of the procedure, if patients experience severe GI symptoms such as nausea, vomiting, retching, abdominal bloating, or abdominal pain, it may be prudent to consider postponing the elective procedure after discussing potential risks with the surgeon and the patient. In the absence of such symptoms and with appropriate suspension of GLP-1 agonists, the procedure can proceed as planned. However, if patients have not adhered to the recommended suspension of GLP-1 agonists, proceeding with caution or evaluating gastric volume through ultrasound, if possible, is recommended. If this is not feasible, considering a delay or proceeding with 'full stomach' precautions is advised, again after discussing potential risks with the surgeon and the patient. While no definitive fasting duration is established for patients on GLP-1 agonists, adhering to current American Society of Anesthesiologists (ASA) fasting guidelines is recommended until further evidence is available.[45][46][47]

## Toxicity

Research into GLP-1 analog overdoses remains limited. Reports exist of symptoms such as nausea, vomiting, diarrhea, excessive belching, and abdominal pain due to toxic ingestion of medication within this class; however, no serious complications, such as pancreatitis or hypoglycemia, have been noted in case studies.[48] Treatment consists of supportive care, including antiemetics, to control excessive nausea and vomiting.[34][49]

## Enhancing Healthcare Team Outcomes 

Treating T2DM and obesity should involve an interprofessional team, including a primary care provider (MD, DO, NP, or PA), diabetes educator (nurse or pharmacist), pharmacist, and possibly an endocrinologist. Providers and pharmacists collaborate on the decision to select a GLP-1 agonist and include a complete medication reconciliation in their decision. The interprofessional approach will maximize positive outcomes and minimize adverse events.

Healthcare professionals like MDs, DOs, NPs, and PAs play a role in prescribing GLP-1 agonists. Clinicians, pharmacists, dieticians, and nurses should educate patients on potential side effects and drug interactions. Regular follow-up appointments with primary care clinicians are necessary to monitor blood glucose levels, weight, and kidney function. Nursing involves monitoring and reporting concerns to the prescriber and pharmacist. A registered dietitian nutritionist should guide food choices. Consult with a gastroenterologist for acute pancreatitis. Endocrinologists offer valuable guidance as well when managing T1DM or T1DM. A cohesive team approach maximizes glycemic control and weight loss while minimizing adverse reactions from GLP-1 agonists.

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Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, Meeran K. Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA. 2018 Apr 17;319(15):1580-1591. [[PMC free article: PMC5933330](/pmc/articles/PMC5933330/)] [[PubMed: 29677303](https://pubmed.ncbi.nlm.nih.gov/29677303)]

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Seufert J, Gallwitz B. The extra-pancreatic effects of GLP-1 receptor agonists: a focus on the cardiovascular, gastrointestinal and central nervous systems. Diabetes Obes Metab. 2014 Aug;16(8):673-88. [[PubMed: 24373150](https://pubmed.ncbi.nlm.nih.gov/24373150)]

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Christensen M, Knop FK. Once-weekly GLP-1 agonists: How do they differ from exenatide and liraglutide? Curr Diab Rep. 2010 Apr;10(2):124-32. [[PubMed: 20425571](https://pubmed.ncbi.nlm.nih.gov/20425571)]

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Chudleigh RA, Platts J, Bain SC. Comparative Effectiveness of Long-Acting GLP-1 Receptor Agonists in Type 2 Diabetes: A Short Review on the Emerging Data. Diabetes Metab Syndr Obes. 2020;13:433-438. [[PMC free article: PMC7035886](/pmc/articles/PMC7035886/)] [[PubMed: 32110076](https://pubmed.ncbi.nlm.nih.gov/32110076)]

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Gupta V. Glucagon-like peptide-1 analogues: An overview. Indian J Endocrinol Metab. 2013 May;17(3):413-21. [[PMC free article: PMC3712370](/pmc/articles/PMC3712370/)] [[PubMed: 23869296](https://pubmed.ncbi.nlm.nih.gov/23869296)]

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Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, Tack CJ, Thomsen M, Vilsbøll T, Warren ML, Bain SC., PIONEER 6 Investigators. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Aug 29;381(9):841-851. [[PubMed: 31185157](https://pubmed.ncbi.nlm.nih.gov/31185157)]

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Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context. 2015;4:212283. [[PMC free article: PMC4509428](/pmc/articles/PMC4509428/)] [[PubMed: 26213556](https://pubmed.ncbi.nlm.nih.gov/26213556)]

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Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011 Jul;141(1):150-6. [[PMC free article: PMC4404515](/pmc/articles/PMC4404515/)] [[PubMed: 21334333](https://pubmed.ncbi.nlm.nih.gov/21334333)]

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Gulak MA, Murphy P. Regurgitation under anesthesia in a fasted patient prescribed semaglutide for weight loss: a case report. Can J Anaesth. 2023 Aug;70(8):1397-1400. [[PubMed: 37280458](https://pubmed.ncbi.nlm.nih.gov/37280458)]

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Crowley K, Scanaill PÓ, Hermanides J, Buggy DJ. Current practice in the perioperative management of patients with diabetes mellitus: a narrative review. Br J Anaesth. 2023 Aug;131(2):242-252. [[PMC free article: PMC10375498](/pmc/articles/PMC10375498/)] [[PubMed: 37061429](https://pubmed.ncbi.nlm.nih.gov/37061429)]

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Elmehdawi RR, Elbarsha AM. An accidental liraglutide overdose: case report. Libyan J Med. 2014;9(1):23055. [[PMC free article: PMC3901387](/pmc/articles/PMC3901387/)] [[PubMed: 24461534](https://pubmed.ncbi.nlm.nih.gov/24461534)]

    

**Disclosure:** Logan Collins declares no relevant financial relationships with ineligible companies.

    

**Disclosure:** Ryan Costello declares no relevant financial relationships with ineligible companies.

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#  Drug Therapies for Diabetes 

by 

Roni Weinberg Sibony

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Saar Dor

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1

Faculty of Medicine, Ben-Gurion University, Beer Sheva 8443944, Israel

2

Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

3

Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel

4

Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 91240, Israel

*

Author to whom correspondence should be addressed. 

†

These authors contributed equally to this work.

_Int. J. Mol. Sci._ **2023** , _24_(24), 17147; <https://doi.org/10.3390/ijms242417147>

Submission received: 25 September 2023 / Revised: 21 November 2023 / Accepted: 29 November 2023 / Published: 5 December 2023

(This article belongs to the Special Issue [Drug Therapies for Diabetes](        
    /journal/ijms/special_issues/IFH5O9B0I6
))  


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                        <strong>Figure 1</strong><br/>
                                                    <p>Drug-Treatment Algorithm for Diabetes. The algorithm outlines our recommendations for diabetes treatment, incorporating the initiation of combined drug therapy and adjusting medications based on the patient’s response.</p>
                                                ")

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## Abstract

**:**

The treatment of type 2 diabetes (T2D) necessitates a multifaceted approach that combines behavioral and pharmacological interventions to mitigate complications and sustain a high quality of life. Treatment encompasses the management of glucose levels, weight, cardiovascular risk factors, comorbidities, and associated complications through medication and lifestyle adjustments. Metformin, a standard in diabetes management, continues to serve as the primary, first-line oral treatment across all age groups due to its efficacy, versatility in combination therapy, and cost-effectiveness. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer notable benefits for HbA1c and weight reduction, with significant cardiovascular benefits. Sodium-glucose cotransporter inhibitors (SGLT-2i) lower glucose levels independently of insulin while conferring notable benefits for cardiovascular, renal, and heart-failure outcomes. Combined therapies emphasizing early and sustained glycemic control are promising options for diabetes management. As insulin therapy remains pivotal, metformin and non-insulin agents such as GLP-1 RA and SGLT-2i offer compelling options. Notably, exciting novel treatments like the dual GLP-1/ glucose-dependent insulinotropic polypeptide (GIP) agonist show promise for substantially reducing glycated hemoglobin and body weight. This comprehensive review highlights the evolving landscape of pharmacotherapy in diabetes, the drugs currently available for treating diabetes, their effectiveness and efficacy, the impact on target organs, and side effects. This work also provides insights that can support the customization of treatment strategies.

Keywords: 

[T2DM](/search?q=T2DM); [disease management](/search?q=disease+management); [combination therapy](/search?q=combination+therapy); [SGLT-2I](/search?q=SGLT-2I); [GLP1 RA](/search?q=GLP1+RA)




##  1\. Introduction

The last decade has seen the advent of new medications for lowering blood glucose levels. These medications also exhibit a remarkable capacity to alleviate cardiovascular risk factors. These drugs demonstrate a significant ability to reduce the rates of cardio-renal events in patients with diabetes, as well as in individuals without the disease [1].

These medications have shifted the focus of cardiologists, nephrologists, and healthcare professionals towards preventing cardio-renal events, partially at the expense of focusing on the importance of maintaining near-normal blood glucose levels [1,2,3]. Simultaneously, several influential studies have highlighted the crucial role of maintaining optimal blood glucose levels for preventing both microvascular and macrovascular complications. These studies raise the fundamental question of whether a 7% hemoglobin A1c (HbA1c) level is an adequate goal or whether we should strive for the normalization of blood glucose levels [4,5].

These studies have also prompted discussions about the early administration of drugs in patients with diabetes, potentially as combination therapies, and their possible role in the management of diabetes and newly diagnosed diabetes [6]. The introduction of these new medications has led to inquiries regarding the role of older drugs in diabetes management and whether discontinuing some of them may be warranted due to the associated potential for harm [5,7].

This review provides a comprehensive overview of oral and injectable non-insulin medications used to improve blood glucose levels (Table 1). The results underscore the importance of early diagnosis and early treatment with combination therapy [4,7,8]. We delve into the concept of precision medicine and explore the role of older drugs in patient management. Furthermore, we present a proposal for a groundbreaking approach to the treatment of type 2 diabetes, with an emphasis on striving for a cure for the disease.

##  2\. Metformin

Sixty years after it was introduced into the diabetes pharmacopeia, metformin remains a cornerstone in the treatment of type 2 diabetes and is recommended as the primary oral drug of choice for the management of T2DM across all age groups [9]. The well-known advantages of this agent include its glucose-lowering efficacy, ease of combination with almost any other glucose-lowering agent, and its low cost. Metformin is well-tolerated, has only mild side effects, carries a low risk of hypoglycemia, and provides modest body-weight reduction [10,11].

Metformin, the first-line medication for treating type 2 diabetes, has complex and not yet fully elucidated mechanisms of action that extend beyond its traditionally understood effects on glucose regulation in the liver. While early evidence highlighted the liver as a primary site of action, recent studies indicate a more multifaceted process involving other body areas, such as the gastrointestinal tract, gut microbiota, and tissue-resident immune cells. Its effects seem to differ based on dosage and treatment duration. While the drug was initially thought to primarily affect hepatic mitochondria, new research suggests a novel target at low concentrations, possibly at the lysosome surface. This research suggests a new mode of action. Amidst ongoing debates and the complexity of available information, recent discoveries suggest that the impact of metformin extends beyond liver functions, involving the gut microbiota and immune-system modulation. The drug’s effects could thus potentially expand its use to conditions beyond diabetes [12].

A recently published meta-analysis suggested that metformin may protect the cardiovascular system. It also noted that not only could the drug be used more widely to improve kidney function, but that it could contribute to kidney protection. Data also indicate that metformin may reduce the risk of neurodegenerative conditions, and trials are ongoing to directly evaluate the drug’s anti-neoplastic properties [13]. Regarding dementia, a meta-analysis demonstrated that diabetic patients treated with metformin had a significantly lower prevalence of cognitive impairment (odds ratio = 0.55, 95% CI 0.38 to 0.78). Furthermore, the incidence of dementia was also significantly reduced in this group (hazard ratio = 0.76, 95% CI 0.39 to 0.88) [14].

Regarding the anti-neoplastic properties of biguanides, metformin has emerged as a promising candidate for anticancer treatment. Accumulating epidemiological, preclinical, and clinical evidence have provided support for the utilization of metformin as a therapeutic agent in cancer [15,16]. There are over 50 recent or active clinical trials investigating the use of metformin for human malignancies. Of particular significance is its ability to reduce circulating insulin levels, which may have significant implications for the treatment of malignancies associated with hyperinsulinemia, such as breast and colon cancers. Furthermore, metformin may exert direct inhibitory effects on cancer cells by targeting the signaling pathway of mammalian target of rapamycin (mTOR) and interfering with protein synthesis [16]. Two studies investigated the effects of metformin administered over periods of three to six months to women who had completed chemotherapy and radiation treatment for breast cancer. The first study focused on women with plasma insulin levels of at least 45 pmol/L. This selection criterion was based on earlier research that had identified these women as being at a heightened risk for breast cancer. In this study, metformin was shown to reduce circulating insulin levels by 22.4% (p = 0.024) [17].

The second study involved women with elevated testosterone levels and compared metformin doses of 1000 mg/day and 1500 mg/day. The higher dose was found to significantly lower serum testosterone levels and the free androgen index compared to the lower dose. These findings highlight the potential of metformin to reduce serum markers associated with an increased risk of breast cancer [17].

In terms of the impact of metformin on cardiovascular disease, a meta-analysis of 13 trials (which included 2079 individuals with T2D who were allocated to metformin and a similar number to the comparison groups of diet and lifestyle changes or placebo) yielded favorable results for the prevention of myocardial infarction/ischemic heart disease. However, no effect reached statistical significance, mainly due to the absence of high-quality evidence [18]. The “UKPDS” study included 4075 early diagnosed diabetic patients randomly assigned to either a healthy-lifestyle intervention or healthy-lifestyle intervention with ADD. Among 342 obese diabetic patients that was randomized to metformin therapy, there was relative risk reduction (RRR) of −32% for diabetes-related endpoints, −42% for diabetes-related deaths, −39% for myocardial infarction, and −36% for overall mortality [19].

Furthermore, a recent clinical trial presented promising findings regarding long Corona virus disease (COVID). Outpatient treatment with metformin reduced the incidence of long COVID by 40% compared with placebo [20]. 

Despite extensive, long-standing experience with the clinical use of metformin, its mode of action is still not fully understood [9].

Notwithstanding the significant benefits of metformin, its high efficacy, and its low risk of side effects, there is increasing consensus that other approaches may be more appropriate as a first line of treatment for some patients [21].

##  3\. Thiazolidinediones

Thiazolidinediones (TZD) work by binding to the peroxisome proliferator-activated receptor gamma (PPAR-γ) in the cell nucleus. This binding modulates gene expression involved in glucose and lipid metabolism, enhancing insulin sensitivity in muscle, fat, and liver cells. The primary advantages of TZD include improved glycemic control by reducing blood sugar levels, potential preservation of pancreatic beta cell function, and in some cases, positive impacts on lipid profiles, cardiovascular health, and the reduction of inflammation [22]. On the other hand, treatment with pioglitazone can increase the risk for weight gain, peripheral and retinal edema, dyspnea, hospitalization for heart failure (HHF), and bone fractures, mainly in women [23].

The PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial presented promising data regarding the beneficial effects of pioglitazone. The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. The results presented a significant decrease in fatal/nonfatal MI (excluding silent MI) [HR = 0.77; 95% CI 0.60–1.00; p = 0.046] and the composite of cardiovascular death, MI (excluding silent MI), and stroke (HR = 0.82; 95% CI 0.70–0.97; p = 0.020) [24].

In contrast, a meta-analysis published in 2022 that examined the effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes found that pioglitazone did not significantly affect major adverse cardiovascular events (MACE), all-cause mortality, or HHF (MH–OR: 0.90, 95% CI 0.78–1.03, 0.91, 95% CI 0.77–1.09) and (MH–OR: 1.16, 95% CI 0.73–1.83), respectively) [25]. The IRIS (Insulin Resistance Intervention after Stroke) trial was a multicenter, double-blind trial that randomly assigned 3876 patients who had recently suffered ischemic stroke or transient ischemic attack to receive either pioglitazone or a placebo. Among the patients who received pioglitazone, the risk of stroke or myocardial infarction was lower than it was among those who received the placebo (HR 0.76, 95% CI, 0.62–0.93; p = 0.007)) [23]. Pioglitazone has positive effects in nonalcoholic steatohepatitis (NASH) in both diabetic and non-diabetic patients [26]. In 2006, a randomized control trial with 55 patients presented proof of concept that pioglitazone plus diet, as compared with diet plus placebo, normalized liver aminotransferase levels, as it decreased plasma aspartate aminotransferase levels by 40% vs. 21% (p = 0.04), decreased alanine aminotransferase levels by 58% vs. 34%, (p < 0.001), decreased hepatic fat content by 54% vs. 0% (p < 0.001), and increased hepatic insulin sensitivity by 48% vs. 14% (p = 0.008) [27].

A meta-analysis that evaluated the effects of thiazolidinediones for the treatment of patients with prediabetes or T2DM combined with Nonalcoholic fatty liver disease (NAFLD) found that pioglitazone significantly improved insulin sensitivity and the results of liver histology. Additionally, it significantly reduced fasting blood glucose, glycosylated hemoglobin, plasma AST, ALT, and other liver biological indicators [28].

In 2012, the American Association for the Study of Liver Disease (AASLD) added pioglitazone as a treatment option for patients with biopsy-proven NASH [29].

##  4\. Dipeptidyl Peptidase-4 Inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are common oral anti-hyperglycemic agents that are widely used worldwide. DPP-4 is an important modulator of the incretin system. DPP-4 inhibitors increase the concentrations of both active incretin hormones. They affect levels of GLP-1 by removing the N-terminal His7Ala8 from the active form of GLP-1 and glucose-dependent insulinotropic polypeptide [30]. Blocking incretin degradation with DPP4-i allows postprandial insulin release. The first DPP4-i, sitagliptin, received U.S Food and Drug Administration (FDA) approval in 2006. Extensive data from major clinical trials present the benefits of DPP4-i, such as lowering of HbA1c levels and reductions in inflammation and adipocyte size [30]. Some DPP4-i, like sitagliptin and saxagliptin, did not increase risk of major adverse cardiovascular events in diabetic patients with known cardiovascular disease [31,32]. In the SAVOR trial, saxagliptin increased the risk for HHF. Similar non-significant results were demonstrated in the EXAMINE trial [33], although the reason is currently unknown [32,34]. Therefore, the FDA does not recommend saxagliptin or alogliptin for patients with HF. DPP4-i may also decrease renal microalbuminuria. The SAVOR-TIMI53 trial presented positive renal outcomes with saxagliptin, which reduced the development and progression of microalbuminuria in patients with diabetes [32,35]. DPP4-i are known to be weight-neutral and carry a very low risk of hypoglycemia. Concerns were raised about possible risks for pancreatic cancer, neuroendocrine tumors, and pancreatitis with DPP4-i treatment. However, in 2014, the FDA and the European Medicines Agency (EMA) announced they could not establish a clear relationship between DPP4-i and pancreatitis or pancreatic cancer [36].

##  5\. Sulfonylureas

Sulfonylureas lower blood glucose levels by increasing insulin secretion in the beta cells by blocking the KATP channels. They also limit gluconeogenesis in the liver. Sulfonylureas decrease the breakdown of lipids to fatty acids and reduce clearance of insulin in the liver [10]. 

Sulfonylureas are assessed as having high efficacy in lowering blood glucose levels but lack a durable effect and is associated with weight gain and hypoglycemia [10,21]. Use of sulfonylureas or insulin for early intensive blood glucose control significantly decreased the risk of microvascular complications, underscoring the importance of early and continued glycemic management [37].

At the same time, due to their glucose-independent stimulation of insulin secretion, sulfonylureas are associated with an increased risk of hypoglycemia [10]. Moreover, concerns about their cardiovascular safety have been raised in several retrospective studies, suggesting a greater risk of cardiovascular disease in patients treated with some of the sulfonylureas that prevent the preconditioning ischemia in the heart [38].

Nonetheless, sulfonylureas such as gliclazide and repaglinide do not block NA+/K+ ATPase in the heart vessels, and were not shown to increase cardiovascular events or mortality. [39].

Because novel glucose-lowering agents are available, because sulfonylureas carry the risk of hypoglycemia and weight gain, and because the effects of sulfonylureas decline over the long term, sulfonylureas should not be considered as first- or second line. Their use should be considered in patients who are not well-controlled with metformin, and for whom SGLT-2i, GLP1 RA, and DPP-4i are contraindicated or not tolerated, unavailable, or unaffordable. The expert opinion consensus panel published in Diabetes, Obesity and Metabolism in 2020 advised including sulfonylureas as a third-line treatment option [40]. A quadruple treatment combination therefore would include metformin, SGLT-2i, GLP-1RA, and sulfonylureas to provide additional decreases in HbA1c, mainly to achieve microvascular protection [40].

##  6\. Glinides

Glinides, also known as meglitinides, are insulin secretagogues that depolarize pancreatic β-cells and consequently increase insulin release. Glinides include the drugs repaglinide and nateglinide [41]. Glinides and sulfonylureas differ in structure, yet both stimulate insulin secretion through distinct β-cell receptors [9]. When used as monotherapies, they exhibit similar clinical efficacy [42].

Glinides are rapid-acting, prandial glucose regulators that, unlike sulfonylureas, have a short duration of action. These characteristics render them effective in mitigating postprandial hyperglycemia when they are administered along with meals and are especially advantageous for individuals with inconsistent mealtimes [43]. Glinides are useful in patients with chronic kidney disease, as they are predominantly metabolized by the liver and therefore may be a useful alternative to metformin in this population [44].

In a Cochrane review of 15 trials that assessed the effects of glinides in patients with T2DM, both repaglinide and nateglinide led to reductions in HbA1c levels. Repaglinide resulted in a decrease of 0.1% to 2.1% in HbA1c, compared to 0.2% to 0.6% for nateglinide. Repaglinide was comparable to metformin in its effectiveness in reducing HbA1c levels, but nateglinide was not [45]. Combination therapy with metformin and glinides may improve glycemic control compared to metformin monotherapy [46]. 

Hypoglycemia is one of the major concerns associated with the use of glinides. Nevertheless, most episodes are mild to moderate and do not require assistance. Severe hypoglycemic episodes are rare but may occur; thus, glucose monitoring is important when treatment is initiated until safety is established [45,47]. Hypoglycemic events appear to be more common with sulfonylureas compared to glinides, and both can lead to weight gain [47].

Long-term studies investigating the effect of glinides on cardiovascular outcomes or mortality in patients with T2DM are lacking, and there is no compelling evidence that glinides increase cardiovascular risk [45,48]. Glinides are mostly used as an additional hypoglycemic agent for patients who fail to achieve their glycemic targets with metformin, but they are also useful as monotherapies when metformin or sulfonylureas are contraindicated.

##  7\. Alpha-Glucosidase Inhibitors

Polysaccharides and disaccharides undergo enzymatic cleavage by alpha-glucosidase to monosaccharides in the upper intestine. Alpha-glucosidase inhibitors reversibly inhibit the enzymatic cleavage of complex carbohydrates to simple absorbable sugars, thereby reducing post-prandial hyperglycemia with no risk of hypoglycemia, subsequently reducing HbA1c [49].

In 1999, acarbose (Precose), an alpha-glucosidase inhibitor, was the first drug of this type approved by the FDA. In a multicenter, double-blind, placebo-controlled trial published in 1995, three doses of acarbose (100, 200, and 300 mg three times daily) were compared with placebo. After 16 weeks of treatment, acarbose-treated patients had significant reductions in mean HbA1c levels of 0.78%, 0.73%, and 1.10% (relative to placebo) in the 100 mg, 200 mg, and 300 mg groups, respectively. Gastrointestinal side effects (e.g., abdominal pain, flatulence, and diarrhea) and elevated serum transaminase levels were reported more frequently by the patients treated with acarbose than by those who received the placebo [50].

Acarbose can be an option for diabetic patients with constipation. Note that in the case of hypoglycemia in patients with concurrent treatment with acarbose, glucose/dextrose-only solutions are recommended.

##  8\. Glucagon-like Peptide-1 Receptor Agonists—GLP 1 RA

GLP-1 RA has an excellent effect on the cardiovascular system and the brain, but its effects on heart failure and kidney failure are controversial. GLP-1 is a peptide hormone with multiple effects, including increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent matter. Additionally, GLP-1 delays gastric emptying and increases satiety. Currently, there are multiple options for the use of GLP-1RA, which has substantial HbA1c-reduction properties [51]. In addition to their significance as glucose-lowering agents, GLP-1RAs present encouraging characteristics, including anti-inflammatory and anti-obesity properties, protective effects on the lungs, and a positive influence on the composition of the gut microbiome [52].

Nevertheless, GLP-1RAs are associated with common adverse gastrointestinal effects, which affect more than a third of patients [51].

The recently published STEP 1 (Semaglutide Treatment Effect in People with Obesity) [53], STEP 2 [54], STEP 3 [55], and STEP 4 [56], trials demonstrate the tremendous impact of weekly GLP-1RA treatment with semaglutide on weight loss and cardiovascular risk factors. The results of the trials led to the conclusion that 2.4 mg semaglutide once a week provides impressive weight loss and improvement in cardiovascular risk factors. It is approved for chronic weight management in adults with Body Mass Index (BMI) ≥ 30 kg/m2 or BMI ≥ 25 kg/m2 with concomitant conditions such as T2D, hypertension, or hyperlipidemia [57]. Additional metabolic benefits included improvements in liver fat content and reduced visceral and subcutaneous abdominal adipose-tissue volumes [21].

GLP-1RAs have additional benefits on blood pressure, with significant decreases in systolic blood pressure among hypertensive patients. Diastolic blood pressure is affected less. However, a significant increase in heart rate of 2–4 beats per minute has also been observed [58]. Furthermore, a meta-analysis published in November 2022 indicates an increased risk of both all thyroid cancer and medullary thyroid cancer associated with the use of GLP-1 RA, particularly after 1–3 years of treatment [59].

Cardiovascular outcome trials (CVOT) showed that treatment with GLP-1RA is associated with significant cardiovascular benefits [60].

In August 2023, Novo Nordisk disclosed the headline findings of the SELECT cardiovascular outcomes study. This double-blind trial investigated the use of subcutaneous, weekly 2.4 mg semaglutide in addition to standard care for the prevention of MACE over a period of up to five years, compared to a placebo. The study involved 17,604 adults ages 45 years or older who were diagnosed with overweight or obesity and established cardiovascular disease but who had no previous history of diabetes. The trial successfully met its primary objective by showing a statistically significant 20% reduction in MACE among individuals treated with 2.4 mg semaglutide in comparison to those who received the placebo. Real-world studies investigating cardio-renal outcomes of GLP-1RA suggest that initiation of GLP-1RA was associated with benefits for composite cardiovascular outcomes, MACE, all-cause mortality, myocardial infarction, stroke, cardiovascular death, and peripheral artery disease [60]. A study that examined the effects of the use of GLP-1 RA on stroke found that the use of semaglutide reduced the incidence of stroke compared to placebo among people with type 2 diabetes at high cardiovascular risk. This outcome was driven mainly by the prevention of small-blood-vessel blockage [61]. It has been shown that GLP 1 reduces proteinuria, but its effect on kidney function is still questionable. Some studies showed that GLP 1 increases cystatin C43, which raises concerns about possible negative renal outcomes [62]. Recently, the Icelandic Medicines agency reported about 150 cases of suicidal thoughts and self-injury among people using liraglutide and semaglutide medicines [63]. As a result, the EMA’s Safety Committee stated that it will review data on the risk of suicidal thoughts and self-harm as a potential adverse effect of GLP-1 RA use [64]. Clinical trials with GLP-1 RA such as SCALE and STEP usually exclude patients with major depressive disorders and previous suicidal attempts; thus, data about the increased risk of self-harm is limited. As of the writing of this review, we did not find compelling evidence in the literature of an increased risk of suicide and self-harm related to GLP-1 RA use [53,65]. Nonetheless, the EMA review is ongoing, and further recommendations cannot be made on this matter.

Oral GLP-1RA were first introduced in 2019 with oral semaglutide (Rybelsus). When compared with 1 mg subcutaneous semaglutide, there was no significant difference in weight loss and HbA1c at 20 mg and 40 mg doses, with standard escalation. The 2.5 mg, 5 mg and 10 mg groups were all inferior to 1 mg subcutaneous semaglutide in decreasing HbA1c (−0.4%, −0.9%, −1.2% and −1.9%, respectively). The 5 mg and 10 mg doses resulted in body weight decrease of −1.5 kg and −3.6 kg, respectively. Most adverse events are mild, with the most common being gastrointestinal disorders; these results are similar to those seen with the subcutaneous formulation [66].

In 2019, the PIONEER 6 trial was published as well. PIONEER 6 was a randomized, double-blind, placebo-controlled trial involving diabetic patients at high cardiovascular risk. A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. Major adverse cardiovascular events occurred in 3.8% of patients in the oral semaglutide group and 4.8% of patients in the placebo group (HR 0.79; 95% CI, 0.57 to 1.11; p < 0.001 for noninferiority). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide [67].

In a randomized, placebo-controlled trial published in September 2023 that involved patients with heart failure with preserved ejection fraction and obesity, the administration of a weekly 2.4 mg dose of semaglutide resulted in more significant reductions in heart failure-related symptoms, physical limitations, and greater weight loss compared to the placebo over a 52-week period. Moreover, semaglutide also led to an increased 6-min walk distance, yielded more favorable outcomes in the evaluation of the hierarchical composite endpoint, and lowered C-reactive protein levels to a greater extent than the placebo did. Notably, the semaglutide treatment group experienced fewer serious adverse events when compared to the placebo group, and both groups had a similar frequency of discontinuation due to serious adverse events [3].

In a phase II, randomized, double-blind trial published in September 2023, a newly developed oral GLP-1RA named orforglipron showed promising results. The study included adults who either were diagnosed with obesity or who were overweight with at least one coexisting condition related to weight and who did not have diabetes. A total of 272 participants were randomly assigned. At the beginning of the trial, the average BMI was 37.9. By week 36, the average change ranged from −9.4% to −14.7% for those taking orforglipron, in contrast to a change of −2.3% observed with the placebo. The most frequently reported adverse events were gastrointestinal, which led to the discontinuation of orforglipron in 10% to 17% of participants across different dosage groups [68].

In recent years, promising novel treatment options in various research phases have joined the incretin mimetics drug class, including dual GLP-1/GIP agonists and GLP-1/glucagon agonists. GIP is a four-amino acid peptide produced by the K cells of the duodenum and jejunum. Like GLP-1, GIP is secreted rapidly after ingestion and stimulates insulin production in a glucose-dependent manner. GIP receptors are almost exclusively found in pancreatic β-cells, whereas GLP-1 receptors are found also in the α-cells of the endocrine pancreas, heart, central and peripheral nervous systems, stomach, and adipose tissue.

Tirzepatide, a dual GLP-1/GIP agonist administered once weekly, was approved in 2022 by the FDA for patients with T2D [2].

The SURPASS-2 trial, published in 2021, was a phase III, open-label trial wherein 1879 patients were randomly assigned to receive tirzepatide at 5 mg, 10 mg, or 15 mg doses or semaglutide at a dose of 1 mg. All three tirzepatide doses were superior to semaglutide regarding the mean decrease in HbA1c of - 0.15 percentage points (95% CI −0.28–−0.03; p = 0.02 for 5 mg), −0.39 percentage points (95% CI, −0.51–−0.26; p < 0.001 for 10 mg), and −0.45 percentage points (95% CI, −0.57–−0.32; p < 0.001 for 15 mg). Furthermore, the patients in the tirzepatide groups lost more weight than did those in the semaglutide group (least-squares mean estimated treatment difference, −1.9 kg, −3.6 kg, and −5.5 kg, respectively; p < 0.001 for all comparisons). Although the percentage of patients reporting any adverse event was similar across the groups (with GI events the most common), there was a significant increase in serious adverse events in the tirzepatide groups (5.3–7%) compared to the semaglutide group (2.8%) [69].

In 2022, the SURMOUNT-1 trial, a phase III, double-blind, randomized controlled trial was published. It included 2539 non-diabetic patients who were randomized to receive once-weekly, subcutaneous tirzepatide in 5 mg, 10 mg, or 15 mg dosages or placebo for 72 weeks, including a 20-week dose-escalation period. Tirzepatide was associated with a substantial reduction in body weight, with a mean percent decrease in weight at week 72 of −15.0% (95% CI, −15.9–−14.2) with 5 mg, −19.5% (95% CI, −20.4–−18.5) with 10 mg, and −20.9% (95% CI, −21.8–−19.9) with 15 mg. The mean percent decrease was −3.1% (95% CI, −4.3–−1.9) with placebo (p < 0.001 for all comparisons with placebo) [2].

In 2023, The “SURMOUNT-2” was published. This double-blind, randomized, multicenter, placebo-controlled, phase III trial assessed the efficacy and safety of tirzepatide versus placebo for weight management in people living with obesity and type 2 diabetes. This aim was in contrast to that of the “SURMOUNT-1” trial, wherein type 2 diabetes was a key exclusion criterion [70]. The co-primary endpoints were bodyweight reduction of 5% or more and percent change in body weight from baseline. A total of 938 participants were randomly assigned and received at least one 10 mg dose of tirzepatide (n = 312), 15 mg dose of tirzepatide (n = 311), or placebo (n = 315). Least-squares mean changes in body weight at week 72 with 10 mg and 15 mg tirzepatide were −12.8% (SE 0.6) and −14.7% (0.5), and −3.2% (0.5), respectively, resulting in an estimated treatment differences versus placebo of −9.6% (95% CI −11.1–−8.1) with 10 mg tirzepatide and −11.6% (−13.0–−10.1) with 15 mg tirzepatide (all p < 0.0001). From a baseline HbA1c of 8.02% (64.1 mmol/mol), HbA1c improved by −2.1% (SE 0.06) with 10 mg tirzepatide, −2.1% (SE 0.07) with 15 mg tirzepatide, and −0.5% (SE 0.07) with placebo (p < 0.0001 for all comparisons vs. placebo). At week 72, the mean HbA1c values were 6.0%, 5.9%, and 7.5%, with 10 mg tirzepatide, 15 mg tirzepatide, and placebo, respectively. The proportion of participants in each group reaching HbA1c levels of less than 7.0%, 6.5% or less, or less than 5.7% was significantly higher in the 10 mg and 15 mg tirzepatide groups compared with placebo (87% [n = 271] and 84% [n = 262] vs. 36% [n = 114], 80% [n = 249] and 79% [n = 247] vs. 20% [n = 63], and 46% [n = 144] and 49% [n = 151] vs. 4% [n = 12], respectively [70,71].

Retatrutide, another novel incretin-mimetic drug, is an agonist of the GLP-1, GIP and glucagon receptors. The Retatrutide Phase 2 trial, published in August 2023, was a phase II, double-blind, randomized, placebo-controlled trial involving 338 non-diabetic adults who had a BMI of 30 or higher, or a BMI of 27 to less than 30 and at least one weight-related condition. Participants were randomized to administration of subcutaneous retatrutide at varying doses (1 mg, 4 mg [initial dose: 2 mg], 4 mg [initial dose: 4 mg], 8 mg [initial dose: 2 mg], 8 mg [initial dose: 4 mg], or 12 mg [initial dose: 2 mg]), or a placebo, weekly, over 48 weeks. At 48 weeks, the least-squares mean percentage weight changes in the retatrutide groups were as follows: −8.7% in the 1 mg group, −17.1% in the combined 4 mg group, −22.8% in the combined 8 mg group, and −24.2% in the 12 mg group, compared to −2.1% in the placebo group. Weight reductions of 5% or more, 10% or more, and 15% or more were observed in 92%, 75%, and 60% of participants receiving 4 mg of retatrutide; 100%, 91%, and 75% for those on 8 mg; 100%, 93%, and 83% for those on 12 mg; and 27%, 9%, and 2% for those receiving placebo. The predominant adverse events in the retatrutide groups were gastrointestinal. These adverse events were dosage-dependent, were mainly of mild to moderate intensity, and were somewhat alleviated with a lower initial dosage (2 mg versus 4 mg) [72].

##  9\. Sodium-Glucose Cotransporter Inhibitors (SGLT-2i)

SGLT-2 inhibitors are a class of medications primarily used for managing type 2 diabetes. They provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubules, consequently lowering blood glucose levels. One of the significant benefits of SGLT-2i is their association with weight loss due to the elimination of excess glucose. Moreover, these drugs are associated with consistent reductions in blood pressure. They have a relatively low risk of causing hypoglycemia compared to other diabetes medications, making them a safer option, especially in combination with other anti-diabetic drugs. Beyond their glucose-lowering effects, SGLT-2i exhibit notable cardiovascular benefits, as demonstrated by a reduced risk of heart failure and cardiovascular events. Furthermore, they have shown promise in slowing the progression of kidney disease in diabetic patients. These conclusions are drawn from reliable clinical trials and studies, positioning SGLT-2i as a valuable addition to the management of type 2 diabetes, with potential multifaceted health benefits [1,10,21,73,74,75].

Cardiorenal outcome trials have shown the effectiveness of these drugs in lowering the risk of MACE, HHF, all-cause mortality, and renal deterioration [1,5,21,75].

Furthermore, SGLT-2i improve the outcomes of patients with HF or chronic kidney disease (CKD) regardless of whether they have T2DM or not [1,5,75].

SGLT-2i may reduce the risk of cardiovascular death or HHF for both diabetic and non-diabetic patients with HF with reduced ejection fraction (HFrEF) [5,75].

Additionally, in patients with HF with preserved ejection fraction (HFpEF), SGLT-2i reduce the combined risk of cardiovascular death or HHF and improve symptoms related to HF and physical limitations [76,77,78].

Empagliflozin and dapagliflozin are also associated with an improvement in left-ventricle structure and function in patients with HF, but more information is required to further clarify these effects [79,80].

In patients with CKD, SGLT-2i use is associated with a reduction in the decline of glomerular filtration rate (GFR), proteinuria, end-stage renal disease, and the risk of death from renal or cardiovascular causes [1].

In a 2020 study published in the New England Journal of Medicine, 4304 participants with an estimated GFR ranging from 25 to 75 mL per minute per 1.73 m2 of body surface area and a urinary albumin-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) in the range of 200 to 5000 were administered either 10 mg dapagliflozin daily or a placebo. For patients with chronic kidney disease, irrespective of the presence or absence of diabetes, the study revealed that the risk of the composite outcome, including a sustained decline in estimated GFR of at least 50%, end-stage kidney disease, or death from renal failure, was significantly lower in the group receiving dapagliflozin compared to that in the group receiving the placebo (95% CI, 0.45–0.68; p < 0.001). The HR for the composite outcome of death from cardiovascular causes or HHF was 0.71 (95% CI, 0.55–0.92; p = 0.009) [1].

A recent meta-analysis of randomized controlled trials compared the efficacy and safety of various drug treatments for T2DM and found that compared to other drugs, SGLT-2i increased the risk of diabetic ketoacidosis (DKA) (OR 2.07, 95% CI 1.44–2.98), genital infection (OR 3.30, 95% CI 2.88–3.78) and probably amputation (OR 1.27, 95% CI 1.01–1.61) [81].

The DKA associated with SGLT-2i may manifest as euglycemic DKA in some patients with T2DM, specifically in those with a glucose level of less than 200 mg/dL. This potential adverse effect requires vigilance from healthcare providers, as euglycemic DKA can be life-threatening and is easily missed [82].

Canagloflizin may increase the risk for amputation and fractures [83,84,85]. It has been suggested that other SGLT-2i may also increase the risk of bone fractures, but this finding was not confirmed in subsequent meta-analyses, although additional data are required to establish a firm conclusion [86,87].

In a meta-analysis conducted for patients with NAFLD, SGLT-2i and GLP-1 RA were studied along with thiazolidinediones. These drugs were found to improve liver enzymes, BMI, blood lipid levels, blood glucose and insulin resistance in patients with NAFLD [74].

Considering the many advantages mentioned herein, SGLT-2i are recommended as a first-line therapy for T2DM with CVD or renal disease by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) [21].

##  10\. Is the Combination of SGLT-2i and GLP-1 RA Synergistic?

Robust evidence suggests that SGLT-2i and GLP-1RAs are associated with low risk of hypoglycemia; promote weight loss; and exert a positive impact on vascular, cardiac, and renal endpoints. Several post hoc analyses of cardiovascular outcomes studies involving diabetic patients already treated with GLP1-RA have suggested that the combination of SGLT-2i and GLP-1 exhibits a synergistic effect in protecting the heart and kidney [7,21,40,60].

##  11\. Pharmacotherapy in Pregnancy

Among normo-glycemic women, early pregnancy is characterized by a notable increase in insulin sensitivity. However, the opposite occurs as pregnancy progresses to the second and third trimesters, when insulin sensitivity decreases substantially. This change results in a decrease in glucose uptake by adipose and muscle tissue, as well as decreased insulin-mediated lipolysis and beta-oxidation. In tandem, these adaptations help to meet the surging energy demands of the developing fetus [88].

In women with pre-existing diabetes, these changes in glucose metabolism are more pronounced and may lead to a hyperglycemic state, which makes this population more susceptible to pregnancy complications [88], including congenital malformations, preeclampsia, and preterm delivery. In addition, about half of the women with pre-existing diabetes deliver infants who are large for gestational age, which elevates the infants’ risk of birth-related traumas and the risk of developing metabolic syndrome, cardiovascular disease, and type 2 diabetes mellitus later in life [89]. Therefore, glycemic control is of paramount importance in pregnant women with pre-existing diabetes.

The glucose targets for pregnant women with pre-existing diabetes or gestational diabetes mellitus (GDM) recommended by the ADA, as well as the American College of Obstetricians and Gynecologists (ACOG), are fasting glucose, ≤95 mg/dL; glucose 1 h after eating, ≤140 mg/dL; and glucose 2 h after eating, ≤120 mg/dL [90,91]. Although HbA1c is a useful measure of glycemic control in a non-pregnant population, in pregnancy, it seems to less accurately reflect temporary glucose fluctuations due to an increased turnover of red blood cells [89]. In addition, elevations in fasting glucose, in contrast to postprandial elevations, are more predictive of fetal macrosomia. This insight can prove valuable when adjusting insulin regimens [92].

Managing T2DM with hypoglycemic agents, including insulin, during pregnancy, along with proper diet and lifestyle modifications to ensure glycemic control, are paramount for the prevention of pregnancy complications [89].

Pharmacologic treatment of T2DM in pregnancy is based primarily on insulin. Nevertheless, non-insulin hypoglycemic agents are available and include metformin and glyburide. Other classes of diabetic medications are not recommended in pregnancy due to the limited safety and efficacy data available for this population [93].

Both ACOG and the ADA recommend that insulin therapy should be the cornerstone of pharmacotherapy and that the use of other agents should be limited or ceased entirely during pregnancy [88,89].

Metformin is a biguanide that exerts its antihyperglycemic effects by decreasing hepatic gluconeogenesis, decreasing glucose absorption in the intestines, and increasing glucose uptake in the periphery [89]. It is inexpensive and effective in reducing hyperglycemia and is the first-line therapy for many patients with T2DM [94]. In pregnant women, metformin seems to improve maternal metabolic outcomes. The Metformin in Women with Type 2 Diabetes in Pregnancy study (MiTy), a multicenter, randomized, controlled trial, compared 2000 mg daily metformin with placebo. Women in the metformin group achieved better glycemic control compared to those given the placebo, as manifested by reduced HbA1c levels (5.9% [SD 0.78] vs. 6.1% [SD 0.94], p = 0.015), lower insulin requirements, less weight gain, and fewer cesarean sections [95]. Nevertheless, metformin, in contrast to insulin, can cross the placenta and potentially affect the growing fetus, which raised concerns regarding its use in pregnancy. A meta-analysis that looked at the use of metformin in the first trimester of pregnancy did not find a significant increase in major congenital malformations [96]. In addition, metformin may reduce birthweight, thereby decreasing the rates at which infants are born large for gestational age and/or with macrosomia and increase the rate of at which infants are born small for gestational age, which is also associated with adverse outcomes [95,97]. In contrast to its effects on birthweight, exposure to metformin in utero is associated with a higher BMI later in life [96,98]. In contrast to these findings, a 24-month follow-up on the children born to women in the MiTy trial concluded that there was no difference in BMI and overall anthropometrics between the children who were exposed to metformin or placebo [99]. In summary, although metformin seems to improve maternal metabolic outcomes in pregnancy, its effects on the fetus are still not clear and additional long-term data are needed to establish a firm recommendation.

Glyburide, also known as glibenclamide, is a long-acting sulfonylurea that exhibits antihyperglycemic effects by stimulating the release of insulin from pancreatic beta cells and increasing peripheral insulin sensitivity. Like metformin, glyburide can cross the placenta and potentially affect a growing fetus [43]. Multiple meta-analyses sought to compare the safety and efficacy of glyburide with metformin therapy in pregnancy, as these are the only oral diabetic agents currently available for this population and are commonly prescribed in combination with insulin [100,101,102,103]. Glyburide is about equal to metformin in its contribution to glycemic control in pregnant women with diabetes. A meta-analysis that compared glyburide and metformin in patients with GDM found no difference in fasting blood glucose (p = 0.821), postprandial blood glucose (p = 0.217) and birth weight (p = 0.194) between the interventions. However, glyburide is associated with more adverse effects, including maternal weight gain, macrosomia, neonatal hypoglycemia, and neonatal disease [100]. When safety and efficacy are evaluated, glyburide seems to be inferior to metformin in the treatment of diabetes in pregnancy because it has more adverse effects and only comparable efficacy, with a lack of long-term data on its effects on the fetus.

Insulin and insulin analogs are the mainstay of treatment for pregnant diabetic women and are universally prescribed for this population [90,93]. Insulin does not cross the placenta [90] and thus is deemed safer for the fetus than oral antihyperglycemic agents; however, the evidence that oral agents are not safe is not convincingly found in the literature due to limited data. Insulin requirements change with gestational age. Therefore, frequent monitoring and adjustments are important to improve efficacy and safety of treatment [90]. In practice, a combination of long-acting and short-acting insulin is used to establish glycemic control. Long-acting insulin creates a sufficient baseline level of insulin, while short-acting insulin accommodates postprandial increases in glucose [93]. Long-acting agents include detemir, glargine, and degludec, and short-acting agents include lispro, aspart, and glulisine.

Insulin analogs are considered safe and efficient for treating diabetes in pregnancy. In a meta-analysis of randomized, controlled trials that compared detemir to neutral protamine Hagedorn (NPH) insulin, detemir was associated with fewer maternal hypoglycemic events and decreased risk of prematurity. Another multicenter, prospective cohort compared detemir to other basal insulins including NPH in pregnant women with pre-existing diabetes and found no difference in efficacy and safety [104,105]. The recently published EXPECT trial found degludec to be non-inferior to detemir, while data on glargine is mostly observational and requires further investigation [106]. Lispro and aspart are at least as safe as NPH. They are better than NPH in postprandial glucose regulation and may create a synergistic effect with long-acting insulin to provide good glycemic control [107]. Currently, data regarding the use of glulisine in pregnancy is lacking compared to data regarding lispro and aspart. It should therefore be prescribed with more caution. Multiple daily injections (MDI) are the standard modality of insulin administration in diabetic pregnant women, but continuous subcutaneous insulin infusion (CSII) with an insulin pump is another available option. Current evidence suggests no advantage to the CSII modality [90,108].

As current evidence stands, insulin supplied in a basal-bolus manner is the first-line pharmacologic treatment for diabetic pregnant women. While metformin may confer some additional benefit, additional long-term data about the effects on offspring are needed to establish a clear recommendation.

##  12\. Breakthrough Research and Future Drugs

In a study examining the molecular basis of insulin resistance, researchers identified a small molecule, Co-Insulin, which binds specifically to insulin rather than to the insulin receptor (IR). This 222 Da molecule binds to a specific site on the A-chain of insulin, initiating interaction between the A and B chains and activating the insulin receptor. This activation triggers a series of events: insulin receptor autophosphorylation, phosphorylation of IRS proteins, and insulin action with ‘Immediate’ and ‘Delayed’ responses. The ‘Immediate’ response involves the known hypoglycemic effect mediated by Glut-4 and influenced by a phosphorylated IRS molecule. Conversely, the ‘Delayed’ response involves the nuclear entry of specific fragments of the phosphorylated insulin receptor, which is potentially facilitated by another phosphorylated IRS. Importantly, Co-Insulin functions solely by initiating insulin signaling events. This pioneering study raises the question of whether similar small molecules play roles in mediating the actions of other peptide hormones in the mammalian system. This research may lead to the development of new diabetes drugs [109].

##  13\. Innovation in the Therapeutic Approach

The importance of normalized blood glucose levels was raised in the DPP-1 study of patients with pre-diabetes [110]. The study evaluated whether healthy lifestyle or metformin led to normalized blood glucose levels in some of the study participants. Even temporary normalization of blood glucose levels was shown to delay the onset of diabetes by several years [110].

Recent studies have highlighted a clear correlation between reducing HbA1c to less than 6.5% and a significant decrease in microvascular and macrovascular complications [66]. When we combine these findings, emphasizing the importance of normalizing blood glucose levels to prevent both the development of diabetes and associated risk factors, our current goals should be to cure diabetes and to aim to lower HbA1c below 5.7%, even if the effect lasts only for several years. This approach could significantly impact outcomes for patients with T2DM, especially considering that most individuals develop the disease after age 50 [66].

The new drugs, which not only lower glucose levels but also reduce cardiovascular risk factors, promote weight loss, and reduce abdominal fat, offer the potential to cure diabetes in a sizable proportion of patients, provided that we diagnose the condition as early as possible. Therefore, the treatment approach should be substantially different from traditional methods. Patients with either pre-diabetes or diabetes should be diagnosed as early as possible. Diabetic patients should be treated as early as possible with healthy-lifestyle interventions and combination therapy including at least one of these new drugs.

Recent studies and meta-analyses suggest the potential benefits of primary combined therapy for glycemic management in diabetes compared to monotherapy with metformin across a wide range of baseline HbA1c levels. Combined treatment can increase the number of patients achieving their glycemic goals. The newer glucose-lowering drugs reduce the risk of hypoglycemia and help reduce patient weight. Furthermore, improving our understanding of the complex pathophysiology of T2DM and the availability of therapies that target specific mechanisms contributing to hyperglycemia should lead to increased adoption of combined treatment, which is pathophysiologically correct. This approach to achieving better glycemic control (both in the short term and in the long term) helps balance the side effects associated with monotherapy and results in better glycemic control. In addition, better balance is maintained over both the short term and the long term [7]. Early diabetes control has a wide-ranging impact on the prevention of disease complications throughout life [62].

The most effective way to manage diabetes is to treat it with a combination therapy from the time of initial diagnosis.

Recovery from diabetes includes two important aspects: weight loss and normalization or near-normalization of blood glucose levels.

The recommendation for optimal glucose balance includes commencing treatment with dual therapy. The question is whether to use metformin together with GLP-1 RA or SGLT-2i, or to initiate combined treatment with GLP-1 RA and SGLT-2i.

If it is not contraindicated, we believe that all diabetic patients with or without cardiovascular or renal disease will benefit from using metformin as part of the combination therapy, together with SGLT-2i or GLP-1 RA. We recommend considering combined treatment with metformin, GLP-1 RA, and SGLT-2i in patients who do not achieve the target of HbA1c or weight loss or who are at increased risk of cardio-renal events, as this has been proven to reduce complications and mortality among patients with these conditions.

There are certain indications for initial therapy with a three-drug combination, including prior failure to achieve success with a two-drug combination, patients with active cardiovascular disease or heart failure, and patients with proteinuria and deterioration in kidney function.

To help medical staff choose the ideal drug combination for each patient, the National Diabetes Council in Israel developed a calculator that recommends the most appropriate combination therapy based on the patient’s BMI, HbA1c levels, and risk for ischemic heart disease, stroke, renal function, and heart failure.

Along with the most appropriate drug treatment, a healthy lifestyle is extremely important. The keys to a healthy lifestyle are exercise, maintaining an appropriate diet, and 7–8 h of sleep a night [111].

Five distinct types of diabetes were recently characterized [112]. Some include issues related to deficient beta-cell mass and function. In these cases, the addition of insulin, sulfonylurea, glinide, and in some instances, TZD or DPP4-i, can maintain the target blood glucose levels for a significant portion of these patients. Consequently, there is a strong case for combining these drugs in the treatment of diabetic patients. This recommendation may be especially important in the coming years, particularly given the high cost of the new drugs, which restricts their use in many patients. Short-term treatment with insulin is recommended for patients with uncontrolled diabetes resulting in clinical symptoms and/or HbA1c greater than 9% (Figure 1).

Hence, our approach to treating recently diagnosed diabetes is as follows:

  * Early diagnosis of abnormal glucose metabolism.

  * Early treatment with combination therapy.

  * Giving preference to medications that simultaneously lower weight and blood glucose levels in those who are overweight or obese, do not cause hypoglycemia, and protect against possible damage to target organs like the heart, the macro- and microvascular systems, the kidneys, the liver, and the brain.

  * Aiming to normalize blood glucose levels using the new drugs and adding the old ones for patients who do not achieve the target HbA1c.




## Author Contributions

All authors contributed to the writing—both original draft preparation and review and editing. All authors have read and agreed to the published version of the manuscript.

## Funding

This research received no external funding.

## Conflicts of Interest

Weinberg Sibony, R.; Segev, O.; and Dor, S. declare no conflict of interest. Raz, I. disclosure: Advisory Board: AstraZeneca, Eli Lilly and Company, Novo Nordisk. J&J, Bayer and CuraLife.

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**Figure 1.** Drug-Treatment Algorithm for Diabetes. The algorithm outlines our recommendations for diabetes treatment, incorporating the initiation of combined drug therapy and adjusting medications based on the patient’s response. 

**Figure 1.** Drug-Treatment Algorithm for Diabetes. The algorithm outlines our recommendations for diabetes treatment, incorporating the initiation of combined drug therapy and adjusting medications based on the patient’s response.

**Table 1.** Anti-Diabetic Drugs. The table provides an overview of oral and injectable non-insulin medications used to improve blood glucose levels. It includes the names of medication groups and specific drugs within each group, as well as information on their effects, side effects, and safety. (‘↑’Aggravation/increase, ‘↓’ improvement/decrease, ‘?’ Not confirmed). 

**Table 1.** Anti-Diabetic Drugs. The table provides an overview of oral and injectable non-insulin medications used to improve blood glucose levels. It includes the names of medication groups and specific drugs within each group, as well as information on their effects, side effects, and safety. (‘↑’Aggravation/increase, ‘↓’ improvement/decrease, ‘?’ Not confirmed).

Drug Group| Specific Drug| Effects| Adverse Effects| Safety  
---|---|---|---|---  
Biguanides| Metformin| HbA1c ↓  
Body weight ↓→  
Cancer ↓?  
Cardiovascular↓?| Gastrointestinal disorders ↑  
Reversible vitamin B12 deficiency↑  
Lactic Acidosis ↑| None  
Glinides| Repaglinide  
Nateglinide| HbA1c ↓   
  
Body weight ↑| Hypoglycemia ↑  
Headache ↑  
Upper respiratory tract infection ↑| None  
Alpha-Glucosidase inhibitors| Acarbose| HbA1c ↓   
Body weight ↓ →| Gastrointestinal disorders ↑  
Serum transaminases (AST, ALT) ↑| None  
SGLT2-I| Empagliflozin  
Dapagliflozin  
Canagliflozin| HbA1c ↓   
Body weight ↓  
BP ↓  
MACE ↓  
Hospitalization for HF ↓  
  
Progression of renal disease ↓| Diabetic ketoacidosis ↑  
Genital infection ↑  
Urinary tract infection ↑  
Hypovolemia ↑  
Acute kidney injury ↑ (related to hypovolemia)   
  
Canagliflozin:  
Amputation ↑  
Bone fracture ↑| None  
Thiazolidineidiones| Pioglitazone| HbA1c ↓   
BP ↓  
NAFLD ↓  
MACE ↓| Body weight ↑  
Peripheral edema ↑  
Anemia ↑  
Hospitalization for HF ↑  
Bone fracture in women ↑| Cancer?  
DPP-4| Sitagliotin  
Saxagliptin  
Alogliptin| HbA1c ↓ | Saxagliptin:  
Hospitalization for HF?|   
Sulfonylureas| Glimepiride  
Gliclazide  
Glibenclamide  
Glipizide| HbA1c ↓ | Body weight ↑  
Hypoglycemia ↑  
Lack of durable effect| Glibenclamide   
Glipizide:  
Cardio-vascular events?  
GLP-1 RA  
  
  
  
  
Combination therapy| Liraglutide Dulaglutide  
Semaglutide  
Orforglipron  
  
Tirzepatide  
Retatrutide| HbA1c ↓↓   
Body weight ↓  
Systolic BP ↓  
MACE ↓  
HF ?  
Quality of life for patients with HF (KCCQ-CSS) ↑  
NAFLD ↓ →| Gastrointestinal disorders ↑  
  
Semaglutide:  
Macular edema  
  
| Pancreatitis  
Bile stones  
Thyroid carcinoma  
  
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---|---  
  
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Weinberg Sibony, R.; Segev, O.; Dor, S.; Raz, I. Drug Therapies for Diabetes. _Int. J. Mol. Sci._ **2023** , _24_ , 17147. https://doi.org/10.3390/ijms242417147 

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Weinberg Sibony R, Segev O, Dor S, Raz I. Drug Therapies for Diabetes. _International Journal of Molecular Sciences_. 2023; 24(24):17147. https://doi.org/10.3390/ijms242417147 

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Weinberg Sibony, Roni, Omri Segev, Saar Dor, and Itamar Raz. 2023\. "Drug Therapies for Diabetes" _International Journal of Molecular Sciences_ 24, no. 24: 17147. https://doi.org/10.3390/ijms242417147 

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Weinberg Sibony, R., Segev, O., Dor, S., & Raz, I. (2023). Drug Therapies for Diabetes. _International Journal of Molecular Sciences_ , _24_(24), 17147. https://doi.org/10.3390/ijms242417147 

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Weinberg Sibony, R.; Segev, O.; Dor, S.; Raz, I. Drug Therapies for Diabetes. _Int. J. Mol. Sci._ **2023** , _24_ , 17147. https://doi.org/10.3390/ijms242417147 

**AMA Style**  


Weinberg Sibony R, Segev O, Dor S, Raz I. Drug Therapies for Diabetes. _International Journal of Molecular Sciences_. 2023; 24(24):17147. https://doi.org/10.3390/ijms242417147 

**Chicago/Turabian Style**  


Weinberg Sibony, Roni, Omri Segev, Saar Dor, and Itamar Raz. 2023\. "Drug Therapies for Diabetes" _International Journal of Molecular Sciences_ 24, no. 24: 17147. https://doi.org/10.3390/ijms242417147 

**APA Style**  


Weinberg Sibony, R., Segev, O., Dor, S., & Raz, I. (2023). Drug Therapies for Diabetes. _International Journal of Molecular Sciences_ , _24_(24), 17147. https://doi.org/10.3390/ijms242417147 

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). 

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