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Role of pancreatic lipase inhibition in obesity treatment: mechanisms and challenges towards current insights and future directions | International Journal of Obesity

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Role of pancreatic lipase inhibition in obesity treatment: mechanisms and challenges towards current insights and future directions 

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Physiology and Biochemistry

# Role of pancreatic lipase inhibition in obesity treatment: mechanisms and challenges towards current insights and future directions

  * Vetriselvan Subramaniyan [ORCID: orcid.org/0000-0002-9629-9494](http://orcid.org/0000-0002-9629-9494)1,2 &
  * Yusoff Umul Hanim [ORCID: orcid.org/0000-0002-5320-5443](http://orcid.org/0000-0002-5320-5443)2



[_International Journal of Obesity_](/ijo) (2025)Cite this article

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### Subjects

  * [Fat metabolism](/subjects/fat-metabolism)
  * [Metabolic syndrome](/subjects/metabolic-syndrome)
  * [Obesity](/subjects/obesity)



## Abstract

The worldwide health emergency of obesity is closely connected to how dietary fats are metabolized, whereas the process is significantly influenced by pancreatic lipase (PL), an enzyme critical for lipid hydrolysis into fatty acids. This narrative review employs a methodological approach utilizing literature searches of PubMed data up to March 2024. The search term criteria encompasses keywords related to the role, mechanism, challenges, and current and future treatments of pancreatic lipase in obesity with an overall references is 106. This paper offers a comprehensive explanation of the role of PL, underlining its significance in the digestive process and lipid imbalances that contribute to obesity and by extension, its impact on obesity development and progression. Additionally, it delves into the dual functionality of the pancreas, emphasizing its impact on metabolism and energy utilization which, when dysregulated, promotes obesity. A focal point of this review is the investigation into the efficacy, challenges, and adverse effects of current pancreatic lipase inhibitors, with orlistat being highlighted as a primary current drug delivery. By discussing advanced obesity treatments, including the exploration of novel anti-obesity medications that target specific biological pathways, this review underscores the complexity of obesity treatment and the necessity for a multifaceted approach. In conclusion, this paper emphasizing the importance of understanding the role of enzymes like pancreatic lipase mechanistic and adopting a multidisciplinary approach to treatment and side effects of current obesity drugs and explore new emerging therapeutic strategies for more effective obesity management.

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Article 17 April 2024

## Introduction

Obesity represents a global public health crisis, with its prevalence continually rising and contributing to a myriad of comorbid conditions, including type 2 diabetes [[1](/articles/s41366-025-01729-1#ref-CR1 "Scully T, Ettela A, LeRoith D, Gallagher EJ. Obesity, type 2 diabetes, and cancer risk. Front Oncol. 2021;10:615375. 
                https://doi.org/10.3389/fonc.2020.615375
                
              ")], cardiovascular diseases [[2](/articles/s41366-025-01729-1#ref-CR2 "Lopez-Jimenez F, Almahmeed W, Bays H, Cuevas A, Di Angelantonio E, le Roux CW, et al. Obesity and cardiovascular disease: mechanistic insights and management strategies. A joint position paper by the World Heart Federation and World Obesity Federation. Eur J Prev Cardiol. 2022;29:2218–37. 
                https://doi.org/10.1093/eurjpc/zwac187
                
              ")], and certain forms of cancer [[3](/articles/s41366-025-01729-1#ref-CR3 "Pati S, Irfan W, Jameel A, Ahmed S, Shahid RK. Obesity and cancer: a current overview of epidemiology, pathogenesis, outcomes, and management. Cancers \(Basel\). 2023;15:485. 
                https://doi.org/10.3390/cancers15020485
                
              ")], that impact millions of people around the world. It is a multifaceted issue marked by an excessive storage of fat, which leads to a heightened risk of many chronic illnesses. Traditional approaches to obesity management have primarily focused on lifestyle modifications [[4](/articles/s41366-025-01729-1#ref-CR4 "Olateju IV, Ogwu D, Owolabi MO, Azode U, Osula F, Okeke R, et al. Role of behavioral interventions in the management of obesity. Cureus. 2021;13:e18080. 
                https://doi.org/10.7759/cureus.18080
                
              ")], such as diet and exercise [[5](/articles/s41366-025-01729-1#ref-CR5 "Vettor R, Di Vincenzo A, Maffei P, Rossato M. Regulation of energy intake and mechanisms of metabolic adaptation or maladaptation after caloric restriction. Rev Endocr Metab Disord 2020;399–409. 
                https://doi.org/10.1007/s11154-020-09565-6
                
              .")], and pharmacological interventions targeting general metabolic pathways. However, these strategies often fall short of providing long-term, sustainable weight loss, highlighting the urgent need for novel therapeutic approaches. In regard to the effective approach in combining pharmacological treatments with effective lifestyle modifications can indeed be challenging but holistic approaches offer a promising solution. Other than lifestyle balance, integrative medicine, such as complementary therapies like yoga and acupuncture manages to improve overall well-being. Collaboration in care model and patient education support offers an important lifestyle change, and providing ongoing support can enhance awareness and improve outcomes among communities.

Within this myriad strategy, our study offers a discussion on inhibiting pancreatic lipase (PL), which is a proven strategy for tackling obesity. This approach effectively interferes with the body's ability to store lipids, thereby aiding in weight loss [[6](/articles/s41366-025-01729-1#ref-CR6 "Kim GN, Shin MR, Shin SH, Lee AR, Lee JY, Seo BI, et al. Study of antiobesity effect through inhibition of pancreatic lipase activity of Diospyros kaki fruit and Citrus unshiu peel. Biomed Res Int. 2016;1723042. 
                https://doi.org/10.1155/2016/1723042
                
              .")]. Pancreatic lipase is a crucial enzyme in the digestive system that plays a role in the process of breaking down lipids into free fatty acids and monoglycerides [[4](/articles/s41366-025-01729-1#ref-CR4 "Olateju IV, Ogwu D, Owolabi MO, Azode U, Osula F, Okeke R, et al. Role of behavioral interventions in the management of obesity. Cureus. 2021;13:e18080. 
                https://doi.org/10.7759/cureus.18080
                
              ")]. This enzyme's activity is crucial for lipid absorption and metabolism, making it a compelling target for obesity intervention. The pancreas' unique role, combining both endocrine and exocrine functions, situates it as a key player in regulating metabolism [[6](/articles/s41366-025-01729-1#ref-CR6 "Kim GN, Shin MR, Shin SH, Lee AR, Lee JY, Seo BI, et al. Study of antiobesity effect through inhibition of pancreatic lipase activity of Diospyros kaki fruit and Citrus unshiu peel. Biomed Res Int. 2016;1723042. 
                https://doi.org/10.1155/2016/1723042
                
              .")]. When these roles are disrupted, it can greatly influence the onset and worsening of obesity, highlighting the importance of PL within the wider scope of metabolic well-being.

Recent studies have illuminated the effectiveness, obstacles, and possible adverse effects associated with existing PL inhibitors. Orlistat, the only FDA-approved pancreatic lipase (PL) inhibitor for long-term use, has been widely used as an anti-obesity drug in the U.S. and Europe for over a decade. Although effective, studies have reported that 91% of patients treated with orlistat experience gastrointestinal issues and other adverse effects [[6](/articles/s41366-025-01729-1#ref-CR6 "Kim GN, Shin MR, Shin SH, Lee AR, Lee JY, Seo BI, et al. Study of antiobesity effect through inhibition of pancreatic lipase activity of Diospyros kaki fruit and Citrus unshiu peel. Biomed Res Int. 2016;1723042. 
                https://doi.org/10.1155/2016/1723042
                
              ."), [7](/articles/s41366-025-01729-1#ref-CR7 "Tak YJ, Lee SY. Long-term efficacy and safety of anti-obesity treatment: where do we stand? Curr Obes Rep. 2021;10:14–30. 
                https://doi.org/10.1007/s13679-020-00422-w
                
              ")]. The evolution of new obesity drugs has been marked by significant challenges due to adverse effects, highlighting the need for future research to focus on safer, more targeted therapies with improved long-term outcomes. However, a large-scale study involving 33,625 patients found no significant link between orlistat use and an increased risk of colorectal cancer. Despite its benefits, the clinical application of orlistat is often hindered by its gastrointestinal side effects and modest weight loss results, prompting the search for alternative and adjunct therapies, including natural products and novel PL inhibitory peptides that may offer better tolerability and effectiveness in managing obesity [7,8,[9](/articles/s41366-025-01729-1#ref-CR9 "Brandfon S, Eylon A, Khanna D, Parmar MS. Advances in anti-obesity pharmacotherapy: current treatments, emerging therapies, and challenges. Cureus. 2023;15:e46623. 
                https://doi.org/10.7759/cureus.46623
                
              ")].

Furthermore, the latest progress in peptide-based treatments [[7](/articles/s41366-025-01729-1#ref-CR7 "Tak YJ, Lee SY. Long-term efficacy and safety of anti-obesity treatment: where do we stand? Curr Obes Rep. 2021;10:14–30. 
                https://doi.org/10.1007/s13679-020-00422-w
                
              ")] and the investigation of new anti-obesity drugs focusing on particular metabolic processes mark considerable progress in the evolution of advanced obesity therapies [[9](/articles/s41366-025-01729-1#ref-CR9 "Brandfon S, Eylon A, Khanna D, Parmar MS. Advances in anti-obesity pharmacotherapy: current treatments, emerging therapies, and challenges. Cureus. 2023;15:e46623. 
                https://doi.org/10.7759/cureus.46623
                
              "), [10](/articles/s41366-025-01729-1#ref-CR10 "Kakouri A, Kanti G, Kapantais E, Kokkinos A, Lanaras L, Farajian P, et al. New incretin combination treatments under investigation in obesity and metabolism: a systematic review. Pharmaceuticals \(Basel\). 2021;14:869. 
                https://doi.org/10.3390/ph14090869
                
              ")]. These advancements highlight the intricate nature of excessive weight as a condition and the need for a comprehensive treatment strategy that includes innovative pharmacological solutions as a comprehensive management plan.

This manuscript aims to explore the significance of pancreatic lipase inhibition in obesity treatment, providing an overview of current insights and future directions. It delves into the mechanistic role of PL in obesity, examines the efficacy and limitations of existing inhibitors, and discusses the potential of emerging treatments. By highlighting the evolving landscape of obesity treatment and the critical role of ongoing research and development, this work underscores the potential of PL inhibition as a cornerstone of more effective and personalized obesity management strategies [[10](/articles/s41366-025-01729-1#ref-CR10 "Kakouri A, Kanti G, Kapantais E, Kokkinos A, Lanaras L, Farajian P, et al. New incretin combination treatments under investigation in obesity and metabolism: a systematic review. Pharmaceuticals \(Basel\). 2021;14:869. 
                https://doi.org/10.3390/ph14090869
                
              ")].

## Mechanistic insights into pancreas lipase

Among the vast array of biological mechanisms involved in the onset and advancement of obesity, the function of digestive enzymes, especially pancreatic lipase (PL), has attracted notable interest. Obesity is a multifaceted disease impacted by genetic, environmental, and lifestyle elements [[5](/articles/s41366-025-01729-1#ref-CR5 "Vettor R, Di Vincenzo A, Maffei P, Rossato M. Regulation of energy intake and mechanisms of metabolic adaptation or maladaptation after caloric restriction. Rev Endocr Metab Disord 2020;399–409. 
                https://doi.org/10.1007/s11154-020-09565-6
                
              ."), [11](/articles/s41366-025-01729-1#ref-CR11 "Wen X, Zhang B, Wu B, et al. Signaling pathways in obesity: mechanisms and therapeutic interventions. Sig Transduct Target Ther. 2022;7:298. 
                https://doi.org/10.1038/s41392-022-01149-x
                
              ")]. Pancreatic lipase plays a key role in the digestive system, crucially breaking down dietary fats into fatty acids and monoglycerides that can be absorbed. This process is vital for the proper digestion and absorption of fats. When this process is disrupted, it can lead to imbalances in lipid levels and, ultimately, obesity or lipid absorption disorder [[12](/articles/s41366-025-01729-1#ref-CR12 "Reis P, Malmsten M, Nydén M, Folmer B, Holmberg K. Interactions between lipases and amphiphiles at interfaces. J Surfactants Deterg 2019;22:1047–58. 
                https://doi.org/10.1002/jsde.12254
                
              "), [13](/articles/s41366-025-01729-1#ref-CR13 "Kowalik B, Majewska M, Miltko R, Bełżecki G. The effect of supplementing sheep with rapeseed and linseed oils on the activity of pancreatic digestive enzymes. J Anim Physiol Anim Nutr. 2018;102:1194–8. 
                https://doi.org/10.1111/jpn.12936
                
              ")].

Recent advancements in molecular biology and biochemistry have shed light on the intricate mechanisms governing PL activity and its regulation within the gastrointestinal tract. Understanding these mechanistic insights is crucial for unraveling the complex interplay between dietary fat metabolism and the pathogenesis of obesity. This section seeks to provide a comprehensive overview of its role in energy homeostasis and its key role in managing and preventing obesity in the context of the significance of PL functions and related of the biochemical pathways.

### Overview of pancreas roles

Pancreas is a vital organ that serves key functions within both the digestive and endocrine systems. It is essential for the metabolism and breakdown of fats and proteins [[14](/articles/s41366-025-01729-1#ref-CR14 "Karpińska M, Czauderna M. Pancreas—its functions, disorders, and physiological impact on the Mammals' organism. Front Physiol. 2022;13:807632. 
                https://doi.org/10.3389/fphys.2022.807632
                
              ")]. However, it is susceptible to a variety of diseases and disorders that can impact an individual's health severely. The pancreas has dual roles [[6](/articles/s41366-025-01729-1#ref-CR6 "Kim GN, Shin MR, Shin SH, Lee AR, Lee JY, Seo BI, et al. Study of antiobesity effect through inhibition of pancreatic lipase activity of Diospyros kaki fruit and Citrus unshiu peel. Biomed Res Int. 2016;1723042. 
                https://doi.org/10.1155/2016/1723042
                
              .")]; its exocrine function involves producing digestive enzymes like trypsin, chymotrypsin (proteases) for proteins, amylase for carbohydrates, and lipase for fats, along with pancreatic juices that aid in the digestion process in the duodenum (Fig. [1](/articles/s41366-025-01729-1#Fig1)).

**Fig. 1: Role of pancreas as dual function-related endocrine and exocrine systems.**

[![figure 1](//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41366-025-01729-1/MediaObjects/41366_2025_1729_Fig1_HTML.png)](/articles/s41366-025-01729-1/figures/1)

The pancreas regulates blood glucose via insulin and glucagon, with dysfunction worsening diabetes and obesity.

[Full size image](/articles/s41366-025-01729-1/figures/1)

Its endocrine role is essential in regulating blood glucose levels, primarily through the secretion of insulin and glucagon. The pancreas extends horizontally across the abdomen, with its wider section situated on the right and narrowing towards the spleen. Various conditions can impact the pancreas, such as pancreatitis, pancreatic cancer, cysts, insufficiency, and fluid accumulation, each carrying significant health implications [[15](/articles/s41366-025-01729-1#ref-CR15 "Awosika T, Aluko R. Inhibition of the in vitro activities of α‐amylase, α‐glucosidase and pancreatic lipase by yellow field pea \(Pisum sativum l.\) protein hydrolysates. Int J Food Sci Technol. 2019;54:2021–34. 
                https://doi.org/10.1111/ijfs.14087
                
              ")]. The pancreas plays a critical role in managing the body's metabolism and energy expenditure via its insulin production. However, disturbances in this function can lead to obesity by altering the manner in which the body stores and utilizes fats [[16](/articles/s41366-025-01729-1#ref-CR16 "Deora N, Venkatraman K. Lipase activity inhibited by Aloenin A: glycoside from Aloe vera \(l.\) burm. f.—in vitro and molecular docking studies. J Mol Recognit. 2022;36. 
                https://doi.org/10.1002/jmr.3002
                
              .")].

### Overview of lipid metabolism and enzymes

Lipids, which include fats, lipoids, and their derivatives, serve a variety of functions in the body. Triglycerides, or triacylglycerol, are the main form of stored fats found in adipose tissue and make up a significant portion of the body's weight in a healthy state [[17](/articles/s41366-025-01729-1#ref-CR17 "Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8:1–8. 
                https://doi.org/10.1002/cphy.c170012
                
              ")]. Lipoids, such as phospholipids and glycolipids, are crucial for the structural integrity of tissues and play important roles in energy storage and consumption, particularly during times of high-energy demand. A small percentage of the body's total lipids, known as blood lipids, consists of phospholipids, triglycerides, cholesterol, free fatty acids, and small amounts of fat-soluble vitamins and steroid hormones [[18](/articles/s41366-025-01729-1#ref-CR18 "Park J, Choi J, Kim DD, Lee S, Lee B, Lee Y, et al. Bioactive lipids and their derivatives in biomedical applications. Biomol Ther \(Seoul\). 2021;29:465–82. 
                https://doi.org/10.4062/biomolther.2021.107
                
              ")]. These free fatty acids, mainly produced from the breakdown of triglycerides in adipose tissue, are vital for metabolic activities.

The metabolism of lipids starts with the breakdown of ingested fats into smaller particles by bile, followed by the conversion into free fatty acids and monoglycerides by enzymes from the pancreas and small intestine [[19](/articles/s41366-025-01729-1#ref-CR19 "Markovic M, Ben-Shabat S, Aponick A, Zimmermann EM, Dahan A. Lipids and lipid-processing pathways in drug delivery and therapeutics. Int J Mol Sci. 2020;21:3248. 
                https://doi.org/10.3390/ijms21093248
                
              ")] (Fig. [2](/articles/s41366-025-01729-1#Fig2)). A portion of these fatty acids is further broken down into glycerol and fatty acids. Following their breakdown, substances such as glycerol and fatty acids with short-to-medium chains are directly taken up into the bloodstream through the walls of the small intestine. In contrast, monoglycerides and fatty acids with longer chains undergo reassembly into triglycerides within the cells of the small intestine [[15](/articles/s41366-025-01729-1#ref-CR15 "Awosika T, Aluko R. Inhibition of the in vitro activities of α‐amylase, α‐glucosidase and pancreatic lipase by yellow field pea \(Pisum sativum l.\) protein hydrolysates. Int J Food Sci Technol. 2019;54:2021–34. 
                https://doi.org/10.1111/ijfs.14087
                
              ")]. These triglycerides are then combined with phospholipids, cholesterol, and proteins to create chylomicrons (transporter), which enter the circulatory system through the lymphatic route. The liver and pancreas play crucial roles in the various stages of lipid management, including digestion, absorption, production, and distribution within the body [[20](/articles/s41366-025-01729-1#ref-CR20 "Hasan B, Nayfeh T, Alzuabi M, Wang Z, Kuchkuntla AR, Prokop LJ, et al. Weight loss and serum lipids in overweight and obese adults: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2020;105:dgaa673. 
                https://doi.org/10.1210/clinem/dgaa673
                
              ")].

**Fig. 2: Lipid metabolism.**

[![figure 2](//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41366-025-01729-1/MediaObjects/41366_2025_1729_Fig2_HTML.png)](/articles/s41366-025-01729-1/figures/2)

Divided into two pathways, including exogenous and endogenous pathways.

[Full size image](/articles/s41366-025-01729-1/figures/2)

Lipases are key enzymes in the pancreas for this process, including pancreatic triglyceride lipase and its variants, which are essential for fat digestion, especially in newborns. Disruptions in the expression of these enzymes can affect fat digestion and increase the risk of pancreas and intestine diseases [[21](/articles/s41366-025-01729-1#ref-CR21 "Michael OA, Bimbola FM, Rotimi O. The relationship between measures of obesity and atherogenic lipids among Nigerians with hypertension. Malawi Med J. 2019;31:193–7. 
                https://doi.org/10.4314/mmj.v31i3.5
                
              ")].

Pancreatic lipase plays a crucial role in the digestion process, specifically in converting dietary fats into monoacylglycerols and fatty acids within the duodenum. Its function is regulated by several factors to reduce side effects associated with medications and improve digestive efficiency [[15](/articles/s41366-025-01729-1#ref-CR15 "Awosika T, Aluko R. Inhibition of the in vitro activities of α‐amylase, α‐glucosidase and pancreatic lipase by yellow field pea \(Pisum sativum l.\) protein hydrolysates. Int J Food Sci Technol. 2019;54:2021–34. 
                https://doi.org/10.1111/ijfs.14087
                
              ")]. This enzyme's activity is integral to the lipid metabolism pathway, which includes both the exogenous and endogenous pathways [[14](/articles/s41366-025-01729-1#ref-CR14 "Karpińska M, Czauderna M. Pancreas—its functions, disorders, and physiological impact on the Mammals' organism. Front Physiol. 2022;13:807632. 
                https://doi.org/10.3389/fphys.2022.807632
                
              "), [15](/articles/s41366-025-01729-1#ref-CR15 "Awosika T, Aluko R. Inhibition of the in vitro activities of α‐amylase, α‐glucosidase and pancreatic lipase by yellow field pea \(Pisum sativum l.\) protein hydrolysates. Int J Food Sci Technol. 2019;54:2021–34. 
                https://doi.org/10.1111/ijfs.14087
                
              ")]. The exogenous pathway involves the digestion and absorption starting from dietary fats, while the endogenous pathway manages the liver's production and distribution of fats within the body which involves the group of lipoprotein which is very low-density lipoprotein (VLDL) primarily responsible for transporting triglycerides (the most common type of fat in the body) from the liver to various tissues. After delivering triglycerides to tissues, VLDL is converted into low-density lipoprotein (LDL) referred to as bad cholesterol yet high-density lipoprotein (HDL) is good cholesterol [[22](/articles/s41366-025-01729-1#ref-CR22 "Karam I. Hyperlipidemia background and progress. SM Atheroscler J. 2017;1:1–8.")].

### Unique role of pancreatic lipase in the duodenum: focuses on minimizing drug-related side effects

Pancreatic lipase (PL) is pivotal in the digestion process within the duodenum, specifically in breaking down dietary fats into absorbable molecules [[14](/articles/s41366-025-01729-1#ref-CR14 "Karpińska M, Czauderna M. Pancreas—its functions, disorders, and physiological impact on the Mammals' organism. Front Physiol. 2022;13:807632. 
                https://doi.org/10.3389/fphys.2022.807632
                
              "), [15](/articles/s41366-025-01729-1#ref-CR15 "Awosika T, Aluko R. Inhibition of the in vitro activities of α‐amylase, α‐glucosidase and pancreatic lipase by yellow field pea \(Pisum sativum l.\) protein hydrolysates. Int J Food Sci Technol. 2019;54:2021–34. 
                https://doi.org/10.1111/ijfs.14087
                
              "), [22](/articles/s41366-025-01729-1#ref-CR22 "Karam I. Hyperlipidemia background and progress. SM Atheroscler J. 2017;1:1–8.")]. This process can be leveraged to address obesity by inhibiting PL activity, thus reducing fat absorption and caloric intake, which are essential for weight management. Despite its importance, the complete role of PL and other pancreatic enzymes in fat digestion is not fully understood, indicating a need for further research. Pancreatic enzyme replacement therapies that include PL have been beneficial for patients with pancreatic insufficiency, highlighting PL's therapeutic value.

The encoded PL involves the pancreatic lipase gene (PNLIP), which primarily acts in the duodenum by hydrolyzing triglycerides into monoacylglycerols and fatty acids [[17](/articles/s41366-025-01729-1#ref-CR17 "Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8:1–8. 
                https://doi.org/10.1002/cphy.c170012
                
              ")]. Its activity can be enhanced by altering the phospholipid composition of fat droplets and is complemented by gastric lipase's partial hydrolysis of triglycerides. Pancreatic juice, which is rich in digestive enzymes including PL, plays a crucial role in digestion by neutralizing stomach acid and providing enzymes necessary for nutrient breakdown [[19](/articles/s41366-025-01729-1#ref-CR19 "Markovic M, Ben-Shabat S, Aponick A, Zimmermann EM, Dahan A. Lipids and lipid-processing pathways in drug delivery and therapeutics. Int J Mol Sci. 2020;21:3248. 
                https://doi.org/10.3390/ijms21093248
                
              ")].

In the context of minimizing drug-related side effects, which is a major goal in medical treatment and drug development. Strategies such as gradual drug titration, understanding drug–target interactions for repurposing, system-wide approaches in drug development, optimized dosing, and improved drug delivery systems are all aimed at reducing these side effects [[19](/articles/s41366-025-01729-1#ref-CR19 "Markovic M, Ben-Shabat S, Aponick A, Zimmermann EM, Dahan A. Lipids and lipid-processing pathways in drug delivery and therapeutics. Int J Mol Sci. 2020;21:3248. 
                https://doi.org/10.3390/ijms21093248
                
              ")].

The modulation of PL activity presents a unique opportunity to minimize side effects associated with drug therapy, especially for conditions related to dietary fat absorption. Previous studies explored the effects of apple polyphenol extract (APE) and procyanidin significantly reduced pancreatic lipase activity in vitro [[23](/articles/s41366-025-01729-1#ref-CR23 "Sugiyama H, Akazome Y, Shoji T, Yamaguchi A, Yasue M, Kanda T, et al. Oligomeric procyanidins in apple polyphenol are main active components for inhibition of pancreatic lipase and triglyceride absorption. J Agric Food Chem. 2007;55:4604–9. 
                https://doi.org/10.1021/jf070569k
                
              ")]. While other polyphenols in APE, such as catechins, chalcones, and phenol carboxylic acids, demonstrated minimal impact on lipase activity. The study found that the inhibitory power of pancreatic lipase is closely related to the degree of polymerization, with oligomeric procyanidin being a key contributor. Further investigation through a triglyceride tolerance test on both mice and humans revealed that consuming APE alongside triglycerides notably prevented the rise in plasma triglyceride levels in both subjects. This implies that oligomeric procyanidins within APE can reduce triglyceride absorption in the digestive system by targeting and inhibiting pancreatic lipase activity, making it a potential agent for managing triglyceride levels in the body potential in offering a new therapeutic approach [[23](/articles/s41366-025-01729-1#ref-CR23 "Sugiyama H, Akazome Y, Shoji T, Yamaguchi A, Yasue M, Kanda T, et al. Oligomeric procyanidins in apple polyphenol are main active components for inhibition of pancreatic lipase and triglyceride absorption. J Agric Food Chem. 2007;55:4604–9. 
                https://doi.org/10.1021/jf070569k
                
              ")].

Additionally, the new finding in current decades, i.e., the investigation of nutmeg’s capacity as a novel inhibitor of pancreatic lipase (PL) has been studied. Nutmeg, known for its culinary and medicinal uses, was examined for its effectiveness in blocking PL. Initial in vitro experiments revealed that nutmeg strongly inhibited PL activity by 66.24% [[24](/articles/s41366-025-01729-1#ref-CR24 "Yakaiah V, Dakshinamoorthi A, Sudha Ty S. Novel aspects in inhibiting pancreatic lipase with potential new compound from nutmeg in connection with obesity—in vitro, in silico, in vivo and ex vivo studies. Maedica \(Bucur\). 2021;16:445–52. 
                https://doi.org/10.26574/maedica.2021.16.3.445
                
              ")]. Further investigations have identified a novel compound, tetrahydrofuran (THF), as a key player indicating the effective PL inhibitor. Collectively, these diverse research approaches strongly suggest that nutmeg, particularly through THF, holds potential as a natural inhibitor of pancreatic lipase, offering a promising strategy for obesity management by reducing the absorption of dietary fats [[22](/articles/s41366-025-01729-1#ref-CR22 "Karam I. Hyperlipidemia background and progress. SM Atheroscler J. 2017;1:1–8."), [24](/articles/s41366-025-01729-1#ref-CR24 "Yakaiah V, Dakshinamoorthi A, Sudha Ty S. Novel aspects in inhibiting pancreatic lipase with potential new compound from nutmeg in connection with obesity—in vitro, in silico, in vivo and ex vivo studies. Maedica \(Bucur\). 2021;16:445–52. 
                https://doi.org/10.26574/maedica.2021.16.3.445
                
              ")].

The choice of emulsifying agents and the role of micelles in PL activation are areas that could influence the development of interventions to control PL function effectively. Previous studies examined the impact of substituting traditional soybean phospholipid (SPL) emulsifiers with milk-derived polar lipid (MPL) emulsifiers in the diets of mice fed a high-fat regimen, focusing on obesity-related outcomes, such as adiposity and metabolic inflammation. The findings revealed that unlike SPLs, which contributed to an increase in the number of white adipose tissue (WAT) hypertrophy, inflammation, and liver steatosis, diets incorporating MPLs did not negatively affect adiposity or liver lipid concentrations [[25](/articles/s41366-025-01729-1#ref-CR25 "Lecomte M, Couëdelo L, Meugnier E, Plaisancié P, Létisse M, Benoit B, et al. Dietary emulsifiers from milk and soybean differently impact adiposity and inflammation in association with modulation of colonic goblet cells in high-fat fed mice. Mol Nutr Food Res. 2016;60:609–20. 
                https://doi.org/10.1002/mnfr.201500703
                
              ")]. Instead, MPLs were linked to beneficial effects on intestinal health, notably an increase in colonic goblet cells, suggesting an enhancement of the gut barrier. This improvement might stem from specific sphingomyelin (SM)-derived lipids in MPLs, which also correlated with reduced signs of macrophage infiltration in the WAT, indicating lower inflammation [[25](/articles/s41366-025-01729-1#ref-CR25 "Lecomte M, Couëdelo L, Meugnier E, Plaisancié P, Létisse M, Benoit B, et al. Dietary emulsifiers from milk and soybean differently impact adiposity and inflammation in association with modulation of colonic goblet cells in high-fat fed mice. Mol Nutr Food Res. 2016;60:609–20. 
                https://doi.org/10.1002/mnfr.201500703
                
              ")].

### The role of adipose tissue towards approaching to combat obesity

Research into adipose tissue identifies two main varieties: white adipose tissue (WAT), which is widely distributed across the body, and brown adipose tissue (BAT), which is found in particular locations like the neck, shoulder area, and around certain internal organs [[26](/articles/s41366-025-01729-1#ref-CR26 "Maurer S, Harms M, Boucher J. The colorful versatility of adipocytes: white-to-brown transdifferentiation and its therapeutic potential in humans. FEBS J. 2021;288:3628–46. 
                https://doi.org/10.1111/febs.15470
                
              "), [27](/articles/s41366-025-01729-1#ref-CR27 "Scheja L, Heeren J. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat Rev Endocrinol. 2019;15:507–24. 
                https://doi.org/10.1038/s41574-019-0230-6
                
              ")], as illustrated in Fig. [3](/articles/s41366-025-01729-1#Fig3). White adipose tissue is primarily found beneath the skin in the abdominal, gluteal-femoral, and visceral regions, serving as energy storage, mechanical cushioning, insulation, and protection against infections [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              ")]. Conversely, BAT is characterized by its ability to burn energy and produce heat, whereas it enriches mitochondria content and the action of uncoupling protein 1 (UCP-1), which helps in heat generation from fats. Besides its energy storage function, WAT is implicated in obesity due to its secretion of substances that regulate metabolism, inflammation, vascular function, and reproductive processes, including hormones like leptin and adiponectin, which influence body weight, and others that play roles in local inflammation and vascular health [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              ")].

**Fig. 3**

[![figure 3](//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41366-025-01729-1/MediaObjects/41366_2025_1729_Fig3_HTML.png)](/articles/s41366-025-01729-1/figures/3)

Role of adipocytes and location in the human body.

[Full size image](/articles/s41366-025-01729-1/figures/3)

White adipose tissue (WAT) is vital in maintaining energy balance within the body, serving both as a repository for energy storage and as an endocrine entity that releases hormones like adiponectin and leptin. These hormones play crucial roles in managing metabolic functions, such as the oxidation of fatty acids, and are deeply involved in the pathophysiology of obesity [[29](/articles/s41366-025-01729-1#ref-CR29 "Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27:68–83. 
                https://doi.org/10.1016/j.cmet.2017.12.002
                
              "), [30](/articles/s41366-025-01729-1#ref-CR30 "Freitag Luglio H. Genetic variation of fatty acid oxidation and obesity, a literature review. Int J Biomed Sci. 2016;12:1–8.")].

White adipose tissue (WAT) tends to proliferate under conditions of reduced physical activity, exposure to thermoneutral environments, consumption of calorie-rich diets, decreased levels of saturated free fatty acids, imbalance of leptin and adiponectin hormone levels, and increased interleukin-6 (IL-6). On the contrary, brown adipose tissue (BAT) expands with regular exercise, cold exposure, lower calorie diets, elevated free fatty acids (FFAs), increased levels of both leptin and adiponectin hormones, and a rise in IL-6. Adipocyte mainly summarizes the conditions that influence the accumulation or reduction of white and brown adipose tissues, highlighting the impact of lifestyle, environmental factors, and biochemical signals on body fat composition [[29](/articles/s41366-025-01729-1#ref-CR29 "Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27:68–83. 
                https://doi.org/10.1016/j.cmet.2017.12.002
                
              ")].

Adiponectin, part of the adipokines hormone released by fat cells, plays a crucial role in improving insulin sensitivity and managing blood sugar and lipid metabolism [[29](/articles/s41366-025-01729-1#ref-CR29 "Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27:68–83. 
                https://doi.org/10.1016/j.cmet.2017.12.002
                
              ")]. Unlike most fat-derived hormones, adiponectin levels tend to decrease with an increase in body fat percentage in adults, linking lower adiponectin concentrations with obesity [[27](/articles/s41366-025-01729-1#ref-CR27 "Scheja L, Heeren J. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat Rev Endocrinol. 2019;15:507–24. 
                https://doi.org/10.1038/s41574-019-0230-6
                
              "), [29](/articles/s41366-025-01729-1#ref-CR29 "Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27:68–83. 
                https://doi.org/10.1016/j.cmet.2017.12.002
                
              ")]. This hormone is instrumental in promoting the breakdown of fatty acids, which has significant implications for addressing obesity. It enhances the burning of fats in muscle and liver tissues by activating the adenosine monophosphate-activated protein kinase (AMPK). This essential enzyme regulates cellular energy balance by promoting energy-producing activities such as glucose absorption and lipid catabolism. The stimulation of AMPK in muscle and liver leads to more efficient fat breakdown, preventing fat buildup in these organs and thus contributing to obesity prevention. Furthermore, adiponectin supports the absorption of glucose by cells, which in turn lowers insulin production by the pancreas and decreases fat storage. This enhancement of insulin sensitivity guarantees a more efficient transformation of glucose and fats into energy, thus reducing their storage as body fat [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              "), [30](/articles/s41366-025-01729-1#ref-CR30 "Freitag Luglio H. Genetic variation of fatty acid oxidation and obesity, a literature review. Int J Biomed Sci. 2016;12:1–8.")].

Leptin, also secreted by white adipose tissue (WAT), functions as a hunger-suppressing signal that helps regulate energy equilibrium by curbing appetite, leading to decreased food consumption and increased energy utilization. Its involvement in lipid metabolism and the management of obesity extends to controlling energy expenditure [[31](/articles/s41366-025-01729-1#ref-CR31 "Cao J, Lei S, Zhao T, Xie Y, Zhou Z, Cheng S, et al. Changes in fat oxidation and body composition after combined exercise intervention in sedentary obese Chinese adults. J Clin Med. 2022;11:1086. 
                https://doi.org/10.3390/jcm11041086
                
              ")]. High levels of leptin, which are common in individuals with obesity due to leptin resistance, fail to properly signal satiety, leading to continued food intake and reduced energy expenditure [[32](/articles/s41366-025-01729-1#ref-CR32 "Zhou B, Yuan Y, Shi L, Hu S, Wang D, Yang Y. et al. Creation of an anti-inflammatory, leptin-dependent anti-obesity celastrol mimic with better druggability. Front Pharmacol. 2021;12:705252. 
                https://doi.org/10.3389/fphar.2021.705252
                
              .")]. Although leptin primarily regulates appetite and satiety, it also has effects on glucose metabolism and fatty acid oxidation through its impact on insulin sensitivity. However, in the context of obesity, the effectiveness of leptin in promoting fatty acid oxidation is diminished due to leptin resistance. In the context of obesity, impaired secretion of adiponectin and leptin leads to decreased breakdown of fatty acids and heightened fat storage. Diminished adiponectin levels result in less effective fatty acid oxidation, causing fat to accumulate in tissues and potentially leading to insulin resistance. At the same time, resistance to leptin during obesity impairs the regulation of hunger and energy use, further contributing to fat accumulation [30,31,[32](/articles/s41366-025-01729-1#ref-CR32 "Zhou B, Yuan Y, Shi L, Hu S, Wang D, Yang Y. et al. Creation of an anti-inflammatory, leptin-dependent anti-obesity celastrol mimic with better druggability. Front Pharmacol. 2021;12:705252. 
                https://doi.org/10.3389/fphar.2021.705252
                
              .")].

The relationship between adiponectin levels and obesity is complex, with some individuals with obesity showing high adiponectin levels without associated metabolic problems, suggesting a nuanced interaction between adiponectin and obesity. This complexity is further heightened by differences in adiponectin production between visceral and subcutaneous fat, notably with obesity-associated declines in adiponectin from subcutaneous sources [[33](/articles/s41366-025-01729-1#ref-CR33 "Liu T, Wu F, Chen K, Pan B, Yin X, You Y, et al. Sweet potato extract alleviates high-fat-diet-induced obesity in C57BL/6J mice, but not by inhibiting pancreatic lipases. Front Nutr. 2022;9:1016020. 
                https://doi.org/10.3389/fnut.2022.1016020
                
              ")]. These intricate connections between hormones produced by adipose tissue and obesity underscore crucial mechanisms by which obesity fosters inflammation, insulin resistance, and metabolic conditions like type 2 diabetes. Understanding these processes offers opportunities for targeted treatments that focus on enhancing fat breakdown and metabolic health by modulating the effects of adiponectin and leptin [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              "), [29](/articles/s41366-025-01729-1#ref-CR29 "Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27:68–83. 
                https://doi.org/10.1016/j.cmet.2017.12.002
                
              "), [31](/articles/s41366-025-01729-1#ref-CR31 "Cao J, Lei S, Zhao T, Xie Y, Zhou Z, Cheng S, et al. Changes in fat oxidation and body composition after combined exercise intervention in sedentary obese Chinese adults. J Clin Med. 2022;11:1086. 
                https://doi.org/10.3390/jcm11041086
                
              ")].

## Current PL inhibitors and their efficacy

The rising global incidence of obesity is an urgent public health issue linked to numerous metabolic diseases, including type 2 diabetes, heart disease, and some cancers. The metabolism of dietary fats is key to the onset and advancement of obesity. Recent research efforts have concentrated on the development and assessment of inhibitors of pancreatic lipase as a strategy for addressing obesity, especially when linked to diets rich in fats [[26](/articles/s41366-025-01729-1#ref-CR26 "Maurer S, Harms M, Boucher J. The colorful versatility of adipocytes: white-to-brown transdifferentiation and its therapeutic potential in humans. FEBS J. 2021;288:3628–46. 
                https://doi.org/10.1111/febs.15470
                
              ")]. These inhibitors work by limiting the digestion and absorption of fats, leading to reduced calorie consumption and supporting weight reduction [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              ")]. Pancreatic lipase inhibitors, a category of medications aimed at obesity treatment, inhibit the pancreatic lipase enzyme. This enzyme's role is to break down dietary triglycerides in the intestines. By blocking this enzyme, triglycerides are not converted into free fatty acids that can be absorbed, resulting in their excretion without digestion. This process helps reduce the number of calories absorbed from fat, aiding in weight loss. Orlistat, one of the most well-known PL inhibitors, offers a case study on the effectiveness, challenges, and side effects associated with this therapeutic approach [[24](/articles/s41366-025-01729-1#ref-CR24 "Yakaiah V, Dakshinamoorthi A, Sudha Ty S. Novel aspects in inhibiting pancreatic lipase with potential new compound from nutmeg in connection with obesity—in vitro, in silico, in vivo and ex vivo studies. Maedica \(Bucur\). 2021;16:445–52. 
                https://doi.org/10.26574/maedica.2021.16.3.445
                
              ")]. In this section, the article reviews the current landscape of pancreas lipase inhibitors, including synthetic drugs and natural compounds, their mechanisms of action, clinical efficacy, and safety profiles. Several FDA-approval drugs will be discussed, including liraglutide, semaglutide, tirzepatide, orlistat, and combinations like phentermine/topiramate and bupropion/naltrexone, noting their effectiveness in obesity management [[34](/articles/s41366-025-01729-1#ref-CR34 "Dąbrowski G, Czaplicki S, Szustak M, et al. The impact of selected xanthophylls on oil hydrolysis by pancreatic lipase: in silico and in vitro studies. Sci Rep. 2024;14:2731."), [35](/articles/s41366-025-01729-1#ref-CR35 "Telci Caklili O, Cesur M, Mikhailidis DP, Rizzo M. Novel anti-obesity therapies and their different effects and safety profiles: a critical overview. Diabetes Metab Syndr Obes 2023;16:1767–74. 
                https://doi.org/10.2147/DMSO.S392684
                
              ")] (Table [1](/articles/s41366-025-01729-1#Tab1)).

**Table 1 Adverse effects associated with current obesity treatment drug delivery information.**

[ Full size table](/articles/s41366-025-01729-1/tables/1)

### Drug discovery

The fundamental strategy to combat obesity includes the adoption of healthier eating patterns and engaging in consistent to moderate physical activity. However, despite initial significant weight loss, many individuals find it challenging to adhere to these lifestyle modifications, often experiencing a rebound in weight within 2 years [[35](/articles/s41366-025-01729-1#ref-CR35 "Telci Caklili O, Cesur M, Mikhailidis DP, Rizzo M. Novel anti-obesity therapies and their different effects and safety profiles: a critical overview. Diabetes Metab Syndr Obes 2023;16:1767–74. 
                https://doi.org/10.2147/DMSO.S392684
                
              ")].

Although pharmacological treatments have progressed, effectively integrating them with sustainable lifestyle changes remains a major hurdle in the successful management of obesity. Drug discovery can be related to the lipid pathways and molecular mechanisms due to its roles in various biological processes. Basically, lipids play crucial roles in energy storage, cell membrane structure, and signaling. By targeting specific enzymes, transport proteins, and regulatory pathways, new drugs can be developed to modulate lipid metabolism in a way that is both effective and tailored to individual patient needs [[19](/articles/s41366-025-01729-1#ref-CR19 "Markovic M, Ben-Shabat S, Aponick A, Zimmermann EM, Dahan A. Lipids and lipid-processing pathways in drug delivery and therapeutics. Int J Mol Sci. 2020;21:3248. 
                https://doi.org/10.3390/ijms21093248
                
              ")]. The initial stage of lipid metabolism begins with the digestion of dietary fats. Pancreatic lipase plays a pivotal role in this process by hydrolyzing triglycerides (TG) into free fatty acids (FA), and monoglycerides (MG) in the small intestine [[17](/articles/s41366-025-01729-1#ref-CR17 "Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8:1–8. 
                https://doi.org/10.1002/cphy.c170012
                
              ")]. While bile salts, secreted by the liver, emulsify dietary fats, enhancing the action of pancreatic lipase. They also form micelles that incorporate lipid digestion products, facilitating their transport to the intestinal mucosa for absorption [[19](/articles/s41366-025-01729-1#ref-CR19 "Markovic M, Ben-Shabat S, Aponick A, Zimmermann EM, Dahan A. Lipids and lipid-processing pathways in drug delivery and therapeutics. Int J Mol Sci. 2020;21:3248. 
                https://doi.org/10.3390/ijms21093248
                
              ")]. The process of lipid digestion and absorption is crucial for the bioavailability of lipophilic drugs. Drugs designed to exploit these pathways, such as lipophilic prodrugs, can be incorporated into micelles for enhanced solubilization and absorption. This approach is particularly valuable for drugs that require high fat-solubility for efficacy, such as certain anti-cancer agents or drugs targeting metabolic disorders [[5](/articles/s41366-025-01729-1#ref-CR5 "Vettor R, Di Vincenzo A, Maffei P, Rossato M. Regulation of energy intake and mechanisms of metabolic adaptation or maladaptation after caloric restriction. Rev Endocr Metab Disord 2020;399–409. 
                https://doi.org/10.1007/s11154-020-09565-6
                
              ."), [17](/articles/s41366-025-01729-1#ref-CR17 "Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8:1–8. 
                https://doi.org/10.1002/cphy.c170012
                
              "), [19](/articles/s41366-025-01729-1#ref-CR19 "Markovic M, Ben-Shabat S, Aponick A, Zimmermann EM, Dahan A. Lipids and lipid-processing pathways in drug delivery and therapeutics. Int J Mol Sci. 2020;21:3248. 
                https://doi.org/10.3390/ijms21093248
                
              ")]. Furthermore, lipogenesis refers to the synthesis of fatty acids from acetyl-CoA and subsequent conversion into triglycerides, where excess glucose and other carbohydrates are converted into fatty acids for storage. This pathway is regulated by insulin, which promotes the activation of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), the key enzymes in fatty acid synthesis. Excessive lipogenesis can lead to the accumulation of fat in the liver (hepatic steatosis) and other tissues, contributing to obesity and metabolic syndrome. Thus, targeting the enzymes involved in lipogenesis is a promising strategy for the development of anti-obesity and anti-diabetic drugs. For example, ACC inhibitors are being explored for their potential to reduce lipogenesis and thus decrease fat accumulation in the liver and other tissues [[12](/articles/s41366-025-01729-1#ref-CR12 "Reis P, Malmsten M, Nydén M, Folmer B, Holmberg K. Interactions between lipases and amphiphiles at interfaces. J Surfactants Deterg 2019;22:1047–58. 
                https://doi.org/10.1002/jsde.12254
                
              "), [17](/articles/s41366-025-01729-1#ref-CR17 "Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Compr Physiol. 2017;8:1–8. 
                https://doi.org/10.1002/cphy.c170012
                
              "), [19](/articles/s41366-025-01729-1#ref-CR19 "Markovic M, Ben-Shabat S, Aponick A, Zimmermann EM, Dahan A. Lipids and lipid-processing pathways in drug delivery and therapeutics. Int J Mol Sci. 2020;21:3248. 
                https://doi.org/10.3390/ijms21093248
                
              "), [20](/articles/s41366-025-01729-1#ref-CR20 "Hasan B, Nayfeh T, Alzuabi M, Wang Z, Kuchkuntla AR, Prokop LJ, et al. Weight loss and serum lipids in overweight and obese adults: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2020;105:dgaa673. 
                https://doi.org/10.1210/clinem/dgaa673
                
              ")].

The creation of anti-obesity drugs is crucial for those who struggle to lose weight through diet and exercise alone. Yet, the availability of these medications is limited due to safety concerns, with some being removed from the market due to adverse body health impacts.

Therefore, the quest for effective obesity treatments, especially those that target pancreatic lipase for the reduction of fat absorption, reveals both challenges and opportunities. The contemporary therapeutic landscape against obesity mainly includes three key dominant agents: orlistat, a lipase inhibitor; sibutramine, a reuptake inhibitor of serotonin and norepinephrine; and catecholamine-lipolytic regulators [[16](/articles/s41366-025-01729-1#ref-CR16 "Deora N, Venkatraman K. Lipase activity inhibited by Aloenin A: glycoside from Aloe vera \(l.\) burm. f.—in vitro and molecular docking studies. J Mol Recognit. 2022;36. 
                https://doi.org/10.1002/jmr.3002
                
              ."), [28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              "), [36](/articles/s41366-025-01729-1#ref-CR36 "Ashour MM, Mabrouk M, Aboelnasr MA, Beherei HH, Tohamy KM, Das DB. Anti-obesity drug delivery systems: recent progress and challenges. Pharmaceutics. 2023;15:2635. 
                https://doi.org/10.3390/pharmaceutics15112635
                
              ")]. To better understand obesity, it is crucial to explore the molecular mechanisms by which pancreatic lipase (PL) influences lipid metabolism and fat accumulation. Deeper insights into PL's role could reveal novel targets for more effective obesity treatments [[36](/articles/s41366-025-01729-1#ref-CR36 "Ashour MM, Mabrouk M, Aboelnasr MA, Beherei HH, Tohamy KM, Das DB. Anti-obesity drug delivery systems: recent progress and challenges. Pharmaceutics. 2023;15:2635. 
                https://doi.org/10.3390/pharmaceutics15112635
                
              ")].

In the context of new drug discovery, particularly for anti-obesity treatments, addressing the cost-effectiveness and accessibility of these innovations is critical for their widespread clinical adoption. Addressing the cost-effectiveness and accessibility of new anti-obesity treatments is crucial for ensuring that these innovations reach a broader population and provide equitable health benefits. While novel therapies, such as those derived from nanotechnology or personalized medicine, hold great potential for improving treatment outcomes, their high development costs and complexity can limit accessibility for patients. Cost-effectiveness is a key consideration in determining whether a new treatment can be sustainably integrated into healthcare systems. For anti-obesity drugs to be widely adopted, they must not only demonstrate clinical efficacy but also provide a favorable cost–benefit ratio compared to existing treatments. This involves ensuring that the costs associated with drug development, production, and delivery do not make the therapy prohibitively expensive for patients or healthcare providers. Lowering costs can be achieved through innovative manufacturing techniques, economies of scale, and streamlined regulatory pathways [36,37,[38](/articles/s41366-025-01729-1#ref-CR38 "Shapovalov V, Kopanitsa L, Pruteanu L-L, Ladds G, Bailey DS. Transcriptomics-based phenotypic screening supports drug discovery in human glioblastoma cells. Cancers. 2021;13:3780. 
                https://doi.org/10.3390/cancers13153780
                
              ")]. Other than that, the role of epigenetics in drug reaction is being unveiled through extensive analyses and innovative data analysis, underscoring the significance of incorporating epigenetic insights into pharmacological planning [[38](/articles/s41366-025-01729-1#ref-CR38 "Shapovalov V, Kopanitsa L, Pruteanu L-L, Ladds G, Bailey DS. Transcriptomics-based phenotypic screening supports drug discovery in human glioblastoma cells. Cancers. 2021;13:3780. 
                https://doi.org/10.3390/cancers13153780
                
              ")]. Even with advanced pharmacological treatments, the integration of these therapies with effective lifestyle changes continues to be a complex and ongoing challenge. The preference for high-content phenotypic screening in the drug discovery process reflects its comprehensive capacity to generate multi-dimensional data specific to each drug, thereby refining the approach to identifying new therapeutic agents [[36](/articles/s41366-025-01729-1#ref-CR36 "Ashour MM, Mabrouk M, Aboelnasr MA, Beherei HH, Tohamy KM, Das DB. Anti-obesity drug delivery systems: recent progress and challenges. Pharmaceutics. 2023;15:2635. 
                https://doi.org/10.3390/pharmaceutics15112635
                
              "), [37](/articles/s41366-025-01729-1#ref-CR37 "Boniolo F, Dorigatti E, Ohnmacht A, Saur D, Schubert B, Menden M. Artificial intelligence in early drug discovery enabling precision medicine. Expert Opin Drug Discov. 2021;16:991–1007. 
                https://doi.org/10.1080/17460441.2021.1918096
                
              ")].

As Orlistat is one of the drugs that inhibit pancreatic lipase, it has been subjected to extensive research due to its ability to aid in weight loss, yet its potential side effects have been revealed. Mechanistically, by covalently attaching to the serine residue in the pancreatic lipase's active site, orlistat deactivates the enzyme. This prevents the breakdown of dietary fats into free fatty acids and monoglycerides that can be absorbed, leading to a reduction in caloric intake and weight loss [[24](/articles/s41366-025-01729-1#ref-CR24 "Yakaiah V, Dakshinamoorthi A, Sudha Ty S. Novel aspects in inhibiting pancreatic lipase with potential new compound from nutmeg in connection with obesity—in vitro, in silico, in vivo and ex vivo studies. Maedica \(Bucur\). 2021;16:445–52. 
                https://doi.org/10.26574/maedica.2021.16.3.445
                
              ")]. Studies indicate that orlistat not only contributes to significant weight reduction but also ameliorates cardiovascular risk factors in overweight individuals [[39](/articles/s41366-025-01729-1#ref-CR39 "Rössner S, Sjöström L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res. 2000;8:49–61. 
                https://doi.org/10.1038/oby.2000.8
                
              ")]. Despite its effectiveness, the drug's gastrointestinal side effects due to its action on gastrointestinal lipases can affect patient compliance [[40](/articles/s41366-025-01729-1#ref-CR40 "Ameer B, Weintraub M. Pediatric obesity: influence on drug dosing and therapeutics. J Clin Pharmacol. 2018;58:S94–S107. 
                https://doi.org/10.1002/jcph.1092
                
              ")]. Orlistat works by stopping the digestion and absorption of fats from the diet, which supports weight loss management [[41](/articles/s41366-025-01729-1#ref-CR41 "García-Carro C, Vergara A, Bermejo S, Azancot M, Sellarés J, Soler M. A nephrologist perspective on obesity: from kidney injury to clinical management. Front Med. 2021;8:655871. 
                https://doi.org/10.3389/fmed.2021.655871
                
              ")]. Beyond its role in weight loss, orlistat has been shown to positively influence the levels of adiponectin, leptin, and C-reactive protein in the plasma, hinting at its wider metabolic benefits. Investigations into orlistat have also highlighted its potential in exerting anti-tumor effects, showcasing its pharmacological versatility. Current PL inhibitors like orlistat are constrained by limited long-term effectiveness and safety, highlighting the necessity for developing more effective and safer options for managing obesity [[32](/articles/s41366-025-01729-1#ref-CR32 "Zhou B, Yuan Y, Shi L, Hu S, Wang D, Yang Y. et al. Creation of an anti-inflammatory, leptin-dependent anti-obesity celastrol mimic with better druggability. Front Pharmacol. 2021;12:705252. 
                https://doi.org/10.3389/fphar.2021.705252
                
              ."), [41](/articles/s41366-025-01729-1#ref-CR41 "García-Carro C, Vergara A, Bermejo S, Azancot M, Sellarés J, Soler M. A nephrologist perspective on obesity: from kidney injury to clinical management. Front Med. 2021;8:655871. 
                https://doi.org/10.3389/fmed.2021.655871
                
              ")].

Comparative studies on the safety and efficacy of orlistat against other weight-loss drugs suggest that the side effects linked to orlistat are generally minor and temporary [[42](/articles/s41366-025-01729-1#ref-CR42 "Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4:342–7. 
                https://doi.org/10.1111/cob.12075
                
              ")]. Its distinct action of inhibiting fat absorption in the intestines could also play a role in lowering levels of circulating free fatty acids and improving insulin sensitivity [[43](/articles/s41366-025-01729-1#ref-CR43 "Bays HE, Fitch A, Christensen S, Burridge K, Tondt J. Anti-obesity medications and investigational agents: an Obesity Medicine Association \(OMA\) Clinical Practice Statement \(CPS\). Obes Pillars. 2022;2:100018. 
                https://doi.org/10.1016/j.obpill.2022.100018
                
              ")]. Nonetheless, orlistat is associated with an increased rate of gastrointestinal adverse reactions and a noticeable reduction in the uptake of fat-soluble vitamins.

Orlistat has demonstrated effectiveness in managing weight and diminishing the accumulation of harmful visceral fat, yet some users experience adverse reactions and issues with tolerability [[33](/articles/s41366-025-01729-1#ref-CR33 "Liu T, Wu F, Chen K, Pan B, Yin X, You Y, et al. Sweet potato extract alleviates high-fat-diet-induced obesity in C57BL/6J mice, but not by inhibiting pancreatic lipases. Front Nutr. 2022;9:1016020. 
                https://doi.org/10.3389/fnut.2022.1016020
                
              ")]. Research also explores its potential in hindering the growth of cancer cells and cardiovascular health improvement, suggesting wider therapeutic uses [[40](/articles/s41366-025-01729-1#ref-CR40 "Ameer B, Weintraub M. Pediatric obesity: influence on drug dosing and therapeutics. J Clin Pharmacol. 2018;58:S94–S107. 
                https://doi.org/10.1002/jcph.1092
                
              ")]. Nonetheless, the consideration of its potential gastrointestinal side effects and issues with tolerability is important in clinical decisions. Addressing and reducing side effects is a pivotal aspect of medical treatments and the advancement of new pharmaceuticals [[41](/articles/s41366-025-01729-1#ref-CR41 "García-Carro C, Vergara A, Bermejo S, Azancot M, Sellarés J, Soler M. A nephrologist perspective on obesity: from kidney injury to clinical management. Front Med. 2021;8:655871. 
                https://doi.org/10.3389/fmed.2021.655871
                
              "), [42](/articles/s41366-025-01729-1#ref-CR42 "Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4:342–7. 
                https://doi.org/10.1111/cob.12075
                
              ")]. Gradual drug titration can mitigate central nervous system side effects by allowing the body to develop pharmacodynamic tolerance [[44](/articles/s41366-025-01729-1#ref-CR44 "Meador KJ, Laloyaux C, Elmoufti S, Gasalla T, Fishman J, Martin MS, et al. Time course of drug-related treatment-emergent adverse side effects of brivaracetam. Epilepsy Behav. 2020;111:107212. 
                https://doi.org/10.1016/j.yebeh.2020.107212
                
              ")]. Additionally, analyzing drug side effects offers insights into new drug–target interactions, providing opportunities for drug re-purposing [[45](/articles/s41366-025-01729-1#ref-CR45 "Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: focus on adverse side‐effect profiles. Diabetes Obes Metab. 2016;18:558–70. 
                https://doi.org/10.1111/dom.12657
                
              ")]. Employing a holistic approach to drug development can help in reducing potential drug side effects. Tailoring dosing schedules is crucial for the optimal use of antibiotics and in reducing adverse drug reactions [[45](/articles/s41366-025-01729-1#ref-CR45 "Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: focus on adverse side‐effect profiles. Diabetes Obes Metab. 2016;18:558–70. 
                https://doi.org/10.1111/dom.12657
                
              ")]. Furthermore, there is a push towards creating drug delivery systems that enhance drug bioavailability and reduce undesirable effects.

The FDA has approved six drugs for the long-term treatment of obesity, Contrave (bupropion and naltrexone), Saxenda (liraglutide), Xenical and Alli (orlistat), Qsymia (phentermine and topiramate), Wegovy (semaglutide), and Imcivree (setmelanotide) [[43](/articles/s41366-025-01729-1#ref-CR43 "Bays HE, Fitch A, Christensen S, Burridge K, Tondt J. Anti-obesity medications and investigational agents: an Obesity Medicine Association \(OMA\) Clinical Practice Statement \(CPS\). Obes Pillars. 2022;2:100018. 
                https://doi.org/10.1016/j.obpill.2022.100018
                
              "), [45](/articles/s41366-025-01729-1#ref-CR45 "Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: focus on adverse side‐effect profiles. Diabetes Obes Metab. 2016;18:558–70. 
                https://doi.org/10.1111/dom.12657
                
              ")]. These medications mainly work by reducing hunger or enhancing satiety, with the exception of orlistat, which blocks the body's fat absorption [[46](/articles/s41366-025-01729-1#ref-CR46 "Sherman MM, Ungureanu S, Rey JA. Naltrexone/Bupropion ER \(Contrave\): newly approved treatment option for chronic weight management in obese adults. Pharmacy Ther. 2016;41:164–72.")]. Contrave, blending addiction and depression therapies, may elevate the risk of suicide and blood pressure, and commonly causes nausea and headaches [[46](/articles/s41366-025-01729-1#ref-CR46 "Sherman MM, Ungureanu S, Rey JA. Naltrexone/Bupropion ER \(Contrave\): newly approved treatment option for chronic weight management in obese adults. Pharmacy Ther. 2016;41:164–72.")]. Saxenda, an injectable for diabetes management, frequently leads to nausea and vomiting. Qsymia combines a weight-loss stimulant with an epilepsy drug, carrying risks of abuse, heightened heart rate, and possible birth defects. Administered weekly, semaglutide can cause gastrointestinal issues and fatigue [[47](/articles/s41366-025-01729-1#ref-CR47 "Seo YG. Side effects associated with liraglutide treatment for obesity as well as diabetes. J Obes Metab Syndr 2021;30:12–9. 
                https://doi.org/10.7570/jomes20059
                
              ")]. Approved for those over six with specific genetic conditions, Imcivree can decrease hunger and increase resting calorie expenditure, with possible side effects including skin issues, nausea, and changes in mood. Additionally, aminorex and sibutramine have been linked to cardiovascular toxicity, pulmonary hypertension, and a rise in non-fatal cardiovascular incidents [[37](/articles/s41366-025-01729-1#ref-CR37 "Boniolo F, Dorigatti E, Ohnmacht A, Saur D, Schubert B, Menden M. Artificial intelligence in early drug discovery enabling precision medicine. Expert Opin Drug Discov. 2021;16:991–1007. 
                https://doi.org/10.1080/17460441.2021.1918096
                
              "), [39](/articles/s41366-025-01729-1#ref-CR39 "Rössner S, Sjöström L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res. 2000;8:49–61. 
                https://doi.org/10.1038/oby.2000.8
                
              "), [43](/articles/s41366-025-01729-1#ref-CR43 "Bays HE, Fitch A, Christensen S, Burridge K, Tondt J. Anti-obesity medications and investigational agents: an Obesity Medicine Association \(OMA\) Clinical Practice Statement \(CPS\). Obes Pillars. 2022;2:100018. 
                https://doi.org/10.1016/j.obpill.2022.100018
                
              "), [45](/articles/s41366-025-01729-1#ref-CR45 "Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: focus on adverse side‐effect profiles. Diabetes Obes Metab. 2016;18:558–70. 
                https://doi.org/10.1111/dom.12657
                
              "), [46](/articles/s41366-025-01729-1#ref-CR46 "Sherman MM, Ungureanu S, Rey JA. Naltrexone/Bupropion ER \(Contrave\): newly approved treatment option for chronic weight management in obese adults. Pharmacy Ther. 2016;41:164–72.")]. These medications necessitate careful selection and monitoring by healthcare providers due to the potential for side effects and specific application criteria, such as genetic testing for eligibility.

Moreover, this research investigates how astaxanthin, along with other xanthophylls like zeaxanthin and violaxanthin derived from plant and marine foods, can block pancreatic lipase, an essential enzyme in fat digestion. Initial in-silico studies showed these xanthophylls had a higher potential for inhibiting the enzyme compared to orlistat, a drug known for its lipid-lowering effects. However, when these findings were tested under conditions that simulate the natural process of lipid digestion in the gastrointestinal tract, using a method known as the potential of Hydrogen (pH)-stat test, the expected inhibitory effects were not observed. Particularly, sea buckthorn oil, which is rich in native xanthophylls, actually showed an increase in lipolysis by about 22% compared to oils with lower xanthophyll content. This suggests that while xanthophylls can inhibit pancreatic lipase in theoretical models, their amphiphilic nature might enhance the formation of emulsions during actual digestion, thereby increasing the breakdown and absorption of fats rather than inhibiting it [[34](/articles/s41366-025-01729-1#ref-CR34 "Dąbrowski G, Czaplicki S, Szustak M, et al. The impact of selected xanthophylls on oil hydrolysis by pancreatic lipase: in silico and in vitro studies. Sci Rep. 2024;14:2731.")].

### Natural product

Recent studies have highlighted the potential of natural substances in offering alternative treatments for obesity by focusing on their capacity to inhibit pancreatic lipase among other pathways. These natural remedies contribute to weight management through various actions, including boosting metabolism, controlling blood sugar levels, reducing appetite, hindering essential digestive enzymes, enhancing insulin sensitivity, limiting new fat cell formation, and promoting the breakdown of existing fat cells [[48](/articles/s41366-025-01729-1#ref-CR48 "Wang Q, Sun J, Liu M, Zhou Y, Zhang L, Li Y. The new role of AMP-activated protein kinase in regulating fat metabolism and energy expenditure in adipose tissue. Biomolecules. 2021;11:1757. 
                https://doi.org/10.3390/biom11121757
                
              ")]. Key proteins and molecular pathways, such as uncoupling protein-1 and AMP-activated protein kinase, are crucial in the transformation of white adipose tissue into brown adipose tissue, facilitating fat breakdown. Additionally, certain natural substances are known for their ability to reduce inflammation by lowering pro-inflammatory markers and modulating adipokines, which are crucial for managing body weight.

Specifically, plant-derived phytochemicals have been recognized for their effectiveness in combating obesity by inhibiting digestive enzymes like pancreatic lipase and amylase, suppressing appetite, limiting the development of white adipose tissue, or encouraging its conversion to brown adipose tissue. These substances also stimulate proteins that play a role in fat metabolism, reduce levels of the hunger hormone ghrelin, and enhance lipid profiles in the blood. Notable examples of these phytochemicals include curcumin from turmeric, anthocyanins from blueberries, and epigallocatechin gallate from green tea. These compounds are celebrated for their capabilities in hindering the growth of fat cells, promoting the breakdown of fats, and reducing the formation of new fat cells, offering promising avenues for addressing metabolic issues [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              "), [48](/articles/s41366-025-01729-1#ref-CR48 "Wang Q, Sun J, Liu M, Zhou Y, Zhang L, Li Y. The new role of AMP-activated protein kinase in regulating fat metabolism and energy expenditure in adipose tissue. Biomolecules. 2021;11:1757. 
                https://doi.org/10.3390/biom11121757
                
              ")].

Previous research also delves into herbal solutions derived from plants, discussing how obesity stems from an imbalance between fat breakdown and creation, alongside poor regulation of fat cell formation. This imbalance leads to an increase in fat mass due to the expansion and transformation of adipose-derived stem cells, changes in cell shape, and gene activity [[29](/articles/s41366-025-01729-1#ref-CR29 "Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27:68–83. 
                https://doi.org/10.1016/j.cmet.2017.12.002
                
              ")]. Adipogenic regulators such as PPARG and the CEBP family are key in this process, stimulating the expression of proteins essential for fat cell maturation. Additionally, during fat tissue expansion, these stem cells play a significant role in promoting new blood vessel formation and increasing fat content within cells. Herbal compounds like celastrol, extracted from Tripterygium wilfordi, have been identified for their potential in obesity treatment by enhancing leptin sensitivity and inhibiting new blood vessel growth, which may contribute to their effectiveness in reducing fat mass [[32](/articles/s41366-025-01729-1#ref-CR32 "Zhou B, Yuan Y, Shi L, Hu S, Wang D, Yang Y. et al. Creation of an anti-inflammatory, leptin-dependent anti-obesity celastrol mimic with better druggability. Front Pharmacol. 2021;12:705252. 
                https://doi.org/10.3389/fphar.2021.705252
                
              .")]. Celastrol specifically targets the later stages of fat cell development, decreasing fat accumulation by downregulating genes involved in fat cell formation, thus highlighting its potential as a pharmacological strategy in obesity management [[26](/articles/s41366-025-01729-1#ref-CR26 "Maurer S, Harms M, Boucher J. The colorful versatility of adipocytes: white-to-brown transdifferentiation and its therapeutic potential in humans. FEBS J. 2021;288:3628–46. 
                https://doi.org/10.1111/febs.15470
                
              "), [49](/articles/s41366-025-01729-1#ref-CR49 "Kumar V, Singh DD, Lakhawat SS, Yasmeen N, Pandey A, Singla RK. Biogenic phytochemicals modulating obesity: from molecular mechanism to preventive and therapeutic approaches. Evid Based Complement Alternat Med. 2022;2022:6852276. 
                https://doi.org/10.1155/2022/6852276
                
              ")].

Overall, these findings advocate for further exploration of natural product's potential in the innovative treatment strategy for obesity management, and leveraging their diverse mechanisms of action. Their role is to inhibit the development of fat cells, encouraging the breakdown of fats, and reducing the synthesis of new fat cells, thereby helping to manage obesity and related metabolic conditions [[26](/articles/s41366-025-01729-1#ref-CR26 "Maurer S, Harms M, Boucher J. The colorful versatility of adipocytes: white-to-brown transdifferentiation and its therapeutic potential in humans. FEBS J. 2021;288:3628–46. 
                https://doi.org/10.1111/febs.15470
                
              "), [28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              ")].

In addition, a parallel study has discussed the alternative to combating obesity, which is related to herbs derived from plants [[50](/articles/s41366-025-01729-1#ref-CR50 "Hong W, Park J, Yun W, Kang PJ, Son D, Jang J, et al. Inhibitory effect of celastrol on adipogenic differentiation of human adipose-derived stem cells. Biochem Biophys Res Commun. 2018;507:236–41. 
                https://doi.org/10.1016/j.bbrc.2018.11.014
                
              ")]. They discussed, in general, the results of obesity related to from the excessive growth and multiplication of fat cells (adipocytes) due to a disrupted balance between fat breakdown (lipolysis) and fat creation (lipogenesis), alongside poor regulation of fat cell formation (adipogenesis). This process is marked by an increase in fat mass, driven by the growth and transformation of adipose-derived stem cells (ADSCs), alongside changes in cellular morphology and genetic activity that contribute to the enlargement of adipose tissue. Central to this process are adipogenic regulators, such as peroxisome proliferator-activated receptor gamma (PPARG) and the CCAAT/enhancer-binding protein (CEBP) family. These regulators play a pivotal role in initiating the expression of vital proteins necessary for the maturation of fat cells, including those involved in lipid binding, synthesis, and processing. Additionally, as adipose tissue expands, ADSCs play a critical role in fostering new blood vessel formation, boosting the adipogenic potential of stem cells within the tissue, and increasing the lipid content within adipocytes. An emerging approach involves leveraging renowned natural compounds from herbal medicine, such as celastrol, which is celebrated in traditional Chinese medicine for its therapeutic potential in various conditions, including obesity. Celastrol enhances leptin sensitivity, an essential hormone for regulating appetite and metabolism [[32](/articles/s41366-025-01729-1#ref-CR32 "Zhou B, Yuan Y, Shi L, Hu S, Wang D, Yang Y. et al. Creation of an anti-inflammatory, leptin-dependent anti-obesity celastrol mimic with better druggability. Front Pharmacol. 2021;12:705252. 
                https://doi.org/10.3389/fphar.2021.705252
                
              .")]. Research highlights celastrol's capability to suppress angiogenesis, shedding light on its efficacy in diminishing fat mass. Particularly, the application of celastrol during advanced stages of adipocyte differentiation has been observed to curtail fat storage in human adipose-derived stem cells (hADSCs) by suppressing critical genes implicated in adipogenesis [[50](/articles/s41366-025-01729-1#ref-CR50 "Hong W, Park J, Yun W, Kang PJ, Son D, Jang J, et al. Inhibitory effect of celastrol on adipogenic differentiation of human adipose-derived stem cells. Biochem Biophys Res Commun. 2018;507:236–41. 
                https://doi.org/10.1016/j.bbrc.2018.11.014
                
              ")].

These findings indicate celastrol's potential to decrease fat storage and impede the maturation of fat cells by inhibiting the action of PPARG, CEBPA, and fatty acid-binding protein 4 (FABP4). The work underscores celastrol's promise as a pharmacological option for combating obesity and its metabolic repercussions, advocating for further investigation into its mechanisms and therapeutic applications [[50](/articles/s41366-025-01729-1#ref-CR50 "Hong W, Park J, Yun W, Kang PJ, Son D, Jang J, et al. Inhibitory effect of celastrol on adipogenic differentiation of human adipose-derived stem cells. Biochem Biophys Res Commun. 2018;507:236–41. 
                https://doi.org/10.1016/j.bbrc.2018.11.014
                
              ")].

The review suggests that exploring natural products more thoroughly could lead to more effective and safer obesity treatments by harnessing these diverse mechanisms [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              "), [50](/articles/s41366-025-01729-1#ref-CR50 "Hong W, Park J, Yun W, Kang PJ, Son D, Jang J, et al. Inhibitory effect of celastrol on adipogenic differentiation of human adipose-derived stem cells. Biochem Biophys Res Commun. 2018;507:236–41. 
                https://doi.org/10.1016/j.bbrc.2018.11.014
                
              ")].

Recent studies have highly investigated alternatives to current anti-obesity treatments, targeting natural inhibitors of pancreatic lipase, a key enzyme in the digestion of dietary fats. Specifically, a mixed extract from _Diospyros kaki_ fruit and _Citrus unshiu_ peel (PCM) is found to be a potential natural inhibitor that could aid in obesity prevention and treatment [[6](/articles/s41366-025-01729-1#ref-CR6 "Kim GN, Shin MR, Shin SH, Lee AR, Lee JY, Seo BI, et al. Study of antiobesity effect through inhibition of pancreatic lipase activity of Diospyros kaki fruit and Citrus unshiu peel. Biomed Res Int. 2016;1723042. 
                https://doi.org/10.1155/2016/1723042
                
              .")].

At its core, investigating the role of pancreatic lipase in addressing obesity is a dynamic and hopeful field of inquiry. By probing into the intricacies of inhibiting pancreatic lipase, assessing available treatments, confronting existing hurdles, and embarking on new explorations, this research domain endeavors to furnish a thorough insight into both the present and potential future of pancreatic lipase inhibition as a strategy for obesity treatment. This endeavor is dedicated to fostering the creation of innovative and more effective therapeutic options for tackling the widespread challenge of obesity [[51](/articles/s41366-025-01729-1#ref-CR51 "Kuneš J, Pražienková V, Popelová A, Mikulášková B, Zemenová J, Maletínská L.Prolactin-releasing peptide: a new tool for obesity treatment. J Endocrinol2016;230:R51–8. 
                https://doi.org/10.1530/JOE-16-0046
                
              . e14742. 
                https://doi.org/10.15252/emmm202114742
                
              ")].

In this context, examining pancreatic lipase's contribution to obesity management unveils a fertile ground for innovation in therapeutic methods. Concentrating on the intricacies of pancreatic lipase (PL) inhibition, scrutinizing prevailing treatments, surmounting current obstacles, and pioneering future breakthroughs, this discussion aims to deliver an all-encompassing view of the role of PL inhibition in the fight against obesity. It charts a course toward fresh discoveries and progress in addressing this prevalent health dilemma.

### New finding as alternative obesity treatment: PL inhibitory peptides approaches

The previous study explores the potential of natural peptides as inhibitors of pancreatic lipase, aiming to contribute to obesity treatment. Basically, peptides represent a distinct category of biochemical entities, positioned between small molecules and proteins in terms of molecular size, yet they differ significantly in their biochemical and therapeutic properties. Serving as essential signaling agents across numerous bodily functions, peptides hold considerable promise for medical treatments due to their ability to naturally emulate biological processes. Their rapid breakdown in the human body also makes them a relatively safe option for use. Recently, scientists have found 176 pancreatic lipase inhibitory peptides from various sources, including plants-based sources (millet grain, rice bran [[52](/articles/s41366-025-01729-1#ref-CR52 "Ketprayoon T, Noitang S, Sangtanoo P, Srimongkol P, Saisavoey T, Reamtong O, et al. An in vitro study of lipase inhibitory peptides obtained from de-oiled rice bran. RSC Adv. 2021;11:18915–29. 
                https://doi.org/10.1039/d1ra01411k
                
              ")], and cumin seeds), marine life such as those extracted from sea cucumbers, tuna, shark, and dried spirulina seaweed [[53](/articles/s41366-025-01729-1#ref-CR53 "Esfandi R, Seidu I, Willmore W, Tsopmo A. Antioxidant, pancreatic lipase, and α‐amylase inhibitory properties of oat bran hydrolyzed proteins and peptides. J Food Biochem. 2021;46:e13762. 
                https://doi.org/10.1111/jfbc.13762
                
              ")]. The peptides-derived insect sources such as tropical house crickets, mealworms, desert locusts, and dairy sources, including camel and cow casein [[54](/articles/s41366-025-01729-1#ref-CR54 "Gangadaran S, Cheema SK. A high fat diet enriched with sea cucumber gut powder provides cardio-protective and anti-obesity effects in C57BL/6 mice. Food Res Int. 2017;99:799–806. 
                https://doi.org/10.1016/j.foodres.2017.06.066
                
              ")]. These peptides, identified through bioinformatic analyses and molecular docking, show promise due to their structural activity relationships and interaction mechanisms. Unlike weight loss medicine, weight loss devices, bariatric surgery, and liposuction, which may have significant risks or side effects, traditional weight loss methods, such as naturally derived peptides offer a safer, more accessible alternative. The investigation underlines the peptides' hydrophobic nature and their role in reducing macronutrient absorption, highlighting their potential as natural, effective anti-obesity agents [52,53,[54](/articles/s41366-025-01729-1#ref-CR54 "Gangadaran S, Cheema SK. A high fat diet enriched with sea cucumber gut powder provides cardio-protective and anti-obesity effects in C57BL/6 mice. Food Res Int. 2017;99:799–806. 
                https://doi.org/10.1016/j.foodres.2017.06.066
                
              ")].

In short, Obesity, now recognized as a significant medical concern on the current anti-obesity medications works by suppressing appetite through the elevation of neurotransmitters, inhibiting digestive enzymes, and slowing down gastric emptying. However, their side effects on the cardiovascular, psychological, and gastrointestinal systems have prompted the search for safer treatments. Phytochemicals from plants offer a promising alternative, displaying similar beneficial mechanisms with fewer side effects. Notably, natural compounds uniquely contribute to weight management by promoting the browning of white adipose tissue, enhancing thermogenesis, encouraging fat cell death, and blocking fat cell formation [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              ")]. These effects are mediated through several mechanisms, including metabolic stimulation, appetite regulation, inhibition of digestive enzymes, improving in insulin sensitivity, and direct action on fat storage and breakdown processes. Critical proteins and molecular pathways like UCP-1, PRDM16, PPAR-γ, SIRT1, and AMPK play roles in these processes, influenced by phytochemicals to effectively combat obesity through multifaceted actions on fat metabolism and energy expenditure [[28](/articles/s41366-025-01729-1#ref-CR28 "Shaik Mohamed Sayed UF, Moshawih S, Goh HP, Kifli N, Gupta G, Singh SK, et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management. Front Pharmacol. 2023;14:1182937. 
                https://doi.org/10.3389/fphar.2023.1182937
                
              "), [55](/articles/s41366-025-01729-1#ref-CR55 "Park SJ, Park M, Sharma A, Kim K, Lee HJ. Black ginseng and ginsenoside Rb1 promote browning by inducing UCP1 expression in 3T3-L1 and primary white adipocytes. Nutrients. 2019;11:2747. 
                https://doi.org/10.3390/nu11112747
                
              ")].

### Advance emergence-related obesity treatments

In the context of emergence and advanced treatments, peptides, which are a short chain of amino acids are leveraged as precision-targeting agents because of their specificity in binding to designated receptors or biomarkers. These peptides, whether naturally occurring or synthetically crafted, serve dual roles: they are used either as direct drug conjugates or as delivery transporters for drugs encapsulated in nanoparticles. This approach holds significant potential for the treatment of a variety of diseases, including cancer, cardiovascular diseases, and neurological conditions [[35](/articles/s41366-025-01729-1#ref-CR35 "Telci Caklili O, Cesur M, Mikhailidis DP, Rizzo M. Novel anti-obesity therapies and their different effects and safety profiles: a critical overview. Diabetes Metab Syndr Obes 2023;16:1767–74. 
                https://doi.org/10.2147/DMSO.S392684
                
              "), [36](/articles/s41366-025-01729-1#ref-CR36 "Ashour MM, Mabrouk M, Aboelnasr MA, Beherei HH, Tohamy KM, Das DB. Anti-obesity drug delivery systems: recent progress and challenges. Pharmaceutics. 2023;15:2635. 
                https://doi.org/10.3390/pharmaceutics15112635
                
              ")]. Beyond peptides, targeting molecules like aptamers (short DNA or RNA strands that bind specifically to targets), small molecules (designed to interact with disease-related receptors or enzymes), and carbohydrates (for targeting specific cell surface lectins or receptors) are also under investigation for their therapeutic potential [56,57,58,59,[60](/articles/s41366-025-01729-1#ref-CR60 "Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Investig 2012;123:215–23.")].

The advent of nanotechnology has paved the way for the development of sophisticated targeted drug delivery systems (DDSs) that leverage nanoparticles engineered with functional capabilities [[61](/articles/s41366-025-01729-1#ref-CR61 "Cheng X, Xie Q, Sun Y. Advances in nanomaterial-based targeted drug delivery systems. Front Bioeng Biotechnol. 2023;11:1177151. 
                https://doi.org/10.3389/fbioe.2023.1177151
                
              ")]. Emerging technologies like nanotechnology hold great promise for revolutionizing anti-obesity treatments by enabling more precise drug delivery and boosting therapeutic effectiveness. Nanomedicine offers a promising approach to address this gap by enabling more precise and effective anti-obesity therapies. Nanoparticles can be engineered to deliver drugs directly to adipose tissue, enhancing the efficacy of weight-loss agents while minimizing systemic side effects. Additionally, nanocarriers can be designed to improve the bioavailability of poorly soluble drugs, allowing for lower dosages and reducing the risk of adverse reactions. These advanced nanocarriers are crafted to carry both targeting molecules and therapeutic compounds directly to the afflicted cells or tissues. This is achieved through surface modifications with targeting ligands, such as antibodies or peptides, enhancing their ability to be taken up by cells and localized precisely at the site of the disease. Despite its potential, the integration of nanomedicine into clinical practice faces challenges, including the need for rigorous safety evaluations, immune reactions, regulatory approval, long-term stability, and the development of scalable manufacturing processes alongside ethical frameworks. Nonetheless, the targeted nature of nanotechnology in drug delivery could revolutionize obesity treatment by providing personalized crowd support with an integrative-care model and more effective interventions. Personalized medicine holds significant potential for advancing anti-obesity treatments by tailoring therapies to individual genetic profiles and metabolic responses, thereby enhancing treatment efficacy and minimizing adverse effects.

In the realm of creating targeted DDSs, there are three prominent synthetic methods for producing polymer–drug conjugates: binding therapeutic compounds to synthetic polymeric carriers, incorporating therapeutic molecules with monomers prior to the polymerization process, and embedding drugs into polymers during their formation [[62](/articles/s41366-025-01729-1#ref-CR62 "Clark ST, Arras MM, Sarles SA, Frymier PD. Modeling the saturation of detergent association in mixed liposome systems. Colloids Surf B Biointerfaces. 2021;206:111927.")]. These innovative conjugates bring forth numerous benefits, such as improved drug bioavailability and biodegradability, minimized drug toxicity, increased water solubility and stability, enhanced biocompatibility, and precise control over drug release. These advantages are crucial for overcoming drug resistance. Nonetheless, deploying polymer–drug conjugates, particularly in multi-drug regimens, presents hurdles, including identifying the ideal drug-to-therapeutic agent ratios and addressing concerns related to low drug loading capacities [[56](/articles/s41366-025-01729-1#ref-CR56 "Di Maio G, Alessio N, Demirsoy IH, Peluso G, Perrotta S, Monda M, et al. Evaluation of browning agents on the white adipogenesis of bone marrow mesenchymal stromal cells: a contribution to fighting obesity. Cells. 2021;10:403."), [57](/articles/s41366-025-01729-1#ref-CR57 "Peng M, Ping H, Chun-Yang X, Bi-Yu H, Qiang G-F, Guan-Hua D. Recent developments in natural products for white adipose tissue browning. Chin J Nat Med 2020;18:803–17."), [60](/articles/s41366-025-01729-1#ref-CR60 "Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Investig 2012;123:215–23.")].

Furthermore, the advanced emergence has been explored in RNA-targeted drug discovery and RNA bioengineering is providing new insights into the dynamic structure landscape of RNA, which has implications for drug discovery [[63](/articles/s41366-025-01729-1#ref-CR63 "Pamplona JH, Zoehler B, Shigunov P, Barisón MJ, Severo VR, Erich NM, et al. Alternative methods as tools for obesity research: in vitro and in silico approaches. Life \(Basel\). 2022;13:108. 
                https://doi.org/10.3390/life13010108
                
              ")]. Even obesity is a complex issue influenced by multiple factors. Key to understanding these conditions is the role of adipocytes (fat cells) and the process of adipogenesis (the formation of fat cells). Central to the development of obesity is the growth of white adipose tissue (WAT), marked by both an enlargement (hypertrophy) and a proliferation (hyperplasia) of fat cells, or adipocytes. WAT is composed not only of adipocytes but also mesenchymal stem cells (MSCs) which serve as precursors to these fat cells, in addition to containing endothelial and immune cells [[30](/articles/s41366-025-01729-1#ref-CR30 "Freitag Luglio H. Genetic variation of fatty acid oxidation and obesity, a literature review. Int J Biomed Sci. 2016;12:1–8.")]. MSCs have the potential to evolve into new adipocytes, which subsequently store triglycerides within their lipid droplets [[50](/articles/s41366-025-01729-1#ref-CR50 "Hong W, Park J, Yun W, Kang PJ, Son D, Jang J, et al. Inhibitory effect of celastrol on adipogenic differentiation of human adipose-derived stem cells. Biochem Biophys Res Commun. 2018;507:236–41. 
                https://doi.org/10.1016/j.bbrc.2018.11.014
                
              "), [63](/articles/s41366-025-01729-1#ref-CR63 "Pamplona JH, Zoehler B, Shigunov P, Barisón MJ, Severo VR, Erich NM, et al. Alternative methods as tools for obesity research: in vitro and in silico approaches. Life \(Basel\). 2022;13:108. 
                https://doi.org/10.3390/life13010108
                
              ")]. By delving into the dynamics of adipose stem cells and the adipogenesis process, scientists can uncover innovative avenues for tackling obesity. The complexity of adipogenesis, involving numerous molecular mechanisms, makes the study of regulators of this process and their potential as anti-obesity medication targets (AOM) particularly valuable. This approach includes exploring RNA functions, gene expression, and metabolic regulation during the adipogenesis of human mesenchymal stem cells (MSCs) and the breakdown of fats in lipolysis [[50](/articles/s41366-025-01729-1#ref-CR50 "Hong W, Park J, Yun W, Kang PJ, Son D, Jang J, et al. Inhibitory effect of celastrol on adipogenic differentiation of human adipose-derived stem cells. Biochem Biophys Res Commun. 2018;507:236–41. 
                https://doi.org/10.1016/j.bbrc.2018.11.014
                
              "), [63](/articles/s41366-025-01729-1#ref-CR63 "Pamplona JH, Zoehler B, Shigunov P, Barisón MJ, Severo VR, Erich NM, et al. Alternative methods as tools for obesity research: in vitro and in silico approaches. Life \(Basel\). 2022;13:108. 
                https://doi.org/10.3390/life13010108
                
              ")]. The exploration of treatments for obesity has advanced into areas of RNA and stem cell research, focusing on the control of fat cell formation (adipogenesis) in mesenchymal stem cells (MSCs). This is seen as a promising approach for addressing people with obesity and related conditions associated with aging.

## Orlistat: Understanding the pharmacokinetic efficacy and potential side effects

Orlistat is a well-researched pancreatic lipase inhibitor recognized for its weight reduction capabilities and positive impact on cardiovascular risk markers in patients with obesity. Despite its effectiveness, the drug's gastrointestinal side effects, stemming from its action of blocking fat absorption, can affect adherence. Orlistat works by hindering the absorption of dietary fats, leading to weight loss, and also shows potential in enhancing metabolic markers like adiponectin and leptin levels [[32](/articles/s41366-025-01729-1#ref-CR32 "Zhou B, Yuan Y, Shi L, Hu S, Wang D, Yang Y. et al. Creation of an anti-inflammatory, leptin-dependent anti-obesity celastrol mimic with better druggability. Front Pharmacol. 2021;12:705252. 
                https://doi.org/10.3389/fphar.2021.705252
                
              ."), [33](/articles/s41366-025-01729-1#ref-CR33 "Liu T, Wu F, Chen K, Pan B, Yin X, You Y, et al. Sweet potato extract alleviates high-fat-diet-induced obesity in C57BL/6J mice, but not by inhibiting pancreatic lipases. Front Nutr. 2022;9:1016020. 
                https://doi.org/10.3389/fnut.2022.1016020
                
              ")]. Beyond its weight loss benefits, scientists have suggested that orlistat might have anti-tumor [[64](/articles/s41366-025-01729-1#ref-CR64 "Maguire OA, Ackerman SE, Szwed SK, Maganti AV, Marchildon F, Huang X, et al. Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer. Cell Metab. 2021;33:499–512.e6.")].

In the context of understanding the pharmacokinetic efficacy of Orlistat, along with its potential side effects, can be influenced by obesity through changes in drug absorption, metabolism, distribution, and excretion. The way a drug is administered plays a crucial role in its systemic availability, with routes like intravenous, subcutaneous, and intramuscular bypassing the liver initially, thus affecting systemic bioavailability. Numerous pharmaceuticals are formulated as ionized salts, incorporating elements like sodium or potassium, to enhance their pharmacokinetic profiles. This includes facilitating dissolution in the gastrointestinal tract to improve absorption, extending the product's shelf life, and streamlining the manufacturing process. Medications such as phentermine hydrochloride (HCl), naltrexone HCl, and bupropion HCl are examples where the salt form significantly influences their pharmacokinetic behaviors.

When compared to other medications for obesity management, orlistat stands out primarily due to its gastrointestinal side effects which are typically manageable. Its distinctive mechanism of action reduces the absorption of fats, potentially benefiting insulin sensitivity and reducing levels of circulating fatty acids. However, concerns about its impact on gastrointestinal health and the potential for decreased absorption of fat-soluble vitamins persist. Despite these challenges, orlistat is acknowledged for its effectiveness in weight management and its potential for anti-cancer research, mainly attributed to its role as a gastrointestinal lipase inhibitor that limits dietary fat absorption [[39](/articles/s41366-025-01729-1#ref-CR39 "Rössner S, Sjöström L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res. 2000;8:49–61. 
                https://doi.org/10.1038/oby.2000.8
                
              "), [41](/articles/s41366-025-01729-1#ref-CR41 "García-Carro C, Vergara A, Bermejo S, Azancot M, Sellarés J, Soler M. A nephrologist perspective on obesity: from kidney injury to clinical management. Front Med. 2021;8:655871. 
                https://doi.org/10.3389/fmed.2021.655871
                
              "), [42](/articles/s41366-025-01729-1#ref-CR42 "Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4:342–7. 
                https://doi.org/10.1111/cob.12075
                
              ")].

Thus, orlistat is effective in weight management and poses cardiovascular benefits, yet its gastrointestinal side effects and impact on vitamin absorption necessitate careful consideration. Ongoing research into its various pharmacological effects and potential beyond obesity treatment is encouraged.

### Adverse effects: addresses current clinical challenges with Orlistat-related gastrointestinal

Orlistat, aimed at treating obesity, effectively aids in weight loss but is frequently linked to adverse gastrointestinal disorder reactions including oily stools, diarrhea, stomach pain, and fecal incontinence. The gastrointestinal side effects associated with certain treatments play a crucial role in clinical practice due to their impact on patient adherence to therapy. Orlistat operates by inhibiting enzymes in the gastrointestinal tract responsible for fat digestion, consequently reducing fat absorption by ~30% [[65](/articles/s41366-025-01729-1#ref-CR65 "Wit M, Trujillo-Viera J, Strohmeyer A, Klingenspor M, Hankir M, Sumara G. When fat meets the gut-focus on intestinal lipid handling in metabolic health and disease. EMBO Mol Med. 2022;14:e14742. 
                https://doi.org/10.15252/emmm.202114742
                
              ")]. Additionally, challenges in its formulation due to poor solubility and low oral bioavailability complicate its clinical use (Table [1](/articles/s41366-025-01729-1#Tab1)).

Scientists focusing on the specific adverse effects of fecal spotting and other related issues underscores the necessity for a deeper comprehension of these reactions and the development of management strategies to mitigate them. Studies have also delved into orlistat's impact on lipid metabolism and its potential link to cancer, finding no substantial influence on the progression of colorectal cancer [[43](/articles/s41366-025-01729-1#ref-CR43 "Bays HE, Fitch A, Christensen S, Burridge K, Tondt J. Anti-obesity medications and investigational agents: an Obesity Medicine Association \(OMA\) Clinical Practice Statement \(CPS\). Obes Pillars. 2022;2:100018. 
                https://doi.org/10.1016/j.obpill.2022.100018
                
              ")]. Moreover, its utility alongside lifestyle modifications in treating conditions like polycystic ovary syndrome highlights its potential advantages for certain groups.

In essence, while orlistat's role in weight reduction is established, its associated gastrointestinal adverse effects present significant hurdles in clinical practice. There is a pressing need for further investigation to understand these effects better and to devise effective management approaches that could enhance patient experience and adherence to orlistat treatment.

### Adverse effects: Orlistat-associated to liver failure

Orlistat, a drug inhibiting pancreatic lipase and aimed at aiding weight loss, has been linked to severe liver-related side effects, including the formation of gallstones, liver inflammation with bile obstruction, and acute liver failure, as highlighted in various studies [[5](/articles/s41366-025-01729-1#ref-CR5 "Vettor R, Di Vincenzo A, Maffei P, Rossato M. Regulation of energy intake and mechanisms of metabolic adaptation or maladaptation after caloric restriction. Rev Endocr Metab Disord 2020;399–409. 
                https://doi.org/10.1007/s11154-020-09565-6
                
              ."), [42](/articles/s41366-025-01729-1#ref-CR42 "Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4:342–7. 
                https://doi.org/10.1111/cob.12075
                
              "), 66,67,68,[69](/articles/s41366-025-01729-1#ref-CR69 "Palacios-Martinez D, Garcia-Alvarez JC, Montero-Santamaria N, Villar-Ruiz OP, Ruiz-Garcia A, Diaz-Alonso RA. Macrocytic anemia and thrombocytopenia induced by orlistat. Int J Endocrinol Metab. 2013;11:e6721. 
                https://doi.org/10.5812/ijem.6721
                
              ")]. Research findings have underscored instances of grave liver conditions connected to the consumption of orlistat, leading to regulatory in safety guidelines regarding its use [[5](/articles/s41366-025-01729-1#ref-CR5 "Vettor R, Di Vincenzo A, Maffei P, Rossato M. Regulation of energy intake and mechanisms of metabolic adaptation or maladaptation after caloric restriction. Rev Endocr Metab Disord 2020;399–409. 
                https://doi.org/10.1007/s11154-020-09565-6
                
              ."), [68](/articles/s41366-025-01729-1#ref-CR68 "Martínez Insfran LA, Alconchel Gago F, Parrilla Paricio P. Fulminant liver failure secondary to submassive hepatic necrosis in a patient treated with Orlistat. A case report. Rev Esp Enferm Dig. 2019;111:83. 
                https://doi.org/10.17235/reed.2018.5740/2018
                
              ")]. In addition, orlistat's potential to cause liver damage and its association with severe liver outcomes, such as gallstone formation, obstructive jaundice, and acute liver failure, have been documented [[68](/articles/s41366-025-01729-1#ref-CR68 "Martínez Insfran LA, Alconchel Gago F, Parrilla Paricio P. Fulminant liver failure secondary to submassive hepatic necrosis in a patient treated with Orlistat. A case report. Rev Esp Enferm Dig. 2019;111:83. 
                https://doi.org/10.17235/reed.2018.5740/2018
                
              "), [70](/articles/s41366-025-01729-1#ref-CR70 "Wasta Esmail VA, Al-Nimer MSM, Mohammed MO. Effects of orlistat or telmisartan on the serum free fatty acids in non-alcoholic fatty liver disease patients: an Open-Labeled Randomized Controlled Study. Turk J Gastroenterol. 2022;33:421–6. 
                https://doi.org/10.5152/tjg.2020.19365
                
              ")]. The drug has also been related to the formation of silent gallstones and significant weight reduction in certain individuals [[42](/articles/s41366-025-01729-1#ref-CR42 "Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4:342–7. 
                https://doi.org/10.1111/cob.12075
                
              ")]. Despite the low incidence of serious side effects and discontinuation of treatment due to these effects reported in clinical trials, the prevalence of gallstones and obstructive jaundice linked to orlistat demands attention [[42](/articles/s41366-025-01729-1#ref-CR42 "Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4:342–7. 
                https://doi.org/10.1111/cob.12075
                
              "), [71](/articles/s41366-025-01729-1#ref-CR71 "Douglas IJ, Langham J, Bhaskaran K, Brauer R, Smeeth L. Orlistat and the risk of acute liver injury: self controlled case series study in UK Clinical Practice Research Datalink. BMJ. 2013;346:f1936. 
                https://doi.org/10.1136/bmj.f1936
                
              ")]. It is crucial to acknowledge that the occurrence of adverse events, especially those affecting the liver due to orlistat, might be underrepresented in published reports [[72](/articles/s41366-025-01729-1#ref-CR72 "Deng Z, Meng C, Huang H, Song S, Fu L, Fu Z. The different effects of psyllium husk and orlistat on weight control, the amelioration of hypercholesterolemia and non-alcohol fatty liver disease in obese mice induced by a high-fat diet. Food Funct. 2022;13:8829–49. 
                https://doi.org/10.1039/d2fo01161a
                
              ")]. Therefore, the potential for serious hepatic adverse effects should be carefully considered when prescribing orlistat for weight management.

### Adverse effects: Orlistat-associated acute kidney injury and enteric hyperoxaluria

Investigating the reflection of Orlistat, acute kidney injury, and enteric hyperoxaluria is vital due to the rare yet serious adverse effects linked to Orlistat. Enteric hyperoxaluria, which results from enhanced oxalate absorption in the intestine, is known to cause kidney stones, chronic kidney damage, and acute oxalate nephropathy [[73](/articles/s41366-025-01729-1#ref-CR73 "Bao D, Wang Y, Yu X, Zhao M. Acute oxalate nephropathy: a potential cause of acute kidney injury in diabetes mellitus—a case series from a single center. Front Med \(Lausanne\). 2022;9:929880. 
                https://doi.org/10.3389/fmed.2022.929880
                
              "), [74](/articles/s41366-025-01729-1#ref-CR74 "Solomon LR, Nixon AC, Ogden L, Nair B. Orlistat-induced oxalate nephropathy: an under-recognised cause of chronic kidney disease. BMJ Case Rep. 2017. 
                https://doi.org/10.1136/bcr-2016-218623
                
              ")]. The mechanisms involved encompass numerous gastrointestinal disorders that lead to poor fat absorption and reduced secretion of oxalate in the gut, which are linked to hyperoxaluria associated with obesity [[75](/articles/s41366-025-01729-1#ref-CR75 "Witting C, Langman CB, Assimos D, Baum MA, Kausz A, Milliner D, et al. Pathophysiology and treatment of enteric hyperoxaluria. Clin J Am Soc Nephrol. 2021;16:487–95. 
                https://doi.org/10.2215/CJN.08000520
                
              ")]. Moreover, secondary hyperoxaluria, prompted by enhanced absorption of dietary oxalate, can increase the risk of developing kidney stones and oxalate nephropathy, especially in individuals with gastrointestinal complications or those who have undergone intestinal surgeries [[76](/articles/s41366-025-01729-1#ref-CR76 "Chen T, Qian B, Zou J, Luo P, Zou J, Li W, et al. Oxalate as a potent promoter of kidney stone formation. Front Med \(Lausanne\). 2023;10:1159616. 
                https://doi.org/10.3389/fmed.2023.1159616
                
              ")]. This section underscores the importance of investigating the relationship between enteric hyperoxaluria and the onset of acute kidney injury, particularly in the context of conditions such as inflammatory bowel disease, short bowel syndrome, and following bariatric surgery [[75](/articles/s41366-025-01729-1#ref-CR75 "Witting C, Langman CB, Assimos D, Baum MA, Kausz A, Milliner D, et al. Pathophysiology and treatment of enteric hyperoxaluria. Clin J Am Soc Nephrol. 2021;16:487–95. 
                https://doi.org/10.2215/CJN.08000520
                
              ")].

## Pharmacodynamics of orlistat on drug absorption and interaction complications

Orlistat, known for its effectiveness in weight management by blocking lipase enzymes, significantly affects the absorption and effectiveness of various medications, including warfarin, amiodarone, ciclosporin, and thyroxine, as well as fat-soluble vitamins [[77](/articles/s41366-025-01729-1#ref-CR77 "Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacotherapy. 2000;20:270–9. 
                https://doi.org/10.1592/phco.20.4.270.34882
                
              ")]. This interference is primarily due to orlistat's ability to reduce fat absorption, which in turn impacts the bioavailability of these medications. Key interactions, such as reduced cyclosporin absorption leading to Evan's syndrome relapse, and enhanced effects of warfarin's anticoagulation due to decreased vitamin absorption, underline the importance of vigilant monitoring and potentially supplementing vitamins in individuals taking orlistat [[39](/articles/s41366-025-01729-1#ref-CR39 "Rössner S, Sjöström L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res. 2000;8:49–61. 
                https://doi.org/10.1038/oby.2000.8
                
              "), [42](/articles/s41366-025-01729-1#ref-CR42 "Sall D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4:342–7. 
                https://doi.org/10.1111/cob.12075
                
              ")].

These observations, derived from various studies and case reports, emphasize the critical need for healthcare providers to be vigilant about potential drug interactions when prescribing orlistat, especially for patients on concurrent medications that might be impacted by altered lipid absorption dynamics. Orlistat operates by inhibiting your body's ability to absorb some of the fat from the foods you consume. It is advised to take it with water either during your meal or within an hour afterward [[43](/articles/s41366-025-01729-1#ref-CR43 "Bays HE, Fitch A, Christensen S, Burridge K, Tondt J. Anti-obesity medications and investigational agents: an Obesity Medicine Association \(OMA\) Clinical Practice Statement \(CPS\). Obes Pillars. 2022;2:100018. 
                https://doi.org/10.1016/j.obpill.2022.100018
                
              ")]. Given orlistat's potential to impair the absorption of certain vitamins, incorporating a daily multivitamin supplement is recommended, which should be consumed either two hours before or after taking orlistat, or at bedtime. To reduce the likelihood of side effects, it is important to ensure your diet does not exceed 30% fat and maintains a balanced distribution of fats, carbohydrates, and proteins across all three meals. Following a low-calorie diet and exercise regimen, as advised by your healthcare provider is essential. For individuals on cyclosporine or levothyroxine, it is important to time these medications to avoid interference with orlistat; take cyclosporine at least three hours before or after orlistat, and levothyroxine four hours apart from orlistat [[43](/articles/s41366-025-01729-1#ref-CR43 "Bays HE, Fitch A, Christensen S, Burridge K, Tondt J. Anti-obesity medications and investigational agents: an Obesity Medicine Association \(OMA\) Clinical Practice Statement \(CPS\). Obes Pillars. 2022;2:100018. 
                https://doi.org/10.1016/j.obpill.2022.100018
                
              "), [78](/articles/s41366-025-01729-1#ref-CR78 "Grilo CM, White MA. Orlistat with behavioral weight loss for obesity with versus without binge eating disorder: randomized placebo-controlled trial at a community mental health center serving educationally and economically disadvantaged Latino/as. Behav Res Ther. 2013;51:167–75. 
                https://doi.org/10.1016/j.brat.2013.01.002
                
              ")].

## Evolution and challenges of new obesity drugs related to adverse effects and future direction

Combatting obesity represents a major health dilemma, as it contributes to a heightened risk of disease, diminishes the quality of life, and can reduce life expectancy. Despite initiatives aimed at prevention and treatment on both personal and societal fronts, achieving success is challenging. Attempts to implement lifestyle modifications, such as lowering calorie consumption and enhancing physical activity, are often frustrated by complicated adaptations involving hormones, metabolism, and brain chemistry that oppose weight loss and promote the rebound of weight [[31](/articles/s41366-025-01729-1#ref-CR31 "Cao J, Lei S, Zhao T, Xie Y, Zhou Z, Cheng S, et al. Changes in fat oxidation and body composition after combined exercise intervention in sedentary obese Chinese adults. J Clin Med. 2022;11:1086. 
                https://doi.org/10.3390/jcm11041086
                
              "), [43](/articles/s41366-025-01729-1#ref-CR43 "Bays HE, Fitch A, Christensen S, Burridge K, Tondt J. Anti-obesity medications and investigational agents: an Obesity Medicine Association \(OMA\) Clinical Practice Statement \(CPS\). Obes Pillars. 2022;2:100018. 
                https://doi.org/10.1016/j.obpill.2022.100018
                
              ")]. Although weight-loss surgery shows effectiveness in severe cases, complications like weight regain post-surgery remain a concern. Less invasive methods like intra-gastric balloons offer a temporary solution but cannot rival the outcomes of bariatric surgery. Pharmacological interventions have advanced, yet many anti-obesity drugs fail in clinical trials due to severe side effects, limited usage durations, and moderate long-term efficacy. Some new studies on new therapeutic opportunities and drug delivery have been investigated (Table [2](/articles/s41366-025-01729-1#Tab2)). Studies have shown the beneficial effects of long-term use, particularly with natural molecules, as they often present fewer side effects and improved safety profiles. Recent research on new therapeutic opportunities and drug delivery methods highlights the potential of these natural compounds in providing sustainable anti-obesity solutions [[79](/articles/s41366-025-01729-1#ref-CR79 "Reshma A, Tamilanban T, Chitra V, Subramaniyan V, Gupta G, Fuloria NK, et al. Anti-obesity effects of olivetol in adult zebrafish model induced by short-term high-fat diet. Sci Rep 2023;13:18449. 
                https://doi.org/10.1038/s41598-023-44462-3
                
              ")].

**Table 2 Overview of new therapeutic opportunity and drug delivery in anti-obesity medication information.**

[ Full size table](/articles/s41366-025-01729-1/tables/2)

Recently, scientists have identified the advanced technology and key pathways, such as nanotechnology drug carriers involving RNA molecular or other mechanisms, such as the leptin-melanocortin and GLP-1/GLP-1R systems that are crucial in energy balance and appetite regulation [[80](/articles/s41366-025-01729-1#ref-CR80 "Taroeno-Hariadi KW, Hardianti MS, Sinorita H, et al. Obesity, leptin, and deregulation of microRNA in lipid metabolisms: their contribution to breast cancer prognosis. Diabetol Metab Syndr. 2021;13. 
                https://doi.org/10.1186/s13098-020-00621-4
                
              "), [81](/articles/s41366-025-01729-1#ref-CR81 "Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet 2021;398:262–76. 
                https://doi.org/10.1016/S0140-6736\(21\)00536-5
                
              ")]. GLP-1R agonists show promise in weight management however, challenges remain in enhancing their stability and effectiveness in the clinical setting due to natural degradation processes [[79](/articles/s41366-025-01729-1#ref-CR79 "Reshma A, Tamilanban T, Chitra V, Subramaniyan V, Gupta G, Fuloria NK, et al. Anti-obesity effects of olivetol in adult zebrafish model induced by short-term high-fat diet. Sci Rep 2023;13:18449. 
                https://doi.org/10.1038/s41598-023-44462-3
                
              "), [80](/articles/s41366-025-01729-1#ref-CR80 "Taroeno-Hariadi KW, Hardianti MS, Sinorita H, et al. Obesity, leptin, and deregulation of microRNA in lipid metabolisms: their contribution to breast cancer prognosis. Diabetol Metab Syndr. 2021;13. 
                https://doi.org/10.1186/s13098-020-00621-4
                
              ")].

GLP-1, a peptide hormone composed of 30 or 31 amino acids, is synthesized in the intestines and plays a pivotal role in boosting insulin secretion while lowering glucagon levels under normal physiological conditions. It was identified in 1983 as a product of proglucagon conversion by L cells in the lining of the intestines and is also produced by pancreatic α-cells, as well as being present in islet β-cells and the intestine [[82](/articles/s41366-025-01729-1#ref-CR82 "Nauck MA. Glucagon-like peptide 1 \(GLP-1\): a potent gut hormone with a possible therapeutic perspective. Acta Diabetol. 1998;35:117–29. 
                https://doi.org/10.1007/s005920050116
                
              ")]. Crucial for the regulation of glucose tolerance, GLP-1 acts through GLP-1 receptors, which belong to the glucagon receptor family and are located in several tissues, including the pancreas and heart [[79](/articles/s41366-025-01729-1#ref-CR79 "Reshma A, Tamilanban T, Chitra V, Subramaniyan V, Gupta G, Fuloria NK, et al. Anti-obesity effects of olivetol in adult zebrafish model induced by short-term high-fat diet. Sci Rep 2023;13:18449. 
                https://doi.org/10.1038/s41598-023-44462-3
                
              ")]. GLP-1 receptor agonists, targeting the entero-insular axis, mimic the insulin-boosting effects of bariatric surgery. These drugs offer a novel approach to obesity treatment, although their precise action mechanism and long-term safety and effectiveness require further clinical validation [[83](/articles/s41366-025-01729-1#ref-CR83 "Wang JY, Wang QW, Yang XY, Yang W, Li DR, Jin JY, et al. GLP-1 receptor agonists for the treatment of obesity: role as a promising approach. Front Endocrinol \(Lausanne\). 2023;14:1085799. 
                https://doi.org/10.3389/fendo.2023.1085799
                
              ")].

The exploration of nanotechnology-based therapies has unveiled potential solutions to overcome the drawbacks of conventional anti-obesity medications, including their nonspecific actions and the temporary impact on weight reduction. Emerging nanotechnology-based therapies should be thoroughly evaluated for their potential in anti-obesity treatment, as they offer innovative approaches for targeted drug delivery and improved therapeutic outcomes. A comprehensive examination of these technologies could lead to significant advancements in managing obesity [[84](/articles/s41366-025-01729-1#ref-CR84 "Sibuyi NRS, Moabelo KL, Meyer M, Onani MO, Dube A, Madiehe AM. Nanotechnology advances towards development of targeted-treatment for obesity. J Nanobiotechnol. 2019;17:122. 
                https://doi.org/10.1186/s12951-019-0554-3
                
              ")]. The pressing need for novel interventions has directed scientific research towards nanotechnology as a viable route for crafting more efficient treatments for obesity. A comprehensive review identifies three innovative nanotechnology-driven strategies aimed at targeting and altering white adipose tissues (WATs) and their vasculature to combat obesity. These methods encompass obstructing the vascular supply to WATs, transforming WATs into thermogenic brown adipose tissues (BATs), and utilizing photothermal techniques to dissolve WATs [[85](/articles/s41366-025-01729-1#ref-CR85 "Jiang C, Cano-Vega MA, Yue F, Kuang L, Narayanan N, Uzunalli G, et al. Dibenzazepine-loaded nanoparticles induce local browning of white adipose tissue to counteract obesity. Mol Ther. 2017;25:1718–29. 
                https://doi.org/10.1016/j.ymthe.2017.05.020
                
              ")]. Utilizing a range of nanocarriers, including liposomes, polymeric nanoparticles, and gold nanoparticles, these nanotechnology strategies promise enhanced efficacy, greater tolerance, and fewer adverse effects compared to traditional treatment modalities. This progress indicates that targeted nanotherapies may offer a revolutionary approach to addressing obesity and its related health complications.

In parallel with new drug studies, myriad scientist actively works on that. However, when employing strategy-related pharmacotherapy for obesity management, scientists and healthcare providers should adhere to several core guidelines [[86](/articles/s41366-025-01729-1#ref-CR86 "Jeon E, Lee KY, Kim K. Approved anti-obesity medications in 2022 KSSO Guidelines and the Promise of Phase 3 Clinical Trials: anti-obesity drugs in the sky and on the horizon. J Obes Metab Syndrome. 2023;32:106–20. 
                https://doi.org/10.7570/jomes23032
                
              ")]. Firstly, understanding any contraindications and side effects contributed to extensive use. Recognizing obesity as a chronic condition, there is a necessity for continuous use of anti-obesity medications (AOMs) as part of an all-encompassing treatment plan, integrating dietary, exercise, and psychological strategies. Stopping medication often results in weight gain. Secondly, AOMs are designed to target specific biological pathways influencing weight. Thirdly, the objective of treating obesity extends beyond weight loss to include the prevention of obesity-related complications and improvements in comorbid conditions, as evidenced by positive changes in cardiometabolic risk factors observed in Phase 3 clinical trials [[87](/articles/s41366-025-01729-1#ref-CR87 "Tchang BG, Aras M, Kumar RB, et al. Pharmacologic treatment of overweight and obesity in adults. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext 2021. South Dartmouth, MA: MDText.com, Inc.; 2000.")]. Employing a combination of AOMs that work through different mechanisms can effectively address the multifaceted nature of obesity and counteract metabolic adjustments that hinder weight loss. For instance, a patient who has hit a weight plateau with metformin might benefit from the addition of an appetite suppressant like phentermine or the combination of phentermine/topiramate to counteract the increase in hunger often caused by elevated ghrelin levels following significant weight loss through dietary changes. Lastly, there is variability in individual responses to AOMs, although when paired with lifestyle changes, these medications generally lead to significantly more weight loss compared to placebo. Thus, they are supported by stringent Federal Drug Administration (FDA) guidelines ensuring their efficacy and safety [[87](/articles/s41366-025-01729-1#ref-CR87 "Tchang BG, Aras M, Kumar RB, et al. Pharmacologic treatment of overweight and obesity in adults. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext 2021. South Dartmouth, MA: MDText.com, Inc.; 2000.")].

The future direction of obesity treatment is poised for significant advancements with medical professionals, policymakers, and the pharmaceutical industry recognizing the urgent need for effective and safe weight-loss medications. A new wave of anti-obesity medications is making strides in treatment options, heralding a more tailored approach to managing the condition. Currently, a range of anti-obesity medications (AOMs) are in development, showing encouraging outcomes. Noteworthy innovations include dual-action gastrointestinal peptide modulators like tirzepatide and cotadutide, which are demonstrating promise in preliminary trials. In addition, setmelanotide is pioneering a personalized medicine approach to obesity, specifically targeting very rare genetic disorders such as pro-opiomelanocortin (POMC) deficiency, proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor deficiency. Personalized medicine holds significant promise in tailoring healthcare to individual genetic, environmental, and lifestyle factors, thereby enhancing treatment efficacy and reducing adverse effects. By leveraging advancements in genomics and molecular diagnostics, personalized approaches can identify unique patient profiles, allowing for the selection of targeted therapies that align with the specific biological mechanisms driving disease in each patient [[88](/articles/s41366-025-01729-1#ref-CR88 "Ryan DH. Next generation antiobesity medications: setmelanotide, semaglutide, tirzepatide and bimagrumab: what do they mean for clinical practice? J Obes Metab Syndr 2021;30:196–208. 
                https://doi.org/10.7570/jomes21033
                
              ")]. This evolution in medicine also presents challenges, such as the need for robust data integration, ethical considerations, and the development of cost-effective strategies that can be widely implemented in clinical practice. In the context of personalized medicine, anti-obesity drugs play a crucial role in targeting and inhibiting the specific pathways involved in the pathogenesis of obesity. Tailoring these treatments to individual patient profiles can enhance their efficacy in preventing disease progression. [[89](/articles/s41366-025-01729-1#ref-CR89 "Wang L, Wang N, Zhang W, Cheng X, Yan Z, Shao G, et al. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther. 2022;7. 
                https://doi.org/10.1038/s41392-022-00904-4
                
              ")].

On another front, semaglutide 2.4 mg is in the process of seeking approval in both the United States and the European Union, offering significant potential for individuals with obesity or overweight and related comorbidities, as evidenced by its substantial efficacy in phase 3 trials [[88](/articles/s41366-025-01729-1#ref-CR88 "Ryan DH. Next generation antiobesity medications: setmelanotide, semaglutide, tirzepatide and bimagrumab: what do they mean for clinical practice? J Obes Metab Syndr 2021;30:196–208. 
                https://doi.org/10.7570/jomes21033
                
              ")]. The landscape of diabetes treatment is also witnessing advancements with the introduction of semaglutide, a GLP-1 receptor analog. Tirzepatide, which combines the effects of glucose-dependent insulinotropic polypeptide and GLP-1, is undergoing phase 3 research for obesity treatment. Meanwhile, bimagrumab is exploring a new mechanism in phase 2 studies, sparking significant interest in its potential to transform the pharmacotherapy of obesity [90,91,[92](/articles/s41366-025-01729-1#ref-CR92 "Chia TY, Gan C-Y, Shafie MH, Yap PG, Mohd Rodhi A, Ahmad A, et al. A comprehensive review on the pancreatic lipase inhibitory peptides: a future anti-obesity strategy. Electron J Gen Med. 2023;20:em470. 
                https://doi.org/10.29333/ejgm/12943
                
              ")].

## Conclusion

In summary, focusing on pancreatic lipase as a method for treating obesity presents a promising path for crafting impactful therapeutic options. Present understanding suggests that blocking pancreatic lipase activity substantially decreases fat absorption, thus supporting weight control efforts. The weight management focus on weight loss aims to enhance overall health by diminishing the harmful effects of excessive adipose tissue, while also promoting overall bodily health. However, the journey from understanding the basic mechanisms to the application of these insights in clinical settings involves overcoming several challenges, including optimizing drug efficacy, minimizing side effects, and ensuring long-term safety and tolerability. Ideally, society would foster healthy eating and active lifestyles as normative behaviors, free from the pressures of emotional and financial stress. However, recognizing the current challenges, there is a pressing need to develop more effective pharmacological solutions for those requiring assistance in weight management as a means to improve their health. Future directions should focus on advancing our understanding of the molecular interactions and regulatory pathways involved in lipid metabolism and pancreatic lipase function. Additionally, exploring the potential of combination therapies, personalized medicine approaches, and novel delivery systems could enhance the effectiveness and acceptability of pancreatic lipase inhibitors. Ultimately, interdisciplinary collaboration among researchers, clinicians, and pharmaceutical industries is crucial for translating these insights into safe, effective, and accessible obesity treatments. Furthermore, the advent of new-generation anti-obesity drugs offers promising avenues for achieving substantial and healthful weight reduction in many individuals facing obesity. This shift not only propels forward the potential for significant advancements in obesity treatment but also allows a refocus on addressing obesity directly as the underlying cause of numerous comorbidities, rather than solely managing its associated health conditions. The anticipation is that ongoing research and development in this field will equip biomedical scientists and clinical practitioners with innovative strategies and insights for combating obesity more effectively, marking a significant stride towards a holistic approach to obesity medicine.

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The authors are thankful to the School of Medicine, Jeffrey Cheah School of Medicine and Health Sciences, and Monash University Malaysia.

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  1. Pharmacology Unit, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia

Vetriselvan Subramaniyan

  2. Division of Pharmacology, School of Medical and Life Sciences, Sunway University, Sunway, 47500, Malaysia

Vetriselvan Subramaniyan & Yusoff Umul Hanim




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Subramaniyan, V., Hanim, Y.U. Role of pancreatic lipase inhibition in obesity treatment: mechanisms and challenges towards current insights and future directions. _Int J Obes_ (2025). https://doi.org/10.1038/s41366-025-01729-1

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  * Received: 06 June 2024

  * Revised: 16 September 2024

  * Accepted: 24 January 2025

  * Published: 27 February 2025

  * DOI: https://doi.org/10.1038/s41366-025-01729-1




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How glucagon-like peptide 1 receptor agonists work in: Endocrine Connections Volume 10 Issue 7 (2021) 

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#  How glucagon-like peptide 1 receptor agonists work 

in [Endocrine Connections](/view/journals/ec/ec-overview.xml)

Authors:

Christine Rode Andreasen

Christine Rode Andreasen Steno Diabetes Center Copenhagen, Gentofte, Denmark  
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark  
  
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Andreas Andersen

Andreas Andersen Steno Diabetes Center Copenhagen, Gentofte, Denmark  
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark  
  
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Filip Krag Knop

Filip Krag Knop Steno Diabetes Center Copenhagen, Gentofte, Denmark  
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark  
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark  
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark  
  
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Tina Vilsbøll

Tina Vilsbøll Steno Diabetes Center Copenhagen, Gentofte, Denmark  
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark  
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark  
  
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## 

Correspondence should be addressed to T Vilsbøll: [tina.vilsboell.01@regionh.dk](mailto:tina.vilsboell.01@regionh.dk)

DOI: 
     <https://doi.org/10.1530/EC-21-0130>

Volume/Issue: 
     [Volume 10: Issue 7](/view/journals/ec/10/7/ec.10.issue-7.xml)

Page Range: 
     R200–R212 

Article Type: 
     Review Article 

Online Publication Date: 
     17 Jul 2021 

Copyright: 
     © The authors 2021 

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  * Abstract/Excerpt 
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In recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of action, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.

## Abstract

In recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of action, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.

Keywords: [diabetes](/search?q=diabetes); [cardiovascular](/search?q=cardiovascular); [metabolism](/search?q=metabolism); [inflammation](/search?q=inflammation); [obesity](/search?q=obesity)

## Introduction

Glucagon-like peptide 1 (GLP-1) is a gut-derived glucoregulatory hormone secreted in response to food consumption. Human GLP-1 is synthesised from the proglucagon gene and is secreted from the enteroendocrine L cells (1). Some preproglucagon-expressing neurons in the nucleus tractus solitarius of the brain stem have also been shown to synthesise GLP-1 (2). Due to rapid breakdown by dipeptidyl peptidase 4 (DPP-4) and renal clearance, the half-life of circulating GLP-1 is only 1–2 min. Thus, only 10% of the native GLP-1 released from the enteroendocrine L cells reaches the systemic circulation (1). Activation of the GLP-1 receptor (GLP-1R) on the beta-cell enhances glucose-dependent secretion of insulin, thereby improving beta-cell sensitivity to glucose (1). In addition, GLP-1 exhibits a glucagonostatic effect through a glucose-dependent inhibition of glucagon release (3) which, compared to GLP-1-induced insulin secretion, may be equally important for the overall plasma glucose-lowering effect of GLP-1 (4). In normal physiology, GLP-1 modifies gastrointestinal function by decreasing motility of the stomach and intestine, thereby delaying gastric emptying and reducing postprandial plasma glucose excursions (5). Brain-derived GLP-1 acts as a neurotransmitter and can target multiple GLP-1Rs throughout the central nervous systemCNS, including effects on satiety (6). In addition, GLP-1R activation in the brain has been linked to neuroprotective properties in experimental neurodegenerative disease models (6). Deduced from both preclinical and human studies, GLP-1 has extra-pancreatic effects in the gut, kidney, nervous system, heart and immune system (Fig. 1) (2). Multiple GLP-1R agonists (GLP-1RAs) utilising the plasma glucose-lowering and body weight-lowering effects of GLP-1 have been developed, and today, we have more than 15 years of clinical experience with GLP-1RAs for the treatment of T2D and 6 years of clinical experience with GLP-1RA-based treatment of obesity. Despite the long clinical experience with GLP-1RAs, the exact mechanisms by which GLP-1RAs exert their effects are still debated (6). 

![Figure 1](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

![Figure 1](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

View Full Size 

![Figure 1](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

Figure 1

Possible actions of glucagon-like peptide 1 (GLP-1) and the GLP-1 receptor agonists (GLP-1RAs) on various tissue. The applied colour code indicates whether the effect on the target tissue has been observed in preclinical studies (blue boxes), at physiological levels of GLP-1 in clinical studies (green boxes) or after treatment with GLP-1RAs (red boxes) (1, 2). The figure illustrates GLP-1 (7–36) amide.

Citation: Endocrine Connections 10, 7; [10.1530/EC-21-0130](https://doi.org/10.1530/EC-21-0130)

  * [Download Figure](images/EC-21-0130fig1.jpeg)
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## Currently available GLP-1RAs

The first GLP-1RA for the treatment of T2D, exenatide twice daily, was approved by the United States Food and Drug Administration (FDA) in 2005. Since then, several GLP-1RAs have been developed and approved for the treatment of T2D, while albiglutide has been withdrawn due to commercial reasons. Until recently, all available GLP-1RAs were subcutaneously administrated; however, the GLP-1RA semaglutide (see below) is now available as an oral formulation. GLP-1RAs can be categorised based on molecular size, chemical structure and duration of action. As outlined below, the pharmacokinetic properties are important for the mode of action and the efficacy of the individual GLP-1RA. Short-acting GLP-1RAs are characterised by intermittent activation of the GLP-1R, whereas long-acting GLP-1RAs lead to continuous receptor activation over a 24-h period. Liraglutide, semaglutide and dulaglutide are – except for few modifications – highly similar to the structure of human GLP-1, while exenatide and lixisenatide are based on exendin-4, a naturally occurring peptide derived from the saliva of the Gila monster, and only share around 50% homology with the human GLP-1 molecule. Consequently, the exendin-based compounds cause a higher degree of antibody formation, but it is questionable whether this is important for efficacy and safety (7, 8). The pharmacokinetic properties of approved GLP-1RAs are listed in Table 1. 

Table 1

Pharmacokinetic properties of approved GLP-1RAs.

GLP-1RAs | Approval year | Molecular weight (Da) | Pharmacokinetic components | Administration schedule | Dose | Pharmacokinetics (single-dose administration) | Antibody development (% of patients)  
---|---|---|---|---|---|---|---  
FDA | EMA | Time to peak | Half-life | Elimination  
**Short-acting GLP-1RAs**  
Exenatide twice daily | 2005 | 2006 | 4187 | Peptide from the Gila lizard (53% homology with native GLP-1) | Twice daily | 5–10 µg | 2.1–2.2 h | 2.4 h | Mainly renal | 35  
Lixisenatide | 2016 | 2013 | 4859 | Exenatide plus poly-lysine tail | Once daily | 10–20 µg | ≈ 2 h | 3 h | Mainly renal | 56–70  
**Long-acting GLP-1RAs**  
Liraglutide | 2010 | 2009 | 3751 | Modified GLP-1 with free fatty acid side chain attached (97% homology with native GLP-1) | Once daily | 0.6–3 mg | 11.0–13.8 h | 13 h | Peptide hydrolysis, renal (6%)+faecal (5%) | 8.6  
Exenatide once weekly | 2012 | 2011 | 4187 | See exenatide twice daily | Once weekly | 2 mg | Slow* | 2.4 h | Mainly renal | 57  
Dulaglutide | 2014 | 2014 | 59,671 | Modified GLP-1 with attached immunoglobulin (Fc) fragment (~90% homology with native GLP-1) | Once weekly | 0.75–1.5 mg | 3–5 days | 90 h | Peptidases and renal | 1.6  
Semaglutide once weekly | 2017 | 2019 | 4113 | Modified GLP-1 with free fatty acid side chain attached (94% homology to native GLP-1) | Once weekly | 0.5–1 mg | 24 h | 165 h | Peptidases and renal | 0.01–3.50  
Oral semaglutide | 2019 | 2020 | 4114 | See semaglutide once weekly | Once daily | 3–14 mg | 1–4 h | 165–185 h | Peptidases | 0.5  
  
Has been withdrawn in July 2018 for commercial reasons. **Not formally assessed.

EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; GLP-1, glucagon-like peptide-1; GLP-1RAs, glucagon-like peptide-1 receptor agonists.

### Short-acting GLP-1RAs

The short-acting exenatide is identical to the exendin-4 structure, while lixisenatide has been modified from exendin-4 (deletion of proline and an addition of six lysine amino acids at the carboxyl terminus) to make them resistant to degradation by DPP-4 without compromising their GLP-1R activating potencies (9). They are administrated once (lixisenatide) or twice daily (exenatide) in relation to meals and have plasma half-lives in the range of 2.4–3 h resulting in low plasma drug concentrations between injections. Because of their intermittent stimulation of the GLP-1R, short-acting GLP-1RAs retain their ability to delay gastric emptying leading to lower postprandial glucose excursions compared with the long-acting GLP-1RAs, which are associated with the development of tolerance (tachyphylaxis) to GLP-1’s effect on gastric emptying (10).

### Long-acting GLP-1RAs

The long-acting GLP-1RAs are exenatide extended-release (once weekly), liraglutide (once daily), dulaglutide (once weekly) and semaglutide (once weekly injections or once daily oral administration). The long-acting GLP-1RAs have been altered in different ways to prolong plasma drug half-life. These modifications include attachment of a fatty acid chain that aids reversible binding to albumin (liraglutide and semaglutide) and covalent binding to carrier molecules such as antibody fragment (Fc) domains of immunoglobulin G (dulaglutide) (11, 12) (Table 1). Exenatide once weekly contains the same active drug as exenatide twice daily, but it is encapsulated in dissolvable microspheres (13). Oral semaglutide is a combination of semaglutide and the absorption enhancer sodium N-(8-(2-hydroxybenzoyl) amino) caprylate (SNAC), which protects semaglutide from degradation in the stomach and facilitates the absorption of semaglutide across the gastric mucosa (14).

## Effects of GLP-1RAs in type 2 diabetes

### Glycaemia and body weight

All available GLP-1RAs improve glycaemia and have the ability to reduce body weight (15). An overview of the published head-to-head trials that directly compare different pairs of GLP-1RA with the effects on glycaemia and body weight is provided in Fig. 2. The overall glucose-lowering effects, reflected by HbA1c, are generally more pronounced with long-acting GLP-1RAs compared to short-acting GLP-1RAs (Fig. 2). The reduction in HbA1c ranges between 0.8% and 1.8% across trials. As a class, the GLP-1RAs have all been shown to have a body weight-reducing effect without clinically significant differences in body weight reduction between short-acting and long-acting GLP-1RAs. However, there is a large variety in the effects of GLP-1RA treatment between individuals on body weight from weight gain (few) to more than 15% reduction in body weight (16). In most individuals, GLP-1RA-induced body weight loss is achieved within the first 3–6 months of treatment, and in most patients, the body weight loss is maintained if treatment is continued, while discontinuation will lead to some regain of lost body weight. The body weight-reducing effects of the GLP-1RAs in persons with T2D range between 0.3 and 6.3 kg, with the most marked effect observed with dulaglutide (17) and semaglutide (18). 

![Figure 2](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

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Figure 2

Results from clinical trials comparing the GLP-1 receptor agonists (GLP-1RAs) head-to-head in phase III trials. Left panels are trials comparing short-acting GLP-1RAs (97). Middle panels are trials comparing a short-acting GLP-1RA with a long-acting GLP-1RA (7, 98, 99, 100). Right panel are trials comparing long-acting GLP-1RAs (101, 102, 103, 104, 105, 106). Asterisk (*) represents significant differences when comparing the GLP-1RAs.

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GLP-1RA-induced reduction in body weight is caused by the suppression of food intake (2). In preclinical studies, peripherally administrated GLP-1RA reaches and binds to GLP-1Rs in areas of the brain involved in the regulation of food intake in the hypothalamus and hindbrain (2). Peripherally administrated GLP-1RA may also indirectly act on the brain by binding to GLP-1Rs on vagal afferent parasympathetic nerve endings, thereby generating and transmitting satiety signals to the hypothalamus and hindbrain (19). In rodents, peripherally administrated semaglutide can modulate food preferences by modifying the reward system through dopamine changes in the brain (20). In line with this, a study including patients with obesity randomised to treatment with semaglutide had fewer food cravings and could endure food cravings better than during treatment with placebo (21). The multiple ways to affect the brain and modulate eating behaviour seem to explain the differences observed in body weight reductions between GLP-1RA compounds. Thus, smaller molecules have more accessible entree to penetrate the brain, and long-acting GLP-1RAs are capable of maintaining sufficient plasma levels throughout the day.

### GLP-1RAs and CVOTs

Available GLP-1RAs (except for exenatide twice daily) have been examined in multicentre, double-blinded, randomised, placebo-controlled cardiovascular (CV) outcomes trials (CVOTs). In these trials, participants were randomised to the GLP-1RA in question or placebo, and all participants were treated with standard of care with the possibility of adding non-incretin-based diabetes therapies. Currently, seven CVOTs investigating the CV safety of GLP-1RAs in patients with or without established CVD have been published. As mentioned, albiglutide is no longer available, and thus, details on the HARMONY trial are not included in this clinical review. Baseline participant characteristics and primary composite CV endpoints of the remaining six completed CVOTs for GLP-1RA are listed in Table 2. In the majority of the trials, the primary composite CV endpoint was a three-component major adverse CV event (MACE) outcome including CV-related mortality, non-fatal myocardial infarction (MI), and non-fatal stroke (the CVOT investigating lixisenatide, the ELIXA trial, also included time to the first occurrence of hospitalisation for unstable angina pectoris). The CVOTs investigating liraglutide (LEADER), s.c. semaglutide (SUSTAIN-6) and dulaglutide (REWIND) have shown significant GLP-1RA-induced reductions in MACE. In the ELIXA trial, no effect of lixisenatide on MACE was observed; perhaps explained by lixisenatide’s short half-life compared with the long-acting GLP-1RAs being tested in the other CVOTs (Table 1), the short follow-up period of 2 years and the highest percentage of participants on statin therapy (Table 2). The EXSCEL trial did not find any significant difference in the primary outcome between treatment with the long-acting GLP-1RA exenatide once weekly and placebo. This may be explained by a relatively low trial drug exposure (76%) compared to other CVOTs, and that the trial had no run-in period and, therefore, had one of the highest discontinuation rates. Also, the PIONEER-6 showed no treatment effect with oral semaglutide on the primary composite outcome, which seems to be explained by the low power and short duration of PIONEER-6 (1.3 years). Oral semaglutide demonstrated a hazard ratio (HR) of 0.79, which is like what was observed with s.c. semaglutide in SUSTAIN-6 (HR 0.74). Of note, both PIONEER-6 and SUSTAIN-6 were non-inferiority CV safety studies and, thus, not powered to demonstrate superiority. The larger and longer-lasting (5 years) SOUL trial is ongoing and will determine if oral semaglutide has CV benefits in patients with T2D and CVD or chronic kidney disease (22). The REWIND study found CV benefits of treatment with dulaglutide in participants where only 32% had underlying CVD and who had low baseline HbA1c levels, thereby classifying the study population as a low-risk population compared to the other GLP-1RA CVOTs. A recent meta-analysis including all seven GLP-1RA CVOTs, that is, 42,920 patients, showed a 12% relative risk reduction in MACE during GLP-1RA treatment compared to placebo. Also, significant reductions in all of the separate components of MACE were observed (15). In addition, treatment with GLP-1RAs reduced all-cause mortality by 12% and hospital admission for heart failure (HF) by 9% compared with placebo. Treatment with GLP-1RA also led to reductions in systolic blood pressure and body weight as well as a slight, sustained increase in heart rate compared to the control arm (15). Another meta-analysis, including 35 trials with GLP-1RAs investigating changes in lipid profile, found that treatment with GLP-1RAs leads to minor improvements in lipid profile and a modest effect on lipid metabolism (23). 

Table 2

Summary of baseline characteristics and primary composite cardiovascular outcomes of the completed CVOTs for GLP-1RAs.

Trial name | Trial drug | Year of completion | _N_ | Median follow-up (years) | Dose/interval | Exposition of drug in trial (%) | Risk factors at baseline | Main outcomes  
---|---|---|---|---|---|---|---|---  
Age (years) | HbA1c (%) | Baseline BMI | % with CVD | % with heart failure | % of statin use | MACE (HR (95% CI)) | All–cause mortality (HR(95% CI)) | CV mortality (HR(95% CI)) | Non-fatal MI (HR(95% CI)) | Non-fatal stroke (HR (95% CI)) | Time to first occurrence of hospitalisation for UAP (HR (95% CI))  
ELIXA (107) | Lixisenatideonce daily | 2015 | 6068 | 2.1 | 20 µg/day | 90.5 | 60 | 7.7 | 30.1 | 100 | 22.5 | 93 | 1.02 (0.89–1.17) | 0.94 (0.78–1.13) | 0.98 (0.78–1.22) | 1.03 (0.87–1.22) | 1.12 (0.79–1.58) | 1.11 (0.47–2.62)  
LEADER (108) | Liraglutideonce daily | 2015 | 9340 | 3.8 | 1.8 mg/day | 84 | 64 | 8.7 | 32.5 | 81.3 | 17.9 | 72 | 0.89 (0.78–0.97) | 0.85 (0.74–0.97) | 0.78 (0.66–0.93) | 0.86 (0.73–1.00) | 0.86 (0.71–1.06) |   
SUSTAIN-6 (49) | Semaglutide once weekly | 2016 | 3297 | 2.1 | 0.5/1.0 mg/week | 86.5 | 65 | 8.7 | 32.8 | 80 | 23.1 | 73 | 0.74 (0.58–0.95) | 1.05 (0.74–1.50) | 0.98 (0.65–1.48) | 0.81 (0.57–1.16) | 0.65 (0.41–1.03) |   
EXSCEL (109) | Exenatideonce weekly | 2017 | 14,752 | 3.2 | 2 mg/week | 76 | 62 | 8 | 31.8 | 73.1 | 15.8 | 74 | 0.91 (0.83–1.00) | 0.86 (0.77–0.97) | 0.88 (0.76–1.02) | 0.97 (0.85–1.10) | 0.85 (0.70–1.03) |   
REWIND (110) | Dulaglutideonce weekly | 2019 | 9901 | 5.5 | 1.5 mg/week | 82.2 | 66 | 7.3 | 32.3 | 31.4 | 8.6 | 66 | 0.88 (0.79–0.99) | 0.90 (0.80–1.01) | 0.91 (0.78–1.06) | 0.96 (0.79–1.15) | 0.76 (0.62–0.94) |   
PIONEER-6 (111) | Oral semaglutide | 2019 | 3183 | 1.3 | 14 mg/day | 75 | 66 | 8.2 | 32.3 | 84.6 | NR | 85 | 0.79 (0.47–1.11) | 0.51 (0.31–0.84) | 0.49 (0.27–0.92) | 1.04 (0.66–1.66 | 0.76 (0.37–1.56) |   
  
CVD, cardiovascular disease; GLP-1, glucagon-like peptide-1; GLP-1RAs, glucagon-like peptide-1 receptor agonists; HR, hazard ratio; N, number; NR, not reported; UAP, unstable angina pectoris.

### Cardioprotective mechanisms of action

The mechanisms behind the cardioprotective properties of GLP-1RAs are still unclear. Studies have demonstrated that GLP-1RAs exert a direct effect on the heart and blood vessels (6) and an indirect effect via improved glycaemia (24), a reduction in blood pressure and postprandial rise in triglycerides (25), a reduction in markers of oxidative stress and systemic inflammation (26, 27) (Fig. 3). The reduction in MACE observed in treatment with GLP-1RAs is mainly driven by a significant reduction in fatal or non-fatal stroke, but also a significant reduction in risks for CV death and fatal or non-fatal myocardial infarction (15), suggesting that GLP-1RAs may exert their cardioprotective effects through anti-atherosclerotic mechanisms. The atherosclerotic process is complex and strongly associated with inflammation. Treatment with oral semaglutide led to a greater reduction in the inflammatory marker C-reactive protein compared to the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) empagliflozin, without any difference in reduction in body weight between compounds (28). Findings from animal studies suggest that GLP-1R activation may promote anti-arteriosclerotic mechanisms inducing plaque stabilisation and preventing plaque progression (29, 30, 31, 32, 33). Interestingly, GLP-1RA treatment is associated with small reductions in systolic blood pressure, which seem independent of GLP-1RA-induced weight loss (34). This effect is thought to be mediated by increasing natriuresis (35) and vasorelaxation in the renal vasculature (36). In addition, GLP-1RAs increase heart rate in humans, most likely via the GLP-1R located in the sinoatrial node of the heart (37) and perhaps also via activation of the sympathetic nervous system and inhibition of the parasympathetic nervous system as shown in animals studies (38, 39). The increase in heart rate observed in patients treated with GLP-1RAs has led to cautious use of GLP-1RAs in patients with congestive HF New York Heart Associations (NYHA) class IV. In the abovementioned meta-analysis by Kristensen _et al._ (15), a sub-analysis found that GLP-1RAs are safe in patients with HF and in fact reduces their risk of hospitalisation for HF. 

![Figure 3](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

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![Figure 3](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

Figure 3

Possible cardiovascular actions of glucagon-like peptide 1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs).

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### Renal complications

Diabetic kidney disease is a complication of diabetes that leads to increased mortality (40). Most GLP-1RA CVOTs incorporated secondary exploratory renal endpoints. In their meta-analysis, Kristensen _et al._ found that treatment with GLP-1RA leads to a 17% reduction in a broad composite kidney endpoint (development of new-onset macroalbuminuria, doubling of serum creatinine or 40% greater decline in estimated glomerular filtration rate (eGFR), progression to end-stage kidney disease, or kidney-related death), mainly as a result of a reduction in new-onset macroalbuminuria (15). Ongoing trials will determine if liraglutide (41), lixisenatide (ELIXIRS trial) (42) and semaglutide (FLOW trial) (43) reduce dialysis rates and reduce worsening kidney function in people with diabetic kidney disease. The potential nephroprotective mechanisms of GLP-1RAs likely involve GLP-1RA-mediated improvements of conventional risk factors for diabetic kidney disease (control of glycaemia, postprandial lipid level, body weight and blood pressure), but perhaps also direct effects on the kidneys. The exact anatomical location of the GLP-1RA in the human kidney is debated, but the consent is that the GLP-1R is expressed in the renal afferent arterioles, whereas the presence of GLP-1Rs in the renal glomeruli and proximal tubuli remains uncertain (44, 45). Chronic administration of GLP-1RAs have been suggested to affect renal haemodynamic by decreasing eGFR and ameliorating glomerular hyperfiltration in patients with T2D. In addition, GLP-1RAs may have anti-albuminuria actions by increasing natriuresis and decreasing plasma renin activity (46). In addition, the positive effects of GLP-1RA on oxidative stress and inflammation may also contribute to the nephroprotective mechanisms of GLP-1RAs (47, 48).

### Ophthalmic complications

The ELIXA, EXSCEL, HARMONY outcomes and PIONEER-6 trials did not include retinopathy as an outcome. In the SUSTAIN-6 trial, there was a significantly higher event rate of diabetic retinopathy in the semaglutide-treated group compared with the control (49). During the first month of the trial, most events coincided with a rapid and massive drop in HbA1c in dysregulated patients with pre-existing retinopathy. A recent CVOT meta-analysis showed that the magnitude of HbA1c reduction was correlated with retinopathy risk and was not associated with GLP-1RA treatment _per se_ (50). However, a direct and unknown action of GLP-1RAs cannot be excluded. The ongoing FOCUS trial investigates the long-term effects of semaglutide compared with placebo on diabetic retinopathy, including relatively well-regulated (HbA1c 7–10%) patients with T2D (51).

## Treatment with GLP-1RAs for other indications than T2D and obesity

### Liver diseases

Non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH) is highly prevalent in patients with T2D and/or obesity. Currently, there are no FDA-approved treatments for NASH. In a recent phase II trial, patients with liver biopsy-confirmed NASH and liver fibrosis were treated once daily with 0.4 mg s.c. semaglutide for 72 weeks. A higher percentage of patients treated with semaglutide had resolution of NASH than with placebo; however, no improvement in fibrosis was found (52). These results are in line with previous findings on the effect of GLP-1RAs on NASH (53, 54). As the GLP-1R is not expressed on human hepatocytes, the GLP-1RA-mediated effects on fatty liver are probably indirectly mediated through GLP-1RA-induced weight loss and ensuing improvement in insulin resistance, and, potentially, anti-inflammatory effects associated with GLP-1RA treatment (29). Integrating the actions of GLP-1 with other receptor agonists is emerging as a potential new drug class with pharmaceutical potential in treating, for example, liver diseases. The potential of GLP-1/glucagon dual receptor agonist on steatohepatitis, fibrosis and liver regeneration has also shown some promising results in clinical studies (55) and may have a therapeutic potential in NAFLD. In addition, combining semaglutide with cilofexor, a farnesoid X receptor agonist, and/or firsocostat, an acetyl-CoA carboxylase inhibitor, has also shown potential in preclinical studies. Unpublished results from the first phase II trial with the triple combination of semaglutide, cilofexor and/or firsocostat treatment for 24 weeks in 108 patients with NASH showed significant improvements in hepatic steatosis (measured with MRI) and liver injury (measured by serum alanine aminotransferase) in the combination treatment arm vs semaglutide monotherapy (56).

### Type 1 diabetes

By exploiting GLP-1’s glucose-dependent glucagonostatic effect and its inhibiting effect on gastric emptying, treatment with GLP-1RAs could supplement insulin treatment in patients with type 1 diabetes (T1D). Liraglutide (57, 58, 59) and short-acting exenatide (60) have been studied in placebo-controlled trials as an add-on to treatment with insulin in patients with T1D. Liraglutide significantly reduced HbA1c and body weight but caused more hypoglycaemic incidents and a slight increase in ketoacidosis in one trial (57). Treatment with short-acting exenatide leads to a minor reduction in HbA1c and significantly reduced body weight without increasing hypoglycaemia or ketoacidosis (60). Thus, no convincing data support the general use of GLP-1RAs as adjuvant therapy in patients with T1D. Still, with the right combination and timing with insulin, treatment with GLP-1RAs may have the potential of reducing HbA1c, postprandial glycaemic excursions, insulin dose, body weight, and frequency of hypoglycaemic episodes, especially in obese patients with T1D (61).

### Neurodegenerative diseases

T2D is a risk factor for cognitive dysfunction and for developing Alzheimer’s disease (62). In rodents, modulation of GLP-1R activity can influence amyloid-beta peptide aggregation in Alzheimer’s disease (63) and dopamine levels in Parkinson's disease (64). Impaired insulin signalling has been proposed to contribute to the development of Alzheimer’s disease (65). GLP-1RAs have shown some neuroprotective effects in rodents with neurogenerative diseases (65). In a pilot study, treatment with liraglutide increased glucose utilisation in the brain as detected by (18)F-fluorodeoxyglucose(18FDG)-positron emission tomographyPET (PET) scans (66). However, the study was underpowered to make any conclusions on amyloid plaques and cognitive outcome. A phase II study investigating the efficacy and safety of liraglutide in 200 patients with Alzheimer’s disease has recently been completed (67) but remains unpublished. Recently, it was announced that a phase III trial investigating whether oral semaglutide can prevent progression in patients with early Alzheimer’s disease is to be initiated in 2021 (68). In Parkinson’s disease, treatment with exenatide once weekly for 12 months has improved motor symptoms (69). Currently, two ongoing phase II trials investigate the effect of semaglutide (70) and liraglutide (71) on motor symptom progression. Also, one study is evaluating the effect of exenatide once weekly on Parkinson’s disease progression by MRI (72). Even though clinical trials have shown some positive results on motor function in patients with Parkinson's disease treated with exenatide (73), a recent Cochrane review found 'low-certainty evidence that exenatide improves motor impairment' in patients with Parkinson’s disease (74). Further research is needed to elucidate the role of GLP-1RAs in the treatment of neurodegenerative diseases.

## Safety

The most frequently reported side effects of GLP-1RAs are of gastrointestinal (GI) origin, including nausea, vomiting, diarrhoea and obstipation and may be more common in patients with higher age, lower body weight, renal impairment, and if there is a history or currently smoking (75). GI adverse events are usually mild or moderate, dose-dependent, decline with continued treatment and do not affect glycaemic control. GLP-1RA therapy has previously been linked to acute pancreatitis and pancreatic cancer. However, meta-analyses do not support such an association (76, 77), and an increase in amylase and/or lipase levels may be detected (78). When using GLP-1RAs in patients with risk factors for pancreatitis, such as hypertriglyceridaemia or excessive alcohol use, or in persons with previously diagnosed pancreatitis, great caution is recommended. Since the incidence of cholelithiasis and cholecystitis were higher in patients treated with liraglutide (79), concerns about GLP-1RA and gallbladder adverse events have been raised. In the recent STEP 1 trial investigating the body weight-lowering effect of s.c. semaglutide 2.4 mg once weekly in patients with obesity, gallbladder-related disorders (mostly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively (80). Treatment with GLP-1RAs may affect gallbladder motility and thereby prolong gallbladder refilling (81), which perhaps explains the increase in gallbladder adverse events associated with GLP-1RAs.

## Perspectives

Enthused by the results after bariatric surgery where multiple gut hormones are increased (82), peptide multi-agonists are emerging and have shown promising results. By targeting appetite reduction and energy expenditure with dual or triple agonists, it may be possible to pharmacologically mimic the effects seen with bariatric surgery to produce 30–40% body weight reduction, diabetes remission and CV benefits (83, 84). The dual GLP-1R and GIP receptor agonist tirzepatide is administrated once weekly and under development for the treatment of T2D, obesity (85) and NASH (86). In a phase II trial, tirzepatide once weekly was superior to dulaglutide in terms of HbA1c reduction and body weight reduction in patients with T2D with safety data for tirzepatide similar to that of GLP-1RAs (87). Results from the phase III trial (SURPASS 2) investigating the effects of 40 weeks of treatment with tirzepatide vs s.c. semaglutide in patients with T2D have recently been announced, with tirzepatide 15 mg reducing HbA1c levels by 2.46% and body weight reduction by 12.4 kg (13.1%), double the body weight reduction compared to those taking semaglutide 1 mg (88). Tirzepatide has been superior in reducing glycaemia and body weight compared to the GLP-1RA drug class, appearing that GIP adds effectiveness to GLP-1 agonism. CV safety of treatment with tirzepatide in patients with T2D compared to dulaglutide is to be investigated in the SURPASS-CVOT phase III clinical trial scheduled to finish in 2024 (89).

In addition, several dual GLP-1R-glucagon receptor co-agonists are under development, and their therapeutic potential for the treatment of T2D and obesity is being investigated in clinical trials (55, 90, 91, 92). Also, the combination of GLP-1RA with cholecystokinin (CCK) and fibroblast growth factor 21 (FGF21) has been studied in preclinical settings (93, 94). CCK has shown potential in reducing body weight in combination with GLP-1RAs in the mouse models (93). FGF21 is a newly discovered metabolic hormone produced in multiple tissues and secreted in the fasting state and regulates metabolic responses in the pancreas, liver and adipose tissues (95). FGF21 has thermogenic and insulin-sensitising effects when combined with a GLP-1RA with elastin-like polypeptide (ELP) as a flexible linker (94). In a diabetic mouse model, administration of GLP-1RA-ELP-FGF21 reduced glycaemia without incidences of hypoglycaemia and greater body weight reductions compared with the monotherapy or an equimolar mixture of GLP1-ELP and ELP-FGF21 (94). In summary, the combination of GLP-1RAs with other GI peptide receptor agonists appears to amplify the effects of GLP-1R activation, and these combinations are currently being investigated in preclinical and clinical studies, not only for the treatment of T2D but also for the treatment of other metabolic disorders.

## Conclusion

Over the last decades, extensive preclinical and clinical research have revealed the complexity of the (patho-)physiology of GLP-1 in health and disease. This research and knowledge related to the mode of action have been successfully translated into clinical pharmacology and have been and are a game-changer in T2D and, to some extent, in obesity. GLP-1RAs represent an important drug class for the treatment of T2D and offer marked reductions in plasma glucose levels with a low risk of hypoglycaemia, body weight reductions and a reduction in CVD in patients with high CVD risk. Based on the CVOTs, the treatment algorithm of T2D has changed to include GLP-1RAs independent of glycaemia in patients with established CVD or high-risk (96). Ongoing studies explore the potential of CV, renal and neuroprotective benefits of GLP-1RAs and the potential of using GLP-1RAs for other indications, including NASH, neurodegenerative diseases, and T1D. In addition, emerging dual agonists combing the effects of GLP-1RAs with other peptides have shown a huge potential of superior effects on glycaemia and body weight in patients with T2D compared to currently available peptides. Investigating the physiological and cellular interactions of multi-peptide receptor agonist combinations could further elucidate the therapeutic potential as well as minimising unwanted action or adverse events. Future multi-peptide receptor agonist compounds could potentially target selected organ tissues offering an individualised therapy for a variety of diseases.

## Declaration of interest

C R A and A A declare no conflicts of interest. F K K has served on scientific advisory panels and/or been part of speaker’s bureaus, served as a consultant to and/or received research support from Amgen, AstraZeneca, Bayer Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi and Zealand Pharma. M M R is a minority shareholder of and consultant for Antag Therapeutics, Bainan Biotech and Synklino. T V has served on scientific advisory panels, been part of speaker’s bureaus, served as a consultant to and/or received research support from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Gilead, Mundipharma, MSD/Merck, Novo Nordisk, Sanofi and Sun Pharmaceuticals. All authors declare that the study was conducted in the absence of any financial or conflicts of interest.

## Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

## 

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Hare KJVilsbøll TAsmar MDeacon CFKnop FKHolst JJ. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes 2010 59 1765–1770. (https://doi.org/10.2337/db09-1414))| false

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Drucker DJBuse JBTaylor KKendall DMTrautmann MZhuang DPorter L & DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 2008 372 1240–1250. (https://doi.org/10.1016/S0140-6736(0861206-4))| false

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Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD & Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. _Diabetes Care_ 2004 27 2628–2635. (<https://doi.org/10.2337/diacare.27.11.2628>)

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Buse JBHenry RRHan JKim DDFineman MSBaron AD & Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004 27 2628–2635. (https://doi.org/10.2337/diacare.27.11.2628))| false

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Frias JP, Bonora E, Nevarez Ruiz L, Li YG, Yu Z, Milicevic Z, Malik R, Bethel MA, Cox DA. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). _Diabetes Care_ 2021 44 765–773. (<https://doi.org/10.2337/dc20-1473>)

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Frias JPBonora ENevarez Ruiz LLi YGYu ZMilicevic ZMalik RBethel MACox DA. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care 2021 44 765–773. (https://doi.org/10.2337/dc20-1473))| false

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Lingvay I, Hansen T, MacUra S, Marre M, Nauck MA, De La Rosa R, Woo V, Yildirim E, Wilding J. Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events. _BMJ Open Diabetes Research and Care_ 2020 8 1–9. (<https://doi.org/10.1136/bmjdrc-2020-001706>)

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Lingvay IHansen TMacUra SMarre MNauck MADe La Rosa RWoo VYildirim EWilding J. Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events. BMJ Open Diabetes Research and Care 2020 8 1–9. (https://doi.org/10.1136/bmjdrc-2020-001706))| false

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Gabery S, Salinas CG, Paulsen SJ, Ahnfelt-Rønne J, Alanentalo T, Baquero AF, Buckley ST, Farkas E, Fekete C & Frederiksen KS et al.Semaglutide lowers body weight in rodents via distributed neural pathways. _JCI Insight_ 2020 5 e133429. (<https://doi.org/10.1172/jci.insight.133429>)

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Blundell J, Finlayson G, Axelsen M, Flint A, Gibbons C, Kvist T, Hjerpsted JB. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. _Diabetes, Obesity and Metabolism_ 2017 19 1242–1251. (<https://doi.org/10.1111/dom.12932>)

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Blundell JFinlayson GAxelsen MFlint AGibbons CKvist THjerpsted JB. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes, Obesity and Metabolism 2017 19 1242–1251. (https://doi.org/10.1111/dom.12932))| false

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A heart disease study of semaglutide in patients with type 2 diabetes (SOUL). (available at: <https://clinicaltrials.gov/ct2/show/NCT03914326>)

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Ceriello A, Novials A, Canivell S, Sala L, La, Pujadas G, Esposito K, Testa R, Bucciarelli L, Rondinelli M, Genovese S. Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinf lammatory and antioxidant action in type 2 diabetes. _Diabetes Care_ 2014 37 1938–1943.(<https://doi.org/10.2337/dc13-2618>)

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Ceriello ANovials ACanivell SSala LLaPujadas GEsposito KTesta RBucciarelli LRondinelli MGenovese S. Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinf lammatory and antioxidant action in type 2 diabetes. Diabetes Care 2014 37 1938–1943.(https://doi.org/10.2337/dc13-2618))| false

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Ceriello A, Novials A, Ortega E, Canivell S, La Sala L, Pujadas G, Esposito K, Giugliano D, Genovese S. Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes. _Diabetes Care_ 2013 36 2346–2350. (<https://doi.org/10.2337/dc12-2469>)

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Ceriello ANovials AOrtega ECanivell SLa Sala LPujadas GEsposito KGiugliano DGenovese S. Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Diabetes Care 2013 36 2346–2350. (https://doi.org/10.2337/dc12-2469))| false

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Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg SØ, Lingvay I, Søndergaard AL, Treppendahl MB & Montanya E et al.Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the Pioneer 2 trial. _Diabetes Care_ 2019 42 2272–2281. (<https://doi.org/10.2337/dc19-0883>)

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Rodbard HWRosenstock JCanani LHDeerochanawong CGumprecht JLindberg SØLingvay ISøndergaard ALTreppendahl MBMontanya E Oral semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin: the Pioneer 2 trial. Diabetes Care 2019 42 2272–2281. (https://doi.org/10.2337/dc19-0883))| false

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Li QTuo XLi BDeng ZQiu YXie H. Semaglutide attenuates excessive exercise-induced myocardial injury through inhibiting oxidative stress and inflammation in rats. Life Sciences 2020 250 117531. (https://doi.org/10.1016/j.lfs.2020.117531))| false

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Sudo M, Li Y, Hiro T, Takayama T, Mitsumata M, Shiomi M, Sugitani M, Matsumoto T, Hao H, Hirayama A. Inhibition of plaque progression and promotion of plaque stability by glucagon-like peptide-1 receptor agonist: serial in vivo findings from iMap-IVUS in Watanabe heritable hyperlipidemic rabbits. _Atherosclerosis_ 2017 265 283–291. (<https://doi.org/10.1016/j.atherosclerosis.2017.06.920>)

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Lovshin JA, Barnie A, DeAlmeida A, Logan A, Zinman B, Drucker DJ. Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes. _Diabetes Care_ 2015 38 132–139. (<https://doi.org/10.2337/dc14-1958>)

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Lovshin JABarnie ADeAlmeida ALogan AZinman BDrucker DJ. Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes. Diabetes Care 2015 38 132–139. (https://doi.org/10.2337/dc14-1958))| false

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Jensen EP, Poulsen SS, Kissow H, Holstein-Rathlou NH, Deacon CF, Jensen BL, Holst JJ, Sorensen CM. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow. _American Journal of Physiology: Renal Physiology_ 2015 308 F867–F877. (<https://doi.org/10.1152/ajprenal.00527.2014>)

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Jensen EPPoulsen SSKissow HHolstein-Rathlou NHDeacon CFJensen BLHolst JJSorensen CM. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow. American Journal of Physiology: Renal Physiology 2015 308 F867–F877. (https://doi.org/10.1152/ajprenal.00527.2014))| false

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Baggio LLYusta BMulvihill EECao XStreutker CJButany JCappola TPMargulies KBDrucker DJ. GLP-1 receptor expression within the human heart. Endocrinology 2018 159 1570–1584. (https://doi.org/10.1210/en.2018-00004))| false

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Yamamoto H, Lee CE, Marcus JN, Williams TD, Michael Overton JM, Lopez ME, Hollenberg AN, Baggio L, Saper CB & Drucker DJ et al.Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. _Journal of Clinical Investigation_ 2002 110 43–52. (<https://doi.org/10.1172/JCI15595>)

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A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease (FLOW). (available at: <https://clinicaltrials.gov/ct2/show/NCT03819153>)

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Valdecantos MP, Pardo V, Ruiz L, Castro-Sánchez L, Lanzón B, Fernández-Millán E, García-Monzón C, Arroba AI, González-Rodríguez Á & Escrivá F et al.A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice. _Hepatology_ 2017 65 950–968. (<https://doi.org/10.1002/hep.28962>)

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Mathieu C, Zinman B, Hemmingsson JU, Woo V, Colman P, Christiansen E, Linder M, Bode B & ADJUNCT ONE Investigators. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: the adjunct one treat-to-target randomized trial. _Diabetes Care_ 2016 39 1702–1710. (<https://doi.org/10.2337/dc16-0691>)

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Storgaard H, Cold F, Gluud LL, Vilsbøll T, Knop FK. Glucagon-like peptide-1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes. _Diabetes, Obesity and Metabolism_ 2017 19 906–908. (<https://doi.org/10.1111/dom.12885>)

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Storgaard HCold FGluud LLVilsbøll TKnop FK. Glucagon-like peptide-1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes. Diabetes, Obesity and Metabolism 2017 19 906–908. (https://doi.org/10.1111/dom.12885))| false

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Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MALEADER Steering Committee & LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treatedwith liraglutide: results from the LEADER randomized trial. _Diabetes Care_ 2017 40 966–972. (<https://doi.org/10.2337/dc16-2747>)

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Steinberg WMBuse JBGhorbani MLMØrsted DDNauck MALEADER Steering Committee & LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treatedwith liraglutide: results from the LEADER randomized trial. Diabetes Care 2017 40 966–972. (https://doi.org/10.2337/dc16-2747))| false

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Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, Andreasen AH, Jensen CB, DeFronzo RA & NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. _JAMA_ 2015 314 687–699. (<https://doi.org/10.1001/jama.2015.9676>)

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Davies MJBergenstal RBode BKushner RFLewin ASkjøth TVAndreasen AHJensen CBDeFronzo RA & NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA 2015 314 687–699. (https://doi.org/10.1001/jama.2015.9676))| false

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Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD & Wadden TA et al.Once-weekly semaglutide in adults with overweight or obesity. _New England Journal of Medicine_ 2021 384 989. (<https://doi.org/10.1056/NEJMoa2032183>)

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Wilding JPHBatterham RLCalanna SDavies MVan Gaal LFLingvay IMcGowan BMRosenstock JTran MTDWadden TA Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine 2021 384 989. (https://doi.org/10.1056/NEJMoa2032183))| false

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Gether IM, Nexøe-Larsen C, Knop FK. New avenues in the regulation of gallbladder motility – implications for the use of glucagon-like peptide-derived drugs. _Journal of Clinical Endocrinology and Metabolism_ 2019 104 2463–2472. (<https://doi.org/10.1210/jc.2018-01008>)

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Holst JJ, Madsbad S, Bojsen-Møller KN, Svane MS, Jørgensen NB, Dirksen C, Martinussen C. Mechanisms in bariatric surgery: gut hormones, diabetes resolution, and weight loss. _Surgery for Obesity and Related Diseases_ 2018 14 708–714. (<https://doi.org/10.1016/j.soard.2018.03.003>)

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Hasib A Multiagonist unimolecular peptides for obesity and Type 2 diabetes: current advances and future directions. _Clinical Medicine Insights: Endocrinology and Diabetes_ 2020 13 1179551420905844. (<https://doi.org/10.1177/1179551420905844>)

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A study of Tirzepatide (LY3298176) in participants with obesity or overweight (SURMOUNT-1). (available at: <https://clinicaltrials.gov/ct2/show/NCT04184622>)

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A study of Tirzepatide (LY3298176) in participants with nonalcoholic steatohepatitis (NASH) (SYNERGY-NASH). (available at: <https://clinicaltrials.gov/ct2/show/NCT04166773>)

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A study of Tirzepatide (LY3298176) in participants with nonalcoholic steatohepatitis (NASH) (SYNERGY-NASH). (available at: https://clinicaltrials.gov/ct2/show/NCT04166773))| false

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Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, Milicevic Z, Haupt A, Robins DA. Dual GIP and GLP-1 receptor agonist Tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes. _Journal of Clinical Endocrinology and Metabolism_ 2021 106 388–396. (<https://doi.org/10.1210/clinem/dgaa863>)

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Thomas MKNikooienejad ABray RCui XWilson JDuffin KMilicevic ZHaupt ARobins DA. Dual GIP and GLP-1 receptor agonist Tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 2021 106 388–396. (https://doi.org/10.1210/clinem/dgaa863))| false

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Tirzepatide achieved superior A1C and body weight reductions across all three doses compared to injectable semaglutide in adults with type 2 diabetes|Eli Lilly and Company. (available at: <https://investor.lilly.com/news-releases/news-release-details/tirzepatide-achieved-superior-a1c-and-body-weight-reductions>)

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Tirzepatide achieved superior A1C and body weight reductions across all three doses compared to injectable semaglutide in adults with type 2 diabetes|Eli Lilly and Company. (available at: https://investor.lilly.com/news-releases/news-release-details/tirzepatide-achieved-superior-a1c-and-body-weight-reductions))| false

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A study of Tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with Type 2 diabetes (SurPASS-CVOT). (available at: <https://clinicaltrials.gov/ct2/show/NCT04255433>)

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A study of Tirzepatide (LY3298176) compared with dulaglutide on major cardiovascular events in participants with Type 2 diabetes (SurPASS-CVOT). (available at: https://clinicaltrials.gov/ct2/show/NCT04255433))| false

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Visentin R, Schiavon M, Göbel B, Riz M, Cobelli C, Klabunde T, Dalla Man C. Dual glucagon-like peptide-1 receptor/glucagon receptor agonist SAR425899 improves beta-cell function in type 2 diabetes. _Diabetes, Obesity and Metabolism_ 2020 22 640–647. (<https://doi.org/10.1111/dom.13939>)

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Visentin RSchiavon MGöbel BRiz MCobelli CKlabunde TDalla Man C. Dual glucagon-like peptide-1 receptor/glucagon receptor agonist SAR425899 improves beta-cell function in type 2 diabetes. Diabetes, Obesity and Metabolism 2020 22 640–647. (https://doi.org/10.1111/dom.13939))| false

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Parker VER, Robertson D, Wang T, Hornigold DC, Petrone M, Cooper AT, Posch MG, Heise T, Plum-Moerschel L & Schlichthaar H et al.Efficacy, safety, and mechanistic insights of cotadutide, a dual receptor glucagon-like peptide-1 and glucagon agonist. _Journal of Clinical Endocrinology and Metabolism_ 2020 105 803–820. (<https://doi.org/10.1210/clinem/dgz047>)

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Parker VERRobertson DWang THornigold DCPetrone MCooper ATPosch MGHeise TPlum-Moerschel LSchlichthaar H Efficacy, safety, and mechanistic insights of cotadutide, a dual receptor glucagon-like peptide-1 and glucagon agonist. Journal of Clinical Endocrinology and Metabolism 2020 105 803–820. (https://doi.org/10.1210/clinem/dgz047))| false

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A study to evaluate the efficacy and safety of MEDI0382 in the treatment of overweight and obese subjects with type 2 diabetes. (available at: <https://clinicaltrials.gov/ct2/show/results/NCT03235050>)

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Hornigold DC, Roth E, Howard V, Will S, Oldham S, Coghlan MP, Blouet C, Trevaskis JL. A GLP-1:CCK fusion peptide harnesses the synergistic effects on metabolism of CCK-1 and GLP-1 receptor agonism in mice. _Appetite_ 2018 127 334–340. (<https://doi.org/10.1016/j.appet.2018.05.131>)

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Gilroy CA, Capozzi ME, Varanko AK, Tong J, D’Alessio DA, Campbell JE, Chilkoti A. Sustained release of a GLP-1 and FGF21 dual agonist from an injectable depot protects mice from obesity and hyperglycemia. _Science Advances_ 2020 6 eaaz9890. (<https://doi.org/10.1126/sciadv.aaz9890>)

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Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O & Pedersen SD et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. _New England Journal of Medicine_ 2019 381 841–851. (<https://doi.org/10.1056/NEJMoa1901118>)

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Husain MBirkenfeld ALDonsmark MDungan KEliaschewitz FGFranco DRJeppesen OKLingvay IMosenzon OPedersen SD Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine 2019 381 841–851. (https://doi.org/10.1056/NEJMoa1901118))| false

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Online ISSN: 
     2049-3614 

######  Related Articles 

######  Sections 

  * Keywords
  * Introduction
  * Currently available GLP-1RAs
    * Short-acting GLP-1RAs
    * Long-acting GLP-1RAs
  * Effects of GLP-1RAs in type 2 diabetes
    * Glycaemia and body weight
    * GLP-1RAs and CVOTs
    * Cardioprotective mechanisms of action
    * Renal complications
    * Ophthalmic complications
  * Treatment with GLP-1RAs for other indications than T2D and obesity
    * Liver diseases
    * Type 1 diabetes
    * Neurodegenerative diseases
  * Safety
  * Perspectives
  * Conclusion
  * Declaration of interest
  * Funding
  * References



######  Article Information 

Copyright: 
     © The authors 2021 

Article Type: 
     Review Article 

Received Date: 
     26 May 2021 

Accepted Date: 
     16 Jun 2021 

Online Publication Date: 
     17 Jul 2021 

Keywords: 
     [diabetes](/search?q="diabetes"); [cardiovascular](/search?q="cardiovascular"); [metabolism](/search?q="metabolism"); [inflammation](/search?q="inflammation"); [obesity](/search?q="obesity")

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######  Figures 

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  * ![Figure 1](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

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Figure 1 

Possible actions of glucagon-like peptide 1 (GLP-1) and the GLP-1 receptor agonists (GLP-1RAs) on various tissue. The applied colour code indicates whether the effect on the target tissue has been observed in preclinical studies (blue boxes), at physiological levels of GLP-1 in clinical studies (green boxes) or after treatment with GLP-1RAs (red boxes) (1, 2). The figure illustrates GLP-1 (7–36) amide.

  * ![Figure 2](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

[View in gallery ](/view/journals/ec/10/7/images/full-EC-21-0130fig2.jpeg "View in gallery")

Figure 2 

Results from clinical trials comparing the GLP-1 receptor agonists (GLP-1RAs) head-to-head in phase III trials. Left panels are trials comparing short-acting GLP-1RAs (97). Middle panels are trials comparing a short-acting GLP-1RA with a long-acting GLP-1RA (7, 98, 99, 100). Right panel are trials comparing long-acting GLP-1RAs (101, 102, 103, 104, 105, 106). Asterisk (*) represents significant differences when comparing the GLP-1RAs.

  * ![Figure 3](/skin/76726910b25e97d9f403ed1616f57a24fd3e46ff/img/Blank.svg)

[View in gallery ](/view/journals/ec/10/7/images/full-EC-21-0130fig3.jpeg "View in gallery")

Figure 3 

Possible cardiovascular actions of glucagon-like peptide 1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs).




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  * [View raw image](/view/journals/ec/10/7/images/full-EC-21-0130fig1.jpeg)

**Figure 1**

Possible actions of glucagon-like peptide 1 (GLP-1) and the GLP-1 receptor agonists (GLP-1RAs) on various tissue. The applied colour code indicates whether the effect on the target tissue has been observed in preclinical studies (blue boxes), at physiological levels of GLP-1 in clinical studies (green boxes) or after treatment with GLP-1RAs (red boxes) (1, 2). The figure illustrates GLP-1 (7–36) amide.

  * [View raw image](/view/journals/ec/10/7/images/full-EC-21-0130fig2.jpeg)

**Figure 2**

Results from clinical trials comparing the GLP-1 receptor agonists (GLP-1RAs) head-to-head in phase III trials. Left panels are trials comparing short-acting GLP-1RAs (97). Middle panels are trials comparing a short-acting GLP-1RA with a long-acting GLP-1RA (7, 98, 99, 100). Right panel are trials comparing long-acting GLP-1RAs (101, 102, 103, 104, 105, 106). Asterisk (*) represents significant differences when comparing the GLP-1RAs.

  * [View raw image](/view/journals/ec/10/7/images/full-EC-21-0130fig3.jpeg)

**Figure 3**

Possible cardiovascular actions of glucagon-like peptide 1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs).

![](/view/journals/ec/10/7/images/inline-EC-21-0130fig1.jpeg)

![](/view/journals/ec/10/7/images/inline-EC-21-0130fig2.jpeg)

![](/view/journals/ec/10/7/images/inline-EC-21-0130fig3.jpeg)

######  References 

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Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L & DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. _Lancet_ 2008 372 1240–1250. (<https://doi.org/10.1016/S0140-6736(0861206-4>)

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Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, Køber L, Petrie MC, McMurray JJV. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. _Lancet: Diabetes and Endocrinology_ 2019 7 776–785. (<https://doi.org/10.1016/S2213-8587(1930249-9>)

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Kristensen SLRørth RJhund PSDocherty KFSattar NPreiss DKøber LPetrie MCMcMurray JJV. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet: Diabetes and Endocrinology 2019 7 776–785. (https://doi.org/10.1016/S2213-8587(1930249-9))| false

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Fujioka KO’Neil PMDavies MGreenway FC W Lau DClaudius BSkjøth TVBjørn Jensen CP H Wilding J. Early weight loss with liraglutide 3.0 mg predicts 1-year weight loss and is associated with improvements in clinical markers. Obesity 2016 24 2278–2288. (https://doi.org/10.1002/oby.21629))| false

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Frias JPBonora ENevarez Ruiz LLi YGYu ZMilicevic ZMalik RBethel MACox DA. Efficacy and safety of dulaglutide 3.0 mg and 4.5 mg versus dulaglutide 1.5 mg in metformin-treated patients with type 2 diabetes in a randomized controlled trial (AWARD-11). Diabetes Care 2021 44 765–773. (https://doi.org/10.2337/dc20-1473))| false

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Lingvay IHansen TMacUra SMarre MNauck MADe La Rosa RWoo VYildirim EWilding J. Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events. BMJ Open Diabetes Research and Care 2020 8 1–9. (https://doi.org/10.1136/bmjdrc-2020-001706))| false

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Ceriello ANovials ACanivell SSala LLaPujadas GEsposito KTesta RBucciarelli LRondinelli MGenovese S. Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinf lammatory and antioxidant action in type 2 diabetes. Diabetes Care 2014 37 1938–1943.(https://doi.org/10.2337/dc13-2618))| false

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Ceriello ANovials AOrtega ECanivell SLa Sala LPujadas GEsposito KGiugliano DGenovese S. Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Diabetes Care 2013 36 2346–2350. (https://doi.org/10.2337/dc12-2469))| false

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Evaluating liraglutide in Alzheimer’s disease (ELAD). (Available at: <https://clinicaltrials.gov/ct2/show/NCT01843075>)

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Ahmann AJCapehorn MCharpentier GDotta FHenkel ELingvay IHolst AGAnnett MPAroda VR. Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care 2018 41 258–266. (https://doi.org/10.2337/dc17-0417))| false

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Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O & Pedersen SD et al.Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. _New England Journal of Medicine_ 2019 381 841–851. (<https://doi.org/10.1056/NEJMoa1901118>)

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