Exenatide

Risk factors for drug-related impaired gastric emptying: a pharmacovigilance analysis of the FDA adverse event reporting system.

Jie-Hai Chen, Jia-Cong Chen, Ya-Jing Mei +3 more

Pulmonary aspiration remains a major perioperative patient safety issue. Drug-related impaired gastric emptying (IGE) is a recognized yet underappreciated risk factor for aspiration. With the increasing use of medications such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), concerns have grown regarding their potential to delay gastric emptying and thereby elevate aspiration risk. However, real-world data on drug-related IGE remain limited.

Acute glucagon-like peptide-1 receptor agonist, semaglutide, attenuates cue-, drug-, and stress-induced fentanyl seeking in male Sprague-Dawley rats.

Brianna Evans, Nikhil Acharya, Christopher G Brandl +5 more

Opioid overdose deaths continue to be a significant public health problem worldwide, with fentanyl, the primary driver of these losses of life. Indeed, in the USA, overdose deaths continue despite the availability of three food and drug administration-approved medications for the treatment of opioid use disorder (OUD) due to minimal access to these medications and to stigma. Fortunately, a growing preclinical and clinical literature suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists may serve as new treatments for OUD. Exendin-4/exenatide and liraglutide have been found to reduce opioid intake, cravings, and cue-, drug-, and stress-induced opioid seeking. While these are important findings, exenatide has a higher risk of gastrointestinal distress and, due to its short half-life, requires multiple daily injections for treatment. Liraglutide has a longer half-life, is less likely than exenatide to cause gastrointestinal distress, but still requires daily injections, which many patients find objectionable. Semaglutide, on the other hand, is a GLP-1R agonist with a longer half-life that requires once weekly injections in humans. Some evidence suggests that semaglutide can reduce responding for alcohol, but it is not known whether it can reduce responding for opioids. Here we test whether acute treatment with semaglutide at 0.026, 0.056, and 0.078 mg/kg administered subcutaneously can reduce cue-, drug-, and stress-induced fentanyl seeking in rats. Results show that all doses of semaglutide fully prevented drug- and stress-induced reinstatement of fentanyl seeking elicited by an i.v. infusion of 1.85 µg/kg fentanyl or the i.p. administration of 0.5 mg/kg yohimbine, respectively, while the mid (0.056 mg/kg) and higher doses (0.078 mg/kg) most effectively reduced cue-induced fentanyl seeking. These findings suggest that semaglutide may serve as an additional nonopioid GLP-1R agonist for the treatment of OUD.

The GLP-1 agonist exenatide is associated with improved adherence to health behavior and lifestyle treatment in adolescents with obesity, a randomized controlled trial.

Rasmus Stenlid, Sara Y Cerenius, Gabriel Torbahn +13 more

We aimed to study the effects of the glucagon-like peptide-1 receptor agonist exenatide on behavioral outcomes in children and adolescents with obesity.

Exendin-4 averts all-trans-retinal-driven damage to photoreceptors and the retina via the GLP-1R/PKA/CREB1 signaling axis.

Beiting He, Yuling Chen, Peixin Cai +6 more

Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL.

Semaglutide and Neovascular Age-Related Macular Degeneration Among Adults with Type 2 Diabetes: An OHDSI Network Study.

Cindy X Cai, Brian Toy, Benjamin Martin +44 more

or Purpose: To investigate the potential association of semaglutide and neovascular age-related macular degeneration (NVAMD) DESIGN: Retrospective study across 12 databases in the Observational Health Data Sciences and Informatics (OHDSI) network during the study period from 12/1/2017-12/31/2024 SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Adults with type 2 diabetes (T2D) on semaglutide, other glucagon-like peptide-1 receptor agonists (GLP-1RAs) (dulaglutide, exenatide), or non-GLP-1RAs (empagliflozin, sitagliptin, glipizide) METHODS, INTERVENTION OR TESTING: The association between semaglutide and NVAMD was assessed using two approaches: an active-comparator cohort design and a self-controlled case-series (SCCS) analysis. The cohort design used propensity score-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). A random-effects meta-analysis was used to generate network-wide HR and IRR estimates.

A Review of the Oral Semaglutide in Adults with Overweight or Obesity (OASIS) Trials Evaluating Oral Semaglutide (Wegovy) for Chronic Weight Management in Adults With Overweight or Obesity.

Blessing T Ojinna, Sara Tariq, Osamede Agho +2 more

Obesity is an increasingly growing public health issue affecting a substantial proportion of the population in the United States. This condition increases the risk for multiple disease processes, including cardiometabolic disorders, osteoarthritis, gout, respiratory issues, reproductive problems, and some cancers. Glucagon-like peptide-1 (GLP-1) receptor agonists got their first US Food and Drug Administration (FDA) approval in 2005 in the form of exenatide for type 2 diabetes mellitus (T2DM) management. Thereafter, GLP-1 analogs have been increasingly studied as a noninvasive strategy for weight reduction, and they transitioned from diabetes-only therapies to weight management with the approval of once-daily liraglutide prior to weekly semaglutide formulation in 2021. In essence, GLP-1 receptor agonists have emerged as a promising drug for long-lasting weight reduction and blood glucose control for patients with or without type 2 diabetes mellitus, surpassing traditional methods such as lifestyle changes and bariatric surgery. Oral Wegovy (Rybelsus) was approved for T2DM management in 2020; however, it is approved for weight loss after the recent publication of Oral Semaglutide in Adults with Overweight or Obesity (OASIS). This literature review will discuss and summarize weight loss results from OASIS trials 1, 2, 3, and 4. The OASIS 1 and 2 trials compared the therapeutic efficacy and clinical safety profile of once-daily oral semaglutide 50 mg versus placebo on overweight and obese participants without T2DM and both with and without T2DM, respectively. The OASIS 3 trial assessed the therapeutic efficacy and clinical safety profile of once-daily oral semaglutide 50 mg versus placebo in 200 Chinese adults who were obese and overweight with one or more weight-related comorbidities, including T2DM. The OASIS 4 trial evaluated the safety and effectiveness of once-daily semaglutide 25 mg in obese and overweight patients without T2DM. Clinical trial data and relevant literature were retrieved through database searches of the National Center for Biotechnology Information and ClinicalTrials.gov. The OASIS 1, 2, and 4 demonstrated that oral semaglutide has superior efficacy compared to placebo in body weight loss, which helped secure FDA approval for oral Wegovy. Though OASIS 3 is registered in clinical trials, the results of OASIS 3 have not been published in a peer-reviewed journal yet.

Cutaneous Variations in Stem-Cell Population in Those on GLP1-Receptor Agonists: A Comparative Controlled Study.

Maya Firsowicz, Payvand Kamrani, Raheel Zubair +3 more

Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with cutaneous changes including accelerated skin aging and volume loss. The biological mechanisms underlying these effects remain poorly understood, with limited in vivo human data.

GLPs Significantly Decrease the Risk of Postoperative Surgical Complications: A TriNetX Retrospective Cohort Study.

Marie Vu, Madelyn Schmidt, Smiti Gandhi +1 more

Glucagon-like peptide-1 (GLP) receptor agonists have demonstrated anti-inflammatory and wound-healing properties, but their impact on outcomes after dermatologic surgery has not been evaluated.

Evaluation of the safety profile of glucagon-like peptide-1 receptor agonists: a focus on thyroid cancer-related adverse events by using the European pharmacovigilance database.

Antonietta Anatriello, Valerio Liguori, Ciro Pentella +6 more

The therapeutic landscape for the treatment of type 2 diabetes mellitus (T2DM) has greatly evolved with the introduction of glucagon-like peptide-1 receptor agonists (GLP-1 RAs); however, concerns regarding their potential association with thyroid cancer have emerged. The aim of this study is to analyze individual case safety reports (ICSRs) involving GLP-1 RAs, focusing on thyroid cancer-related adverse events (AEs) using the European pharmacovigilance database.

Differential Biliary Adverse Event Signals Among Glp-1 Receptor Agonists: A FAERS Disproportionality Analysis.

Huda Alvina, Chidera N Jaffar, Abdelkader Onwuzo +2 more

Biliary adverse events (AEs) have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs), but within-class differences remain unclear.

Searching for New Pharmacological Treatments of Alcohol Use Disorder (AUD): Focus on GLP-1 Receptor Agonists.

Jolanta B Zawilska, Ewa Zwierzyńska, Jakub Wojcieszak

Alcohol use disorder (AUD) remains a crucial public health challenge worldwide. The currently available medications for AUD remain limited in the number and efficacy, meaning that the development of new treatments is of critical importance. Agonists of glucagon-like peptide-1 receptor (GLP-1RAs) have recently received attention as a potential anti-addiction treatment, particularly in AUD. This review presents data from preclinical studies in rodents and non-human primates, registered clinical trials, observational studies, and social media posts, investigating the effects of GLP-1RAs on alcohol-related behaviors and consumption. Several GLP1-RAs and tirzepatide (a dual agonist of GLP-1R and glucose-dependent insulinotropic polypeptide receptor; GIP-R) reduced alcohol consumption and alcohol-seeking behaviors, alcohol-induced locomotor stimulation and memory of alcohol reward, and suppressed relapse drinking in rodents. In addition, they prevent acute alcohol from activating the mesolimbic dopamine system. There are limited human data on the role of the GLP-1 system in AUD. In registered clinical trials, exenatide, semaglutide, and dulaglutide reduced alcohol consumption. Pharmacoepidemiologic studies documented a decreased risk of alcohol-related events in AUD patients using various GLP-1RAs and tirzepatide. Together, existing preclinical and clinical data suggest that GLP-1 is involved in the AUD process and imply the role of GLP1-RAs as a tentative treatment for AUD.

The Emerging Role of Glucagon-like Peptide 1 (GLP-1)-Based Medications in the Treatment of Heart Failure, with a Focus on Heart Failure with Preserved or Mildly Reduced Ejection Fraction.

Rachel Su Min Lee, Jas-Mine Seah, Sara Baqar +6 more

Glucagon-like Peptide 1 (GLP-1)-based medications have been extensively studied for the management of type 2 diabetes, obesity, chronic kidney disease, and atherosclerotic cardiovascular disease. More recently, their potential role in preventing and treating heart failure has gained increasing attention. Given the strong pathophysiological links among diabetes, obesity, and heart failure, GLP-1-based medications represent a promising therapeutic option to improve morbidity and mortality across these interconnected conditions. In this review, we summarise and discuss recent studies involving GLP-1-based medications that have reported on HF-related outcomes. There is increasing evidence that these medications have beneficial effects on HF outcomes in patients with heart failure with preserved ejection fraction and possibly in those with mildly reduced ejection fraction. The usefulness of GLP-1-based medications in reduced ejection fraction HF remains to be defined.

Advances in GLP-1 receptor agonists delivery systems for obesity and diabetes.

Mehrnaz Abbasi, Kai Sun, Kevin W Huggins +4 more

Obesity and diabetes are chronic metabolic diseases affecting millions worldwide. Current treatments, including lifestyle changes, medications, and surgery, face challenges like poor adherence and side effects. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended innovative medications for these conditions, with studies showing significant clinical benefits. GLP-1RAs are traditionally delivered orally or via subcutaneous injections, but these methods have limitations, including low bioavailability, poor solubility, the need for high doses, gastrointestinal side effects, and frequent dosing requirements. Novel delivery technologies offer promising strategies to overcome these challenges and enhance therapeutic effectiveness. Recent advances in drug delivery technologies, including nanocarrier- and microcarrier-based systems, hydrogels, microneedles, and innovative formulations such as long-acting, co- and/or nano-formulated agents, offer promising strategies to enhance the delivery, efficacy, and patient adherence of GLP-1RAs for obesity and diabetes. This review focuses on innovative delivery technologies developed for three main GLP-1RAs: exenatide, liraglutide, and semaglutide. We present a review of advancements in drug delivery systems, exploring technologies employed in the development of these agents, as well as future challenges. It is crucial to note that these technologies are still in early development, and further studies are needed to confirm their long-term safety, efficacy, and cost-effectiveness in clinical use.

Hemodynamic and metabolomic responses to infusion of GLP-1 agonist exenatide in pulmonary arterial hypertension.

Chinthaka B Samaranayake, Marili Niglas, Nicoleta Baxan +10 more

Preclinical studies suggest beneficial effects of GLP-1 agonists in pulmonary arterial hypertension (PAH). This first-in-disease study evaluated acute hemodynamic effects of GLP-1 agonist, exenatide administered i.v. in patients with idiopathic PAH and CTEPH as well as in a PAH rodent model. Seventeen patients (9 idiopathic PAH) received an exenatide infusion during right heart catheterization, which included multisite sampling for circulating metabolites. Acute effects of exenatide were also assessed by cardiac magnetic resonance imaging in monocrotaline (MCT) PAH and control rats. In the clinical study, exenatide was well tolerated, reduced mean pulmonary artery pressure (45 ± 15 mmHg versus 40 ± 18 mmHg), and improved cardiac index (2.1 ± 0.6 L/min versus 2.4 ± 0.9 L/min/m2) and pulmonary vascular resistance (7.8 ± 8.0 WU versus 5.9 ± 5.0 WU) across all patients. Right ventricular (RV) contractility and afterload improved in a subset of patients undergoing pressure-volume measurements. In an exploratory metabolomics analysis, 47 metabolite levels changed after exenatide infusion, predominantly in free fatty acid pathways. Six metabolites with prognostic relevance in PAH within myocardial glycolytic and lipid oxidation pathways were also altered after exenatide. In MCT rats, exenatide improved RV stroke-volume, RV ejection fraction, and RV-arterial coupling. These findings support the further evaluation of exenatide within chronic studies as a potentially novel pulmonary vasodilator therapy.

Dysesthesia associated with GLP-1 agonist therapies: data-mining analysis and literature review.

Marie-Laure Laroche, Hélène Géniaux, Manon Jardou

An increasing number of anecdotal reports on social media platforms and medical blogs describe dysesthesia, particularly burning skin sensations, in association with glucagon-like peptide-1 receptor (GLP-1R) agonists. We performed a pharmacovigilance data-mining analysis to characterise cases of dysesthesia related to GLP-1R.

Exploring the Use of GLP-1-Based Interventions for Obesity: A Qualitative Analysis of ClinicalTrials.gov Data.

Nouf M Alourfi, Nasser M Alorfi

Glucagon-like peptide-1 (GLP-1) receptor agonists are a key pharmacological target in obesity management, associated with sustained weight loss and broader metabolic benefits beyond glycaemic control.

Small-Molecule Oral Versus Injectable Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists: Comparative Efficacy, Safety, and Future Clinical Perspectives.

Digantkumar Patel

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes (T2D), obesity, and cardiometabolic disease by improving glycemic control, promoting clinically meaningful weight loss, and reducing major adverse cardiovascular events (MACE) in selected populations. Historically, GLP-1RA therapy has relied on injectable peptide agonists (e.g., liraglutide, semaglutide, dulaglutide, and exenatide), which mimic native incretin biology but require parenteral administration and cold-chain logistics. In parallel, oral GLP-1RAs have emerged through two distinct strategies: (1) the oral delivery of peptide agonists using absorption enhancers (e.g., oral semaglutide) and (2) true small-molecule, non-peptide GLP-1 receptor agonists (e.g., orforglipron), designed to be orally bioavailable without peptide constraints. This narrative review compares small-molecule oral GLP-1RAs to injectable peptide agonists across efficacy (glycated hemoglobin {HbA1c} lowering, weight reduction, and cardiometabolic outcomes), safety and tolerability (gastrointestinal {GI} adverse events, gallbladder disease, pancreatitis signals, retinopathy considerations, and rare hepatic signals), real-world adherence, and future innovation. Recent phase 3 evidence suggests that oral small-molecule GLP-1RAs can deliver glycemic and weight benefits approaching injectable standards, while high-dose oral peptide formulations may broaden oral options for obesity management. Remaining challenges include long-term outcome data, the optimization of titration to improve tolerability, and equitable access amid rapid market expansion.

Decoding the hallmarks of GLP-1RA weight-loss super-responders.

A J Venkatakrishnan, Karthik Murugadoss, Venky Soundararajan

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped obesity treatment, yet weight-loss outcomes remain highly uneven in real-world care. Using a federated biomedical platform, we analyzed 135 349 individuals treated with semaglutide and tirzepatide formulations and stratified them as "super responders" (>15% weight loss), "moderate responders" (5%-15% weight loss), "minimal weight-loss group" (<5% weight loss), and "weight regainers." Ozempic, Wegovy, Mounjaro, and Zepbound had similar proportions of patients classified as moderate responders, ranging from 40% to 42%. Rates of super responders were highest for Zepbound (34%), followed by Wegovy (26%), Mounjaro (24%), and Ozempic (10%). Among moderate and super responders, the average weight after 1 year of treatment was similar to the average weight approximately 10 and 20 years prior to treatment initiation, respectively. Compared with patients with minimal or moderate response, super responders were more likely to be younger (mean age 51 years versus 55 years), female (80% versus 58%-65%), and white (90% versus 80%). Baseline clinical characteristics enriched among super responders compared to the minimal response group included fibromyalgia (rate ratio [RR]: 0.2, P = .002) and osteoarthritis (RR = 0.5, P = .001) for Zepbound, and psoriasis (RR = 2.5, P = .03) for Wegovy. These results highlight significant heterogeneity in weight trajectories following sustained exposure to a GLP-1RA therapy and identify factors associated with increased weight loss, likely reflecting a combination of biological, behavioral, and social factors. These insights motivate further prospective analyses to help guide the development of more tailored weight-loss intervention strategies.

Comparison of IBD-related outcomes in patients with obesity treated with GLP-1 receptor agonists versus bariatric surgery.

M Housam Nanah, Arjun Chatterjee, Hisham Wehbe +1 more

The global prevalence of obesity is rising, paralleled by an increase in IBD (inflammatory bowel disease). While studies examining the impact of obesity on IBD have yielded conflicting results, some suggest that obesity may increase adverse outcomes, whereas BS (bariatric surgery) has been associated with improved IBD outcomes in patients with obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a less invasive alternative to BS for managing obesity, with recent studies indicating potential benefits for IBD outcomes. However, GLP-1 RAs have not been directly compared with BS in patients with obesity and IBD.

Effectiveness of GLP-1 Receptor Agonists in Patients With Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Sukainnya Buragohain, Indrani Sarma, Dibyajyoti Saikia +4 more

Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder, and while metformin is widely used in its management, its efficacy remains variable. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as potential alternatives due to their metabolic benefits. In this systematic review, we have evaluated the effectiveness of GLP-1 RAs on body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR), and total testosterone (TT) in women with PCOS. Randomised controlled trials (RCTs) comparing the effect of GLP-1 RAs with metformin, standard, or placebo on BMI, HOMA-IR, and TT in women with PCOS were selected following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. A comprehensive literature search was conducted in various databases, including PubMed, Scopus, Embase, MEDLINE, Web of Science, Cochrane, and CINAHL through May 20, 2025. Eighteen RCTs comparing GLP-1 RAs with placebo, metformin, or standard therapy were included. Quality assessment was done using Cochrane's 'Risk of Bias tool (RoB2)'. Review Manager (RevMan) version 5.4.1 (The Cochrane Collaboration, London, United Kingdom) was used to perform random-effects meta-analysis. Continuous outcomes were pooled as mean differences (MD) when measured on the same scale and as standardised mean differences (SMD) when the scales differed, each with a 95% confidence interval (CI). Inter-study heterogeneity among the trials was assessed using the chi-squared test for heterogeneity, with I² to quantify the level of heterogeneity. The certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. GLP-1 RAs significantly reduced BMI compared with control interventions (MD: -1.09 kg/m²; 95% CI: -1.80 to -0.38; p = 0.003), with liraglutide showing superiority over both metformin and placebo in subgroup analyses. Insulin resistance improved significantly (SMD: -0.38; 95% CI: -0.61 to -0.16; p = 0.001), particularly with exenatide. However, no significant overall effect on TT levels was observed (SMD: -0.10; 95% CI: -0.38 to 0.18; p = 0.49). Risk of bias was generally low, with minor concerns in select domains. Funnel plots suggested minimal publication bias. The certainty of evidence was moderate for BMI and HOMA-IR and very low for TT. GLP-1 receptor agonists are effective in improving metabolic outcomes in PCOS, particularly in reducing BMI and insulin resistance. However, their effect on androgen levels remains inconclusive. These agents may represent a promising therapeutic option, especially in overweight or obese women with PCOS, though further large-scale studies are needed to confirm long-term benefits.

Efficacy and safety of GLP-1 receptor agonists for adolescents and children with obesity: a meta-analysis of randomized controlled trials.

Qirong Chen, Haixia Liu, Jie Xu +2 more

To evaluate the efficacy and safety of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of obesity among children and adolescents.

Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Outcomes in Patients With Atherosclerotic Cardiovascular Disease and Obesity Without Diabetes.

Usman Ali Akbar, Avilash Mondal, Mounica Vorla +7 more

The Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) trial demonstrated cardiovascular benefits of semaglutide in patients with obesity without diabetes; however, the real-world effect across multiple GLP-1 receptor agonist (GLP-1 RA) agents in patients with established atherosclerotic cardiovascular disease (ASCVD) and overweight or obesity without diabetes mellitus remains unknown. We conducted a target trial emulation using data from the TriNetX US Collaborative Network (January 1, 2010-December 1, 2025) in adults aged ≥45 years with established ASCVD (history of myocardial infarction, stroke, or coronary or peripheral revascularization), BMI ≥27 kg/m², and without type 2 diabetes. New initiation of any GLP-1 RA (liraglutide, semaglutide, dulaglutide, or exenatide) was compared with no GLP-1 RA use. The primary outcome was all-cause mortality; secondary outcomes were acute myocardial infarction, stroke, and heart failure hospitalization over 5 years, analyzed using Cox proportional hazards and Fine-Gray subdistribution hazard models to account for the competing risk of death. Among 14,844 propensity-matched patients without diabetes (7,422 per group; median age 63 [IQR 55-71] years; 64% women), GLP-1 RA use was associated with lower all-cause mortality (HR 0.68; 95% CI 0.53-0.88; P=.003), acute myocardial infarction (sHR 0.63; 95% CI 0.41-0.98; P=.040), and heart failure hospitalization (sHR 0.61; 95% CI 0.39-0.95; P=.028); no significant association was observed for stroke (sHR 0.76; 95% CI 0.52-1.10; P=.146). Findings were consistent in landmark and age subgroup analyses; a sensitivity analysis including patients with diabetes (N=31,910 matched pairs) showed similar associations. In conclusion, these real-world findings are broadly directionally consistent with the SELECT trial and provide complementary observational evidence across multiple GLP-1 RA agents in patients with established ASCVD and overweight or obesity without diabetes mellitus, though causal inference cannot be established from observational data alone.

Serial Assessment of NT-proBNP and High-Sensitivity Cardiac Troponin with Glucagon-Like Peptide-1 Receptor Agonist Therapy in Type 2 Diabetes: Insights from EXSCEL.

Veraprapas Kittipibul, Maggie Nguyen, Paul Welsh +6 more

In the EXSCEL trial, exenatide did not reduce major adverse cardiovascular events (MACE), but heterogeneity of benefit and the role of cardiac biomarkers remain uncertain. We evaluated the prognostic value of baseline and 1-year changes in N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (cTnI), and whether baseline biomarker concentrations modified exenatide effects.

The Interplay Between GLP-1-Based Therapies, the Gut Microbiome, and MASLD/MASH in Type 2 Diabetes Mellitus: A Narrative Review.

Boris Dinkov, Diana Pendicheva-Duhlenska

GLP-1-based drugs are approved for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 60% of patients with T2DM, and the gut microbiome plays a critical role in its pathogenesis. The gut-liver axis represents a key mechanistic link between dysbiosis and hepatic steatosis. A narrative literature review was conducted using PubMed, Scopus, and ClinicalTrials.gov (2015-2026). Search terms included "GLP-1 receptor agonist," "microbiome," "MASLD," "MASH," "NAFLD," "NASH," "liraglutide," "semaglutide," "tirzepatide," "dulaglutide," and "exenatide." Of 363 identified articles, 330 were excluded due to duplication or non-relevant study design; 33 studies (18 preclinical, 15 clinical) were included. In preclinical models, liraglutide demonstrated normalization of the Firmicutes/Bacteroidetes ratio and increased Bifidobacterium and Lactobacillus spp., while tirzepatide significantly reduced hepatic steatosis and increased Akkermansia abundance in diabetic mice. Semaglutide improved gut barrier integrity, increased Alloprevotella and Alistipes, and ameliorated MASLD in murine models. In clinical studies, tirzepatide achieved MASH resolution in 44-62% of patients in the phase 2 SYNERGY-NASH trial. In August 2025, the FDA approved semaglutide for MASH with fibrosis based on the Phase 3 ESSENCE trial. A recent longitudinal study in T2DM patients showed that baseline microbiome composition predicted glycemic response to semaglutide, without significant changes in microbiome diversity. In conclusion, GLP-1-based therapies demonstrate consistent preclinical associations with gut microbiome modulation and reduction in hepatic steatosis. Baseline microbiome composition has been suggested as a potential predictor of treatment response, supporting a personalized approach to MASLD management and warranting future clinical studies.

Glucagon-like Peptide-1 Receptor Agonists and Risk of Nonarteritic Anterior Ischemic Optic Neuropathy: Systematic Review and Meta-Analysis.

Thanansayan Dhivagaran, Fahad Butt, Luckshann Arunasalam +7 more

Recent observational studies have reported conflicting evidence regarding an association between glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly semaglutide, and nonarteritic anterior ischemic optic neuropathy (NAION). We aimed to synthesize the pooled evidence assessing the association between GLP-1RA use and NAION risk.

GLP-1 agonists and changes in body mass and composition in adults with overweight or obesity with or without type 2 diabetes mellitus: a systematic review and meta-analysis.

Nadia Sawicka-Gutaj, Dawid Gruszczyński, Kacper Nijakowski +5 more

The systematic review aimed to assess the effects of GLP-1 receptor agonists (GLP-1 RA) and dual GLP-1/GIP agonists on weight loss and body composition in individuals with overweight or obesity, with or without type 2 diabetes mellitus.

Glucagon-Like Peptide-1 Receptor Agonists and Risk of Systemic and Ocular Vascular Complications in Patients with Type 2 Diabetes and Diabetic Retinopathy.

Jui Shah, Bhargav Makwana, Krisha Panchal +11 more

To evaluate the association of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) use on macrovascular and microvascular outcomes in patients with type 2 diabetes (T2D) and diabetic retinopathy (DR)-a high-risk group often excluded from clinical trials.

Integrated Evidence from VigiBase and Clinical Trials: A Comprehensive Pharmacovigilance Analysis of Seven Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs).

Jiaxun Li, Jizhou Liang, Wei Zhang +2 more

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are key therapies for type 2 diabetes and obesity, regulating blood glucose by mimicking endogenous GLP-1. Despite efficacy, GLP-1 RAs are associated with adverse reactions across multiple organ systems. To address the gap in class-wide comparative safety analyses beyond previous studies limited to single drugs or organ systems, this study systematically evaluated adverse events for all approved GLP-1 RAs to identify hidden risks and support clinical decision-making.

The effects of GLP-1 receptor agonists on Alzheimer's pathophysiology: A systematic review.

Eve Corcoran, Michael Kettlety, Urwa Mogul +2 more

The incidence of Alzheimer's disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in AD. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of liraglutide, semaglutide, exenatide and dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and Aβ.

GLP-1 Receptor Agonist Use and Wound Outcomes After Free Flap Breast Reconstruction.

Joy Ha, Ethan Lester, Henning De May +4 more

Background Glucagon-like peptide-1 receptor agonists (GLP-1s) are increasingly used for glycemic control and weight loss, but their impact on surgical wound complications remains unclear. Some studies suggest GLP-1s reduce complications such as infection and dehiscence, though others report increased risk in certain procedures. This study evaluates whether preoperative GLP-1 use is associated with postoperative wound complications in free flap breast reconstruction. Methods We conducted a retrospective cohort study using the TriNetX Research Network, a global database of de-identified health records. Adults (≥18 years) undergoing free flap breast reconstruction (2012-2025) were identified with CPT codes. Patients were stratified into cohorts by GLP-1 use within one year before surgery. Prescriptions for semaglutide, liraglutide, dulaglutide, exenatide, or tirzepatide defined GLP-1 users. Cohorts underwent 1:1 propensity score matching, and matched groups were analyzed for wound outcomes. Subgroup analyses were performed by diabetes status. Results In the pooled cohort, GLP-1 users had significantly lower composite wound complication rates compared with non-users (9.0% vs. 17.1%, p = 0.002), including reduced surgical site infections (4.1% vs. 8.1%, p = 0.026) and wound dehiscence (3.8% vs. 7.8%, p = 0.023). No differences were observed in debridement, seroma, or hematoma rates. In subgroup analyses, GLP-1 use was associated with significantly lower composite wound complications in the non-diabetic subgroup (7.9 vs. 18.6%, p = 0.007), while overall complication rates in the diabetic subgroup were comparable between users and non-users. Conclusion Preoperative GLP-1 use was not linked to increased wound complications and may confer benefit, supporting safety when used perioperatively.

GLP-1 therapies and hair loss: A systematic review of current evidence and implications for counseling.

Aditya K Gupta, Elizabeth M Teasell, Vasiliki Economopoulos +1 more

ObjectiveTo evaluate glucagon-like peptide-1 receptor agonist (GLP-1 RA)-specific associations with hair loss, characterize reported alopecia subtypes and discuss potential underlying mechanisms.MethodsA systematic literature search was conducted across four databases (PubMed, Embase, Scopus, and Web of Science) according to PRISMA guidelines and registered in PROSPERO (CRD420261297384). Studies were included if they were primary articles assessing hair loss related to GLP-1 RA use.ResultsOf 133 studies identified, 24 met inclusion criteria. Among GLP-1 RAs, semaglutide and tirzepatide demonstrated the highest incidence rates of hair loss and more frequent signal detection in pharmacovigilance studies. Although infrequently classified overall, androgenetic alopecia and telogen effluvium were the predominant subtypes of hair loss reported. Tirzepatide, associated with the greatest magnitude of weight loss, was most frequently linked to telogen effluvium. Hair loss associated with semaglutide appeared to be dose-dependent, with doses < 2mg weekly rarely implicated while higher obesity-treatment doses were more commonly associated with hair loss. Females appeared to be disproportionately affected. Rapid weight loss emerged as a potential contributor, particularly for telogen effluvium. In contrast, fewer studies assessed hair loss with liraglutide, dulaglutide, lixisenatide and exenatide, and they typically exhibited lower reported risk when compared to semaglutide and tirzepatide.ConclusionsAccumulating evidence from pharmacovigilance databases and clinical cohorts suggests an increased risk of hair loss with certain GLP-1 RAs, particularly semaglutide and tirzepatide. Further studies are needed to clarify the etiology of drug-induced weight loss, identify vulnerable populations, and establish causality and temporal relationship through large, prospective randomized trials.

Use of Glucagon-Like Peptide-1 Receptor Agonists and Risk of Parkinson's Disease: Scandinavian Cohort Study.

Arvid Engström, Henrik Svanström, Anders Hviid +8 more

To investigate the association between use of GLP-1 receptor agonists and incident Parkinson's disease.

Efficacy of GLP-1 receptor agonists in Parkinson's disease: a systematic review and exploratory network meta-analysis of randomized controlled trials.

Muaz Ali, Arkansh Sharma, Amith Paruchuri +7 more

Current therapies for Parkinson’s disease lack proven disease-modifying effects. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), developed for type 2 diabetes, have shown potential neuroprotective properties. Their comparative efficacy in Parkinson’s disease remains unclear.

Efficacy and safety of novel antidiabetic drugs in patients with type 2 diabetes and chronic kidney disease: a network meta-analysis.

Xiaojian Zhu, Xingjia Wang, Peiru Zhang +6 more

A number of novel antidiabetic drugs have been developed. These drugs include sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is). However, the optimal medication for individuals with type 2 diabetes mellitus (T2DM) and comorbid chronic kidney disease (CKD) has not been established. To this end, this study was conducted to compare specific novel antidiabetic drugs regarding efficacy and safety.

Childhood Obesity, Medications, and Surgeries.

Srinidhi Raghav, William H Frishman

The obesity pandemic continues to increase in prevalence in children and adolescents, with its increase outpacing the rate of adult obesity; the human developmental index, body mass index, and family income all display associations to childhood obesity. There are numerous adverse complications of childhood obesity, including cardiovascular, endocrine, and gastrointestinal manifestations. Obesity is thought to be an interaction of several different factors, such as leptin, proopiomelanocortin, glucose uptake in adipocytes, melanocortin receptor 4, protein convertase 1/3, brain-derived neurotrophic factor, fat-mass and obesity-associated gene, melanocortin receptor 4, tumor necrosis factor, interleukin-6, and long noncoding RNA. Epigenetic regulation, the unique gut microbiome role in contributing to obesity, environmental factors, and the social context of a child can precipitation of childhood obesity. In this review, we hope to explore the different medications for obesity, orlistat, glucagon-like peptide-1 agonists, liraglutide, semaglutide, exenatide, setmelanotide, metreleptin, naltrexone, lorcaserin, phentermine, metformin, fluoxetine, lisdexamfetamine, and zonisamide, while also reviewing surgeries such as the Roux-en-Y gastric bypass, laparoscopic or vertical sleeve gastrectomy, and adjustable gastric banding.

Comparative Cardiovascular Effectiveness of Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Diabetes Mellitus.

Fan Bu, Ruopeng Wu, Anna Ostropolets +18 more

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) have established cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM), with similar class-level effectiveness found in previous studies. However, real-world comparative effectiveness assessments of individual agents remain limited.

Preferred GLP-1 Receptor Agonists in Type 2 Diabetes With Established Cardiovascular Disease or High Cardiovascular Risk: A Network Meta-Analysis of Randomized Trials.

Mustafa Abomohsen, Mohamed Rifai, Ahmed Farid Gadelmawla +5 more

The comparative cardiovascular (CV) efficacy and safety of GLP-1 receptor agonists (GLP-1RAs) in patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or high CV risk remain uncertain.

GLP-1RA Dispensing in Youth With Type 2 Diabetes: 2020 to 2023.

Patricia Y Chu, Andrea Kelly, Sean Hennessy +3 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a novel pharmacotherapeutic option for pediatric type 2 diabetes (T2D); however, little is known about their current use. This study evaluated trends in GLP-1RA dispensing in youth with T2D between 2020 and 2023 and compared use by insurance type (ie, Medicaid vs commercial).

Study on chitosan/carrageenan core-shell nanoparticles for oral co-administration of insulin/exenatide enhance insulin secretion in type 2 diabetes.

Tuong-Vy Nguyen, Ngoc-Hanh Cao-Luu, Thi-Bao-Tran Nguyen +2 more

This study developed and evaluated the feasibility of using core-shell chitosan and carrageenan nanoparticles for insulin and exenatide dual-delivery to control blood glucose levels in type 2 diabetes model. Core-shell nanoparticles were fabricated using the coaxial electrospraying technique, exploiting the electrostatic interactions between components to achieve controlled drug release in physicological media. Experimental results indicated that the prepared nanoparticles demonstrated proper physicochemical properties of an oral delivery system, including a hydrodynamic diameter around 300 nm, fitting well through the digestive wall and remaining somewhat stable in the physiologic milieu throughout time, and exhibited non-toxicity to multiple cell lines. The in vitro drug release approximately 80% from the nanoparticles was triggered by pH-sensitive behavior and controlled in spatiotemporal manners in simulated intestinal fluids with digestive enzymes, resulting in inhibition of premature release and self-sustained drug delivery. In type 2 diabetic mice, a single dose (100 IU kg-1) of nanoparticle generated a pronounced hypoglycemic response, achieving approximately a 45% reduction in blood glucose levels following 4 h oral administration and maintaining insulin plasma at a low level within 12 h owing to insulin and exenatide synergic stimulation effects. Remarkably, treatment with this nanoparticle significantly preserved pancreatic islets and averted type 2 diabetes complications within major organs such as the heart, liver, and kidneys, while maintaining an excellent systemic safety profile. This study evidenced that the nanoparticle-loaded insulin and exenatide were an encouraging long-acting formulation and validated a novel strategy to overcome multiple absorption barriers using polyelectrolyte complex nanoparticles from chitosan and carrageenan.

GLP-1 Receptor Agonist Therapy in Older Adults with Diabetes: A Qualitative Analysis of Phase 4 ClinicalTrials.gov Studies.

Nouf M Alourfi, Nasser M Alorfi

Type 2 diabetes mellitus is highly prevalent among older adults and often requires multidrug therapy to optimize glycemic control while minimizing adverse effects. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are among the most effective antihyperglycemic drugs with demonstrated cardiometabolic benefits. However, their real-world safety, tolerability, and long-term outcomes in geriatric populations remain under-explored.

A Pharmacovigilance Analysis of Ocular Adverse Events Associated with GLP-1 Receptor Agonists.

Abdullah Virk, Karen Allison

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes in addition to other conditions such as obesity. As their use expands, understanding potential ocular safety signals is important, particularly in populations already at risk for diabetic eye disease. The aim of this study is to identify potential pharmacovigilance safety signals for ocular adverse events (AEs) related to GLP-1 RA medications to better inform future clinical practice. Methods: This study utilized the publicly available FDA Adverse Event Reporting System (FAERS) to obtain AE reports related to exenatide, tirzepatide, dulaglutide, liraglutide, and semaglutide from 2005 to 2024. Reports were categorized by demographic and geographic variables. Disproportionality analysis using reporting odds ratios (RORs) was performed to detect potential safety signals. Year-over-year trends in the proportional representation of each drug were also assessed through linear regression and time series plots. Results: Ocular AEs represented 3.61% of all GLP-1 RA related reports. Median age was 63 years, and 62.6% of reports involved female patients. Exenatide accounted for 33.61% of ocular AEs but showed a significant annual decline in reporting (-5.15% per year, p < 0.001). Semaglutide (31.37%) and tirzepatide (12.19%) demonstrated significant year-over-year increases in proportional reporting (2.23% and 0.79% per year, respectively; both p < 0.05), consistent with rapid uptake in clinical practice. Semaglutide demonstrated a modestly elevated ROR (1.46), while tirzepatide showed a low ROR (0.42), though this likely reflects shorter post-marketing exposure rather than lower clinical risk. The most frequently reported events were visual impairment, followed by vision blurred, cataract, and blindness. Conclusions: This pharmacovigilance analysis identifies potential ocular AE signals associated with GLP-1 RAs, particularly semaglutide. While semaglutide showed a statistically significant disproportional reporting signal for ocular AEs, the absence of exposure denominators, comparator groups, and the susceptibility of FAERS to reporting bias means these findings are hypothesis-generating rather than causal. Clinicians should remain vigilant and consider eye care referrals when indicated. Further research is needed to validate these associations and clarify underlying mechanisms.

Circulating GDF15 and HbA1c Response to Add-On Exenatide Therapy in Type 2 Diabetes: A Post Hoc Analysis from a Multicenter Trial.

Qi Wu, Kun Yang, Xinyue Liao +5 more

Objectives: To assess the influences of growth differentiation factor 15 (GDF15) on the reduction in glycated hemoglobin (ΔHbA1c) induced by exenatide in type 2 diabetes mellitus (T2DM). Methods: This analysis included 166 participants with T2DM who received exenatide as add-on therapy for 16 weeks. The effect of baseline GDF15 on ΔHbA1c was evaluated using univariate, multivariate, and bidirectional stepwise linear regression models. Baseline GDF15 was categorized into tertiles with the lowest tertile (tertile 1) serving as reference. A subgroup analysis was performed in the participants aged >35 years to investigate whether age influenced the effect of GDF15 on ΔHbA1c. Results: GDF15 levels were significantly increased from baseline following 16 weeks of exenatide treatment [721.9 (513.6, 997.8) pg/mL vs. 741.4 (510.0, 1203.4) pg/mL, p = 0.031]. Univariate linear regression analysis revealed a positive association between baseline GDF15 (tertile 3: β = 0.553, 95% CI 0.115 to 0.991, p = 0.014) and ΔHbA1c. However, no significant relationship was found between GDF15 (tertile 2: p = 0.403; tertile 3: p = 0.217) and ΔHbA1c after adjusting for age and diabetes duration. Further stepwise regression analysis indicated a non-robust association for GDF15 in the absence of age as GDF15 was excluded from the model. Among the participants >35 years old, GDF15 (tertile 3: β = 0.383, 95% CI 0.002 to 0.764, p = 0.049) remained positively associated with ΔHbA1c, even after adjusting for age. Conclusions: Elevated GDF15 might potentially diminish the reduction in HbA1c following 16-week exenatide treatment, with this effect moderated by age.

Not All GLP-1 Receptor Agonists Are Alike: Real-World Evidence of Differential Endocrine and Dermatologic Safety.

Nai Lee, Yun Kim

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for metabolic disorders, but emerging safety concerns include alopecia and reproductive or endocrine-related adverse events (AEs). This study investigated the association between specific GLP-1 RAs and these endocrine-related AEs using a large-scale pharmacovigilance database.

GLP-1 receptor agonists and sexual function in women and men: a narrative review of emerging evidence and the need for further research.

Zaher Merhi

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may influence reward-related and sexual behaviors.

Muscle atrophy associated with glucagon-like Peptide-1 receptor agonists: A population-based observational study.

Angela T H Kwan, Moiz Lakhani, Roger S McIntyre

Background and AimEmerging evidence suggests that weight loss associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may be in part attributable to changes in lean mass, which has potential clinical implications. This study evaluates the disproportionate reporting of muscle atrophy in association with GLP-1 RA therapy using real-world global data.. MethodsWe analyzed reports of muscle atrophy submitted to the FDA Adverse Event Reporting System (FAERS) database from October 2003 to March 2024 using the validated pharmacovigilance tool OpenVigil 2.1. Disproportionality was assessed using reporting odds ratios (RORs) with 95 % confidence intervals (CIs), the standard metric for pharmacovigilance signal detection worldwide. To contextualize associations, disproportionality estimates were calculated using niacin, simvastatin, and the complete FAERS database (all other drugs) as comparators. ResultsA total of 142 cases of muscle atrophy were identified with GLP-1 RA therapy, the majority occurring in adults aged 18-64 years (43 % female, 57 % male). Disproportionality analysis showed pharmacovigilance signals for semaglutide (ROR = 2.39, 95 % CI = 1.63-3.52) and tirzepatide (ROR = 1.69, 95 % CI = 1.14-2.50), indicating increased reporting of muscle atrophy relative to all other drugs in FAERS. In contrast, exenatide (ROR = 0.26, 95 % CI = 0.12-0.55) and liraglutide (ROR = 0.27, 95 % CI = 0.09-0.83) were associated with significantly lower reporting odds. All significant signals satisfied thresholds of p < 0.05 and IC025 > 0.. ConclusionsCertain GLP-1 receptor agonists demonstrate a pharmacovigilance signal of disproportionate reporting of muscle atrophy. These findings should be interpreted as signal detection rather than evidence of causality and highlight the need for future studies incorporating objective measures of muscle mass and function..

Exenatide attenuates neuroinflammation and rescues sepsis-induced depressive behavior and cognitive dysfunction in a mouse model.

Shenhai Liu, Qiao Chen, Hui Liu +4 more

Sepsis elevates the risk of depression and cognitive impairment. Glucagon-like peptide-1 (GLP-1) analogues exhibit neuroprotective potential, yet their effects on sepsis-induced depression (SID) remain unelucidated. This study explored whether exenatide (Exe) alleviates depressive-like behaviors and cognitive deficits in a murine SID model.

Association between GLP-1 receptor agonist use and worsening mental illness in people with depression and anxiety in Sweden: a national cohort study.

Heidi Taipale, Mark Taylor, Markku Lähteenvuo +3 more

People with diabetes have an elevated risk of developing depression, anxiety, and suicide. GLP-1 receptor agonists are licensed to treat diabetes and obesity, but data on whether these medications alleviate or exacerbate anxiety, depression, and self-harm are mixed. We studied the risk of worsening mental illness in people already diagnosed with depression, anxiety, or both who were prescribed antidiabetic medications including GLP-1 receptor agonists.

A Systematic Review and Meta-Analysis of Efficacy and Safety of Liraglutide in Patients with Type 2 Diabetes Mellitus.

Shashank Joshi, Ashok Kumar Das, Kamlesh Khunti +2 more

Obesity plays a pivotal and modifiable role in the development and progression of type 2 diabetes mellitus (T2DM). Clinicians increasingly use lower doses of liraglutide (1.2 mg and 1.8 mg) to achieve clinically meaningful weight loss while maintaining effective glycemic control in people with T2DM and obesity. In this meta-analysis, we compared the efficacy and safety of liraglutide 1.2 mg and 1.8 mg in this population.

Unimolecular GLP-1/Apelin Hybrid Peptides Cause Prominent Appetite Suppression, as Well as Enhancing Insulin Secretion, Beta-Cell Survival and Glycaemic Regulation.

Ananyaa Sridhar, Ethan S Palmer, Sarah L Craig +3 more

To characterise the metabolic benefits of a GLP-1/apelin hybrid peptide, namely exendin-4-linker-apelin (ELA), and associated acylated forms, including ELA-Lys12(γGluPal), ELA-Lys27(γGluPal) and ELA-Lys38(γGluPal).

Exenatide through PPARδ improved hepatic insulin resistance in patients of type 2 diabetes mellitus via suppressing pyroptosis.

Xizhi Li, Tingting Zhou, Yixi Wu +8 more

Exenatide, the first glucagon-like peptide-1 receptor agonist (GLP-1RA), exerted multiple beneficial effects, including stimulating insulin secretion, slowing gastric emptying, and improving insulin resistance (IR). Our previous work demonstrated that the peroxisome proliferator-activated receptor delta (PPARδ) gene (PPARD) polymorphisms correlated with exenatide monotherapy efficacy, possibly due to the pivotal role of PPARδ in regulating IR. Specifically, PPARδ has been shown to modulate the nucleotide-binding domain and leucine-rich repeat pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of pyroptosis, thereby participating in the regulation of this inflammatory cell death pathway. However, the underlying mechanisms by which exenatide ameliorated hepatic IR in patients with type 2 Diabetes Mellitus (T2DM) remained incompletely understood. Herein, we found that exenatide suppressed pyroptosis and ameliorated hepatic IR; furthermore, it could bind to PPARδ and upregulate PPARδ protein expression both in vitro and in vivo. Notably, PPARδ knockdown abolished the protective effects of exenatide against pyroptosis and hepatic IR, whereas pharmacological activation of PPARδ enhanced these beneficial effects. Moreover, T2DM patients carrying the AA genotype at PPARD rs3777744 and exhibiting higher baseline homeostasis model assessment of insulin resistance (HOMA-IR) showed a superior response to exenatide. Collectively, our findings revealed that exenatide ameliorated hepatic IR by suppressing pyroptosis via PPARδ, underscoring the potential of PPARD rs3777744 as a biomarker for personalized exenatide therapy in T2DM.

Exendin-4 enhances GLP-1 signaling and reduces anxiety-like behaviors in male heroin withdrawal mice.

Yang Xiang, Xiaowei Yan, Rongrong Li +7 more

Anxiety and depression significantly contribute to heroin relapse, and addressing these issues could lower relapse rates. The basolateral amygdala (BLA) and nucleus tractus solitarius (NTS) are involved in regulating these emotions, but the molecular mechanisms during heroin withdrawal are not yet understood. Subcutaneous injection of heroin into C57BL/6J mice to simulate chronic dependence, withdrawal, and Exendin-4 treatment. Assess anxiety and depression-like behaviors using open field test (OFT), elevated plus maze (EPM), forced swimming test (FST), and tail suspension test (TST). Analyze neuronal and protein expression changes in the BLA brain area with Western blotting (WB) and immunofluorescence staining. Heroin dependence reduces glutamatergic neurons in BLA without affecting anxiety and depression-like behaviors, due to the inhibitory effect of heroin reward. During withdrawal, GLP-1 secretion by the NTS rises, increasing c-Fos and GLP-1 receptor expression in glutamatergic neurons of BLA, linked to heightened anxiety but not depression. A 7-day treatment with Exendin-4 (2 µg/kg) alleviates anxiety in withdrawal mice by downregulating GLP-1 signaling in the NTS-BLA circuit, indicating GLP-1's role in regulating anxiety during heroin withdrawal. GLP-1 receptors within BLA may serve as molecular targets for modulating emotional states, thereby offering empirical support for strategies aimed at preventing heroin relapse.

Semaglutide alleviates ovarian ferroptosis in polycystic ovary syndrome and is associated with reduced GPX4 promoter hypermethylation.

Yaling Zhang, Daojuan Wang, Xiaosa Si +4 more

Polycystic ovary syndrome (PCOS) is associated with ovarian granulosa cell dysfunction. Ferroptosis, a regulated cell death driven by lipid peroxidation, represents a novel pathological mechanism. Hypermethylation of the glutathione peroxidase 4 (GPX4) promoter may contribute to its suppression. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve metabolic features of PCOS, their direct effects on ovarian ferroptosis and the underlying epigenetic mechanisms are unclear. To explore the therapeutic potential of GLP-1RAs across PCOS phenotypes, we employed a hyperandrogenism-induced rat model and a letrozole plus high-fat diet mouse model, treating them with exenatide or semaglutide, respectively. Phenotypic assessment included estrous cycle monitoring, ovarian histology, and serum hormone profiling. Ferroptosis was evaluated using a multi-parametric approach, including iron deposition (Perls' staining), lipid peroxidation (MDA), redox status (GSH/GSSG), ultrastructural analysis (TEM), and expression of key regulators. The methylation status of the GPX4 promoter was analyzed by methylation-specific PCR (MSP) and bisulfite sequencing (BSP), alongside the expression of related epigenetic modifiers (DNMTs, TET1). In vitro studies using DHT-stimulated primary granulosa cells further validated the semaglutide effects. GLP-1 RA exenatide alleviated the polycystic ovarian morphology in rats with PCOS, semaglutide treatment not only alleviated PCOS phenotypes but also reversed ovarian ferroptosis markers, restored GPX4 expression, and reduced the GPX4 promoter hypermethylation and DNMTs levels, with efficacy comparable to 5-azacytidine. In vitro, semaglutide corrected DHT-induced GPX4 hypermethylation and ferroptosis in granulosa cells. This study demonstrates that semaglutide alleviates PCOS phenotypes and reverses ovarian granulosa cell ferroptosis. These beneficial effects may be related to the alleviation of GPX4 promoter hypermethylation. Our findings extend the therapeutic rationale for semaglutide in PCOS beyond metabolic benefits, suggesting potential direct ovarian protection via epigenetic modulation.

Baseline metabolite profiles predict the glucose-lowering efficacy of exenatide in patients with type 2 diabetes.

Yunyi Le, Jin Yang, Qi Wu +6 more

Individual heterogeneity in the glucose-lowering response to glucagon-like peptide-1 receptor agonists (GLP-1RAs), including exenatide, limits efficient treatment selection for type 2 diabetes mellitus (T2DM). This study assessed whether baseline clinical characteristics together with serum metabolomic features could predict the glucose-lowering efficacy of exenatide.

Glucagon-like peptide-1 agonists in children with obesity and type 2 diabetes. an umbrella review.

Hyder Mirghani, Laila Albishi, Sawsan Mohmmad Alblewi

Obesity and type 2 diabetes mellitus (Type 2 DM) are rising at an alarming rate among children and adolescents. This population often exhibits suboptimal glycemic control and diabetes-related complications. Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) have emerged as a promising therapeutic option for pediatric patients due to their beneficial effects on weight reduction and glycemic regulation. Literature on this important issue is scarce. We aimed to assess the effects of GLP-1 agonists on body weight, HbA1c, body mass index z (BMI z), and systolic blood pressure (SBP). Additionally, we discussed adverse events and hypoglycemia.

Semaglutide use in a patient with a long-term ileostomy: A case report highlighting clinical risks and evidence gaps.

Gabriela Gaytan, Andrea Pabon, Natalie Rosario

GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide, dulaglutide, liraglutide, and exenatide, are increasingly used to treat type 2 diabetes and support weight loss. These agents function by enhancing glucose-dependent insulin secretion, suppressing inappropriate glucagon secretion, slowing gastric emptying, and regulating appetite through central nervous system pathways. Since semaglutide's approval in 2017 and U.S. market availability in 2018, its use has expanded significantly. However, there remains limited literature evaluating its safety and efficacy in patients with altered gastrointestinal anatomy, particularly those with ostomies.

Association of Glucagon-Like Peptide-1 Receptor Agonists and Suicidality: A Systematic Review.

Hezekiah C T Au, Yang Jing Zheng, Gia Han Le +7 more

Increased risk of suicidality has been reported in association with glucagon-like peptide receptor agonist (GLP-1 RA) prescription. Herein, we conducted a comprehensive review evaluating reports of GLP-1 RA prescription and suicidality.

Effects of Glucagon-Like Peptide-1 Receptor Agonist on Bone Metabolism and the Expression of Insulin Receptor Substrate 1 in an Osteoporotic Rat Model.

Yao Ye, Yu-Ling He, Jie He +2 more

This study aimed to investigate the effects of the GLP-1R agonist Exendin 4 on bone metabolism and insulin receptor Substrate 1 (IRS-1) expression in an osteoporotic (OP) rat model.

Effects of Glucagon-Like Peptide-1 Receptor Agonists (Mono and Combination Therapy) on Energy Expenditure: A Scoping Review.

Flavio T Vieira, ZhiDi Deng, Manfred J Muller +6 more

Weight loss results in reduced energy expenditure (EE) due to body composition alterations (e.g., fat-free mass and fat mass losses) and mass-independent adaptations in EE (e.g., hormones). Glucagon-like peptide-1 receptor agonists (GLP-1RA) are indicated for obesity management; however, their effects on EE remain unclear.

Heterogeneity of Treatment Effects of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss in Adults: A Systematic Review and Meta-Analysis.

G Caleb Alexander, Xuya Xiao, Sophie Dilek +6 more

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a novel class of therapeutics approved to treat chronic conditions such as cardiovascular disease, diabetes, and/or obesity. However, whether GLP-1 RAs' efficacy varies by age, sex, race and ethnicity, baseline body mass index (BMI), and baseline hemoglobin A1c (HbA1c) is unclear.

Sex Differences in [68Ga]Ga-NODAGA-Exendin-4 Uptake in the Pituitary of Individuals With Type 2 Diabetes.

Sevilay Tokgöz, Marti Boss, Rick I Meijer +5 more

Comparative effectiveness of continuous positive airway pressure and glucagon-like peptide-1 receptor agonists in obstructive sleep apnea: A network meta-analysis of randomised trials.

Gaspar R Chiappa, Paula C N Santos, Deivyd Vieira Silva Cavalcante +5 more

To compare the effects of continuous positive airway pressure (CPAP), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), their combination, and no active intervention on respiratory, sleepiness, and metabolic outcomes in adults with obstructive sleep apnea (OSA). We searched PubMed, Embase, and CENTRAL through August 2025 for randomised trials of CPAP, exenatide, liraglutide, tirzepatide, or their combinations. The primary endpoint was apnea-hypopnea index (AHI). Secondary endpoints were Epworth Sleepiness Scale (ESS), body mass index (BMI), systolic and diastolic blood pressure (SBP, DBP), fasting glucose, and glycated haemoglobin (HbA1c). Random-effects network meta-analyses estimated mean differences (MDs) with 95% confidence intervals (CIs). Treatments were ranked using SUCRA, and certainty of evidence was assessed with GRADE. Thirty-four trials including 3964 participants were eligible. CPAP produced the largest reduction in AHI versus no active intervention (MD -22.17 events/h; 95% CI -38.01 to -6.33) and improved ESS (MD -2.75; 95% CI -3.71 to -1.79). Liraglutide reduced BMI (MD -1.60 kg/m2; 95% CI -2.04 to -1.16) and HbA1c (MD -0.19%; 95% CI -0.25 to -0.13), whereas CPAP showed no meaningful metabolic effect. Liraglutide plus CPAP achieved the greatest BMI reduction (MD -2.00 kg/m2; 95% CI -3.49 to -0.51). No intervention significantly changed SBP, DBP, or fasting glucose. According to GRADE, certainty of evidence was moderate for CPAP effects on respiratory and sleepiness outcomes and for GLP-1 receptor agonists on BMI and HbA1c, and low for blood pressure and fasting glucose. CPAP is the most effective therapy for respiratory control, while GLP-1 receptor agonists primarily improve weight and glycaemic indices, supporting an integrated airway-metabolic approach to OSA management.

Effect of GLP-1 Receptor Agonists in Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

Benjamin J Behers, Christian Sanchez, Omar Hozayen +10 more

Heart failure with preserved ejection fraction (HFpEF) affects 32 million people worldwide and is responsible for tens of billions of dollars in healthcare expenditure annually, with costs primarily driven by hospitalizations. HFpEF is notoriously difficult to treat, but emerging studies suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may be effective therapies. We performed a systematic review and meta-analysis of six randomized controlled trials with 5564 total participants investigating GLP-1 RAs in patients with HFpEF. Overall, no significant effect was noted for GLP-1 RAs on our primary outcomes of cardiovascular mortality and worsening heart failure (HF) events, although they were associated with improvement in quality of life measures. Furthermore, safety data favored the GLP-1 RA group, although tolerability did not differ compared with placebo. While the pooled analysis of all GLP-1 RAs showed neutral effects versus hard endpoints, sensitivity analyses excluding older-generation agents (exenatide) revealed a significant 41% reduction in HF events, suggesting that newer, more potent agents (semaglutide, tirzepatide) may offer disease-modifying benefits in HFpEF. Although future studies are needed, GLP-1 RAs appear to be promising for the treatment of HFpEF.

[Mechanism of electroacupuncture on improving insulin resistance and intestinal mucosal barrier injury via the GLP-1R/PKA signaling pathway in type 2 diabetes mellitus rats].

Jiayi Lin, Rui Li, Xiaolu Li +6 more

To observe the effect of electroacupuncture (EA) on the glucagon-like peptide-1 receptor (GLP-1R)/protein kinase A (PKA) signaling pathway in the colon tissue of type 2 diabetes mellitus (T2DM) rats and explore the mechanisms underlying EA's improvement of insulin resistance and intestinal mucosal barrier injury.

The Effect of GLP-1 Receptor Agonists on Alanine Aminotransferase and Other Metabolic Parameters in Youths with Obesity: A Systematic Review and Meta-Analysis.

Lauren A Hertzer, Robert M Siegel, Roohi Y Kharofa +2 more

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) lower body mass index (BMI) in youths with obesity, less is known about their effect on metabolic parameters such as alanine aminotransferase (ALT), high-density lipoprotein, low-density lipoprotein, and hemoglobin A1c levels. We conducted a systematic review of the existing literature and a meta-analysis to determine the effect of GLP-1 RAs on metabolic parameters.

Comparative efficacy of GLP-1 RA, tirzepatide and SGLT-2 inhibitors in metabolic liver disease: A network meta-analysis.

Andrej Belančić, Christina Antza, Anastasios Poutachidis +6 more

Metabolic liver disease, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis, is a major cause of chronic liver dysfunction worldwide, creating an urgent need for effective treatments. This systematic literature review (SLR) and network meta-analysis (NMA) systematically reviews and compares the efficacy and safety of glucagon-like peptide-1 receptor agonists, tirzepatide and sodium-glucose co-transporter-2 inhibitors for this condition. The results of the SLR and NMA were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.