Review
This review synthesizes evidence for glucagon-like peptide-1 receptor agonists (GLP-1RAs) as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, metabolic dysfunction-associated steatohepatitis (MASH), with particular attention to the liver-heart connection. The authors draw on mechanistic studies, biopsy-based randomized trials, real-world data, and cardiovascular outcome trials. Key trial findings highlighted include: liraglutide (LEAN trial) achieving steatohepatitis resolution in 39% vs. 9% of placebo recipients; semaglutide showing dose-dependent histologic resolution (up to 59% vs. 17% in Phase 2) and meeting dual histologic endpoints in F2–F3 MASH at interim analysis; and tirzepatide (SYNERGY-NASH) demonstrating MASH resolution in 44–62% vs. 10% with fibrosis improvement signals. Cardiovascular outcome benefits were observed across LEADER, SUSTAIN-6, SELECT, and REWIND trials. Mechanistically, GLP-1RAs are described as reducing hepatic lipogenesis, inflammation, and insulin resistance while improving systemic cardiometabolic risk factors. The review concludes that semaglutide and tirzepatide may serve as foundational therapies for high-risk MASLD patients, while noting gaps in long-term durability data, optimal treatment duration, and evidence in cirrhosis.
Chronic diseases and translational medicine · Mar 2026DOI ↗ Moderate · human
This phase 2 randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of mazdutide 9 mg — a once-weekly dual glucagon and glucagon-like peptide-1 (GLP-1) receptor agonist — in Chinese adults with obesity (BMI ≥30 kg/m²) without diabetes over 24 weeks. Eighty participants were randomized 3:1 to receive mazdutide 9 mg (n=60) or placebo (n=20). The primary endpoint was percentage change in body weight from baseline to week 24. The study found that participants receiving mazdutide 9 mg experienced a mean body weight reduction of approximately 12.78%, compared to a gain of 1.80% in the placebo group, representing a treatment difference of approximately −14.58% (95% CI: −18.00 to −11.16). The authors concluded that mazdutide 9 mg was safe and produced substantial weight reductions in this population. Key limitations include the relatively small sample size, the short 24-week duration, the single-country (China) population limiting generalizability, the phase 2 (exploratory) design, and industry sponsorship by Innovent Biologics. The findings are described as supportive of further clinical development.
Med (New York, N.Y.) · Mar 2026DOI ↗ Review
This narrative review examines the evolving role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in managing chronic kidney disease (CKD), particularly in patients with type 2 diabetes, obesity, and established cardiovascular disease. The authors summarize evidence from cardiovascular outcomes trials showing that GLP-1RAs are associated with reduced albuminuria and slower estimated glomerular filtration rate (eGFR) decline, with effects that appear additive to those of SGLT2 inhibitors. They highlight dedicated kidney trials—notably with semaglutide—suggesting slowed CKD progression and reduced mortality in diabetic patients with CKD. The review situates GLP-1RAs within a broader therapeutic framework alongside ACE inhibitors/ARBs, SGLT2 inhibitors, and non-steroidal mineralocorticoid receptor antagonists. The authors acknowledge key evidence gaps, including limited data in non-diabetic CKD populations and uncertainty around oral GLP-1RA efficacy and newer dual/triple agonists (GLP-1/GIP/glucagon). As a review, it does not generate new primary data and is subject to potential selection bias in the literature it incorporates. The authors conclude that GLP-1-based therapies represent a potentially transformative approach to improving weight, cardiovascular, and kidney outcomes in high-risk populations.
International journal of nephrology and renovascular disease · Mar 2026DOI ↗ Limited · human
This pharmacovigilance study analyzed ocular adverse event (AE) reports associated with five GLP-1 receptor agonists (exenatide, tirzepatide, dulaglutide, liraglutide, and semaglutide) using the FDA Adverse Event Reporting System (FAERS) from 2005 to 2024. Ocular AEs comprised 3.61% of all GLP-1 RA-related reports; the median patient age was 63 years, and 62.6% of reports involved female patients. Disproportionality analysis using reporting odds ratios (RORs) identified a statistically significant signal for ocular AEs associated with semaglutide, while exenatide showed a significant annual decline in proportional reporting (-5.15% per year). The authors note that semaglutide's signal may partly reflect its growing market dominance rather than a true differential risk. Key limitations acknowledged by the study include the absence of exposure denominators and comparator groups, vulnerability of FAERS to reporting bias (including under- and over-reporting), and inability to establish causality. The authors characterize the findings as hypothesis-generating and recommend clinician vigilance regarding ocular monitoring, particularly in populations already at elevated risk for diabetic eye disease, while calling for further prospective research to validate these associations and explore potential mechanisms.
Journal of clinical medicine · Mar 2026DOI ↗ Review
This narrative review examines the rapidly evolving landscape of obesity pharmacotherapy, moving beyond currently approved injectable GLP-1 receptor agonists (GLP-1RAs). The authors contextualize the global obesity burden—affecting over 2 billion adults—and acknowledge the transformative but limited success of existing GLP-1-based therapies, citing weight loss plateaus, high inter-individual variability, and weight regain upon discontinuation as key unresolved challenges. The review synthesizes emerging drug classes including: oral GLP-1 agonists (e.g., orforglipron) aimed at improving global accessibility; multi-receptor agonists such as triple GLP-1/GIP/glucagon agonists (e.g., retatrutide, reportedly achieving 20–24% weight reduction) and dual GLP-1/glucagon agonists (e.g., survodutide, mazdutide) with potential benefits in metabolic-associated steatotic liver disease; novel dosing strategies via GLP-1/GIP combination agents (e.g., maridebart cafraglutide); amylin pathway agents (e.g., cagrilintide, amycretin); lean-mass-preserving agents (e.g., bimagrumab); and precision approaches for monogenic obesity (e.g., setmelanotide). The authors call for phenotype-stratified trials, long-term safety data, pediatric research, and equitable implementation. As a review, it does not present original trial data and is inherently subject to selection and interpretation bias.
Metabolism open · Mar 2026DOI ↗ Review
This paper is a narrative review examining survodutide, a dual GLP-1 and glucagon receptor agonist, in the context of obesity, metabolic dysfunction-associated steatohepatitis (MASH), and related metabolic conditions including type 2 diabetes and cardiovascular disease. The authors summarize survodutide's proposed mechanism of action — encompassing appetite suppression, improved glucose metabolism, and increased energy expenditure — and compare its dual-agonist profile against single-target incretin-based therapies such as GLP-1 receptor agonists alone. The review synthesizes findings from early-phase clinical trials, which the authors report showed significant weight loss and improvements in metabolic markers. Safety and tolerability are also discussed, alongside broader cardiovascular and metabolic benefits suggested by preliminary data. The authors acknowledge that the evidence base remains limited, stressing that long-term safety, durability of effect, patient-specific responses, and cost-effectiveness have not yet been fully established. Ongoing and future trials are highlighted as essential for clarifying survodutide's clinical role. As a review article, this paper does not generate new primary data, and its conclusions are bounded by the early-stage evidence available at the time of writing.
Minerva endocrinology · Mar 2026DOI ↗ In vitro
This study addressed the growing global burden of obesity and type 2 diabetes by designing novel peptide-based triagonists that simultaneously activate three receptors: GLP-1R (glucagon-like peptide-1 receptor), GCGR (glucagon receptor), and GIPR (glucose-dependent insulinotropic polypeptide receptor). The researchers used computer-aided drug design, bioinformatics analyses, and molecular dynamics simulations to rationally identify key sequence determinants, optimal modification sites, and to understand how peptide "stapling" (a structural stabilization technique) affects alpha-helical stability and conformational rigidity. Based on these computational insights, 22 novel triagonist peptide structures were designed and synthesized. Their activity was evaluated in vitro using fluorescence membrane potential assays, with pharmacological balance assessed via a "balanced triagonism score" measuring consistency of activity across all three receptors. Most compounds showed highly balanced activity profiles. The lead compound, P2-L4, demonstrated low-nanomolar potency across all three receptor targets, with efficacy reported as comparable to existing incretin-based reference therapeutics. The study is limited to in vitro findings only, with no animal or human data reported. Further preclinical and clinical validation is required before any therapeutic conclusions can be drawn.
RSC medicinal chemistry · Mar 2026DOI ↗ Review
This narrative review synthesizes the existing literature on the metabolic benefits of GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists in individuals with overweight or obesity. The authors examine evidence supporting these agents' effectiveness for weight reduction and glycemic control, as well as their purported direct effects on multiple organ systems beyond glucose regulation. The review also explores the medium- to long-term implications for metabolic disease outcomes, including considerations of safety and cost-effectiveness with prolonged use. The authors conclude that GLP-1-based therapies show promise for both the improvement and prevention of metabolic disease, while noting that longer-duration studies are needed to broaden approved indications and confirm the safety profile of these agents. As a narrative review, the paper is subject to inherent limitations including potential selection bias in the literature chosen, the absence of a systematic search protocol or meta-analytic pooling, and reliance on the quality and duration of the underlying primary studies, which the authors themselves acknowledge are insufficiently long in many cases.
Healthcare (Basel, Switzerland) · Mar 2026DOI ↗ Review
This narrative review compares two incretin-based therapies — semaglutide, a selective GLP-1 receptor agonist, and tirzepatide, a dual GIP/GLP-1 receptor agonist — across their mechanisms of action, clinical efficacy, therapeutic indications, and cardiovascular/renal evidence. The authors describe semaglutide as having a well-established clinical profile with demonstrated benefits in glycaemic control, body weight reduction, and cardiovascular and renal outcomes. Tirzepatide is presented as a newer agent offering superior weight loss and improvements in insulin sensitivity, with an expanding range of therapeutic indications, though the authors note its cardiovascular outcomes evidence is less mature than that of semaglutide. The review emphasizes that despite shared benefits in reducing HbA1c and body weight, the two molecules differ meaningfully in their pharmacological mechanisms and evidence bases, requiring individualized clinical decision-making. The authors frame both agents within a broader "incretin revolution" relevant to cardio-reno-metabolic prevention. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and therefore does not provide independent experimental evidence to confirm or quantify any specific clinical claims.
European heart journal supplements : journal of the European Society of Cardiology · Mar 2026DOI ↗ Moderate · human
This meta-analysis pooled data from five randomised controlled trials to evaluate the efficacy and safety of mazdutide — a dual GLP-1 and glucagon receptor agonist — for weight management in non-diabetic adults with overweight or obesity. Searches were conducted across Cochrane Library, PubMed, Google Scholar, and ClinicalTrials.gov, and analyses were performed using random-effects models in RevMan 5.4. The pooled results reported by the study authors indicate that mazdutide was associated with significant reductions in percentage body weight (mean difference –12.42%), absolute body weight (–9.76 kg), and waist circumference (–7.98 cm) compared with control conditions. Secondary cardiometabolic outcomes — including systolic blood pressure (–7.68 mmHg), total cholesterol (–0.57 mmol/L), and LDL cholesterol (–0.37 mmol/L) — also showed reductions. Adverse events were slightly more frequent in the mazdutide groups (RR = 1.12), described as mild to moderate. A dose-wise meta-regression suggested a significant dose-dependent relationship. The authors acknowledge that findings are constrained by the small number of included trials (n = 5), which limits the robustness and generalisability of conclusions.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Review
This paper is a narrative review examining the clinical evidence on retatrutide (LY3437943), a novel triple receptor agonist targeting the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). The authors conducted an electronic literature search across Scopus, PubMed/MEDLINE, and Google Scholar to synthesize available findings. According to the review, studies in people with type 2 diabetes mellitus (T2DM) reported reductions in HbA1c of up to 2.16% and fasting glucose reductions of up to 69.1 mg/dL, alongside weight loss of up to 16.94%. In individuals with overweight or obesity (without T2DM), weight loss reached up to 26.56% (approximately 24.15 kg). Additional findings included reductions in BMI, waist circumference, and systolic blood pressure in those with T2DM and overweight/obesity, as well as a relative liver fat reduction of up to 86% in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD). The most commonly reported adverse events were mild-to-moderate gastrointestinal symptoms, particularly at higher doses. The authors conclude that retatrutide's effects on glycemic control, weight, and potential pleiotropic benefits warrant further investigation through larger, longer-duration trials.
Expert review of clinical pharmacology · Mar 2026DOI ↗ Insufficient
This paper describes a pre-registered protocol for a systematic review and network meta-analysis (NMA) examining the comparative efficacy and safety of GLP-1 receptor agonists (GLP-1 RAs) and novel co-agonists (e.g., dual/triple agonists) for weight loss in adults with overweight or obesity who do not have diabetes. The authors plan to search PubMed, Ovid, and Cochrane CENTRAL for randomized controlled trials (RCTs) comparing these agents against placebo or each other. Trials involving participants with diabetes, specific comorbidities, or prior bariatric surgery will be excluded. The primary outcome is relative change in body weight from baseline at approximately 6 months and 1–1.5 years. Secondary outcomes include absolute weight change, total adverse events, gastrointestinal adverse events, serious adverse events, and death. Frequentist random-effects pairwise and network meta-analyses will be conducted, with treatment rankings generated via the surface under the cumulative ranking curve (SUCRA). Risk of bias will be assessed using the Cochrane RoB 2 tool and the RoB-NMA tool. Importantly, this is a protocol paper only — no data have been collected or analyzed yet — so no results or conclusions about the efficacy or safety of any specific agent are available at this stage.
Systematic reviews · Mar 2026DOI ↗ Limited · human
This Brazilian retrospective regulatory surveillance study examined patterns of GLP-1 receptor agonist (GLP-1 RA) consumption, pharmacovigilance reports, and product falsification alerts between 2020 and 2024. Researchers triangulated data from three official sources: national pharmaceutical sales records classified by the Anatomical Therapeutic Chemical (ATC) system, adverse event reports submitted to Vigimed (Brazil's national pharmacovigilance platform linked to the global VigiBase), and official counterfeit product alerts. The study found that semaglutide was the dominant GLP-1 RA in the Brazilian market. Consumption was heavily concentrated in higher-GDP regions, revealing a geographic and economic disparity that did not align with regional diabetes prevalence rates. Pharmacovigilance data revealed a notable proportion of reports associated with off-label use, suggesting potential gaps in clinical practice and regulatory oversight. Additionally, documented cases of counterfeit GLP-1 RA products highlighted supply chain vulnerabilities. The authors concluded that rising demand, widespread off-label use, and product falsification collectively require a coordinated regulatory response. Limitations include the retrospective and observational nature of the data, reliance on administrative and surveillance databases, and the potential for underreporting in pharmacovigilance systems.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Limited · human
This retrospective observational study analyzed data from the National Poison Data System (NPDS) to characterize and compare glucagon-like peptide-1 receptor agonist (GLP-1 RA) exposures reported to U.S. poison centers between 2017 and 2024, focusing on differences between children (ages 6–17) and adults. Across 13,924 single-substance GLP-1 RA exposures, the authors found a dramatic overall increase of 1,830.8% in exposure rates over the study period, with an even steeper 4,805.0% rise among children 6–17 years old, most of which occurred after 2021. The majority of exposures (91.7%) resulted in no or mild effects; however, moderate effects were seen in 8.0% of cases and major effects in 42 exposures, with two deaths recorded. Children aged 6–17 were significantly more likely to be hospitalized than adults (RR: 2.66), and adolescents aged 12–17 were more likely to experience a serious medical outcome (RR: 1.68). Vomiting was the most common clinical effect in children (88.2%) versus adults (61.3%). Notably, exposures among children were far more likely to be classified as intentional misuse compared to adults (RR: 8.12). Limitations include reliance on voluntarily reported poison center data, potential underreporting, and inability to establish causation.
Journal of medical toxicology : official journal of the American College of Medical Toxicology · Mar 2026DOI ↗ Moderate · human
This systematic review and nonlinear meta-regression examined how body weight changes after people stop taking GLP-1 receptor agonists (GLP-1RAs), a class of medications widely used for obesity management. Researchers searched five major databases through August 2025 and identified 48 eligible studies. The core quantitative analysis focused on six randomised controlled trials (n = 3,236 participants) and applied a mixed-effects exponential recovery model to characterise the trajectory of weight regain over time. The study found that weight regain after GLP-1RA discontinuation follows a predictable, decelerating pattern: approximately 60% of treatment-related weight loss was regained within one year of stopping. The modelled plateau of regain was estimated at 75.3% (95% CI 68.9–81.6%) of lost weight, suggesting a residual but substantially attenuated long-term benefit. The rate constant of 0.0302 per week corresponded to a regain half-life of roughly 23 weeks. Secondary outcomes (HbA1c, systolic blood pressure) were explored but not the primary focus. Limitations include that most included studies carried moderate risk of bias, weight trajectories beyond 52 weeks were extrapolated rather than directly observed, and heterogeneity across study populations, GLP-1RA agents, and treatment durations may affect generalisability.
EClinicalMedicine · Mar 2026DOI ↗ Preclinical
This study investigated whether GLP-1 receptor agonist medicines cause disproportionate loss of lean body mass (LBM) or skeletal muscle in the context of obesity-related weight loss. Researchers conducted four pre-clinical studies in obese mice and a proof-of-concept clinical trial in humans (registered as NCT05606471). In obese mice, GLP-1 medicines primarily reduced body fat, with a small but statistically significant decrease in LBM. Notably, liver mass loss exceeded muscle mass loss among lean tissues. Although absolute muscle mass and strength declined, relative muscle mass and strength improved, leading to better running performance. The study also found that muscle atrophy during immobilization was similar regardless of treatment, but GLP-1 medicines produced a distinct muscle proteome signature compared to calorie restriction alone. In the human trial, patients with obesity treated with GLP-1 medicines showed improved body composition without negative effects on strength. The authors conclude that, in middle-aged mice and humans, GLP-1 medicines slightly reduce absolute muscle values but positively affect overall body composition and mobility. Limitations include the proof-of-concept (small-scale) nature of the clinical component and the use of animal models as a primary evidence base.
Cell reports. Medicine · Mar 2026DOI ↗ Limited · human
This retrospective, claims-based observational study examined real-world persistence, adherence, and weight-loss effectiveness of GLP-1 receptor agonists (semaglutide/Wegovy) and the dual GLP-1/GIP agonist (tirzepatide/Zepbound) among 7,493 adults enrolled in Massachusetts Medicaid (MassHealth) who initiated treatment between July and December 2024. At 6 months, the study found moderate rates of persistence (60.8%, defined as no gap greater than 56 days between fills) and adherence (60.1%, defined as proportion of days covered ≥80%). Male sex and younger age were among the member-specific factors associated with lower persistence and adherence. In a subgroup of highly persistent and adherent members with prior authorization recertification data, both tirzepatide and semaglutide were associated with at least 5% body weight reduction at 6 months. Key limitations include the retrospective claims-based design, which cannot establish causality, the restriction to a Medicaid population limiting generalizability, and the weight-loss outcome being measured only in a select, highly adherent subgroup rather than the full cohort.
Journal of managed care & specialty pharmacy · Mar 2026DOI ↗ Review
This review examines the landscape of next-generation glucagon-like peptide-1 (GLP-1)-based therapeutics in clinical development for type 2 diabetes and obesity, building on the established success of semaglutide and tirzepatide. The authors survey a broad range of investigational agents that target multiple gastro-entero-pancreatic hormone receptors simultaneously — including GIP, glucagon, amylin, and peptide YY receptors — to produce synergistic effects on energy intake, storage, and expenditure. Specific agents discussed include maridebart cafraglutide (GLP-1 agonism/GIP antagonism), survodutide and mazdutide (GLP-1/glucagon coagonists), cagrilintide combined with semaglutide (CagriSema), amycretin (amylin/GLP-1 dual agent), and retatrutide (GIP/GLP-1/glucagon triple agonist). The review also highlights the emergence of oral small-molecule GLP-1 receptor agonists such as danuglipron and orforglipron, which resist enzymatic degradation and may improve patient convenience. The paper does not present original clinical trial data; it synthesizes existing preclinical and clinical development evidence. As a narrative review, it does not meta-analytically pool outcomes, and the included agents are largely at Phase 1–3 stages, meaning long-term efficacy and safety data remain limited.
Endocrine reviews · Mar 2026DOI ↗ Strong · human
This systematic review and meta-analysis pooled evidence from 21 randomized controlled trials (n = 7,024 participants) to evaluate the weight-loss efficacy of GLP-1 receptor agonists (GLP-1 RAs) compared with placebo or active comparators. Across 16 placebo-controlled trials, the study found that a substantially higher proportion of participants achieved weight loss with GLP-1-based agents (78.54%) than with placebo (26.53%), yielding a pooled odds ratio of 11.37 (95% CI: 8.10–15.98). A frequentist network meta-analysis using SUCRA rankings suggested that tirzepatide and semaglutide demonstrated the greatest relative efficacy among agents evaluated. The authors concluded that GLP-1 RAs significantly increase the likelihood of weight loss and support their role in clinical obesity management. Notable limitations include the use of a fixed-effect model despite potential heterogeneity across trials, a binary primary endpoint (any weight loss) rather than magnitude of weight loss, the absence of a pre-registered protocol, and inclusion criteria restricted to the past five years in English only. These methodological choices may affect the precision and generalizability of the pooled estimates.
Review
This paper examines the ethical landscape surrounding semaglutide (marketed as Ozempic, Rybelsus, and Wegovy), a glucagon-like peptide-1 (GLP-1) receptor agonist manufactured by Novo Nordisk and primarily used to treat type II diabetes. The authors note that semaglutide has garnered widespread attention beyond its diabetic indication due to its effects on appetite suppression and weight loss, earning it the popular label of a "miracle drug." The paper surveys a range of ethical concerns that have been raised in both governmental and public discourse — including issues around drug access and equity, medicalization of obesity, societal body-image pressures, and resource allocation — and critically analyzes whether these concerns are sufficient to advise against prescribing semaglutide for weight loss. The authors ultimately argue that, while many of the ethical objections raised are legitimate and deserve serious consideration, none individually or collectively constitute a conclusive reason to withhold semaglutide prescriptions for weight management purposes. As an ethics and policy review, the paper does not present original clinical trial data and offers no empirical findings on patient outcomes. Its conclusions are based on philosophical argument and literature synthesis rather than experimental evidence.
Journal of medical ethics · Feb 2026DOI ↗