Strong · human
This living systematic review and network meta-analysis, commissioned by the American College of Physicians, synthesized evidence from 69 randomized controlled trials involving 112,511 adults with overweight or obesity (BMI ≥25 kg/m²) to compare pharmacologic weight-management treatments. Drugs examined included GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide), dual agonists (tirzepatide, retatrutide, semaglutide-cagrilintide), and other agents (naltrexone-bupropion, phentermine, phentermine-topiramate, orforglipron), with or without lifestyle intervention. The review found that nearly all studied interventions produced greater weight loss than placebo and/or lifestyle intervention alone. Semaglutide was found to probably reduce mortality and major adverse cardiovascular events (MACE). Semaglutide and tirzepatide demonstrated the greatest weight loss in both pairwise and network meta-analyses. However, nearly all active treatments were also associated with more treatment discontinuations due to adverse events compared with placebo. The authors noted that evidence for critical outcomes such as mortality, MACE, and serious adverse events remained limited, and direct head-to-head comparisons between treatments were scarce. Thirty-seven of the 69 included studies were rated at low risk of bias. The living review design allows for ongoing evidence updates as new trials emerge.
Annals of internal medicine · Jun 2026DOI ↗ Insufficient
This scoping review, conducted following PRISMA-ScR guidelines, examines whether GLP-1 receptor agonists (GLP-1 RAs) — including semaglutide, liraglutide, tirzepatide, and retatrutide — may interfere with autologous fat grafting outcomes. The authors note that millions of patients using GLP-1 RAs for weight loss now present to aesthetic surgeons with facial volume loss and soft tissue deflation, conditions commonly treated with fat grafting. The review synthesizes preclinical and clinical evidence on how GLP-1 RA medications affect adipocyte biology, adipose-derived stem cell (ASC) function, and tissue revascularization. The authors identify several theoretical interference points: GLP-1-mediated adipocyte "browning" and thermogenic activation (including UCP1 upregulation), enhanced lipolysis via ATGL and HSL pathways, suppression of white adipogenic differentiation in ASCs favoring beige/thermogenic lineages, and altered angiogenic and inflammatory signaling during the revascularization window critical to graft survival. The authors explicitly acknowledge that no clinical or preclinical studies have directly examined fat graft outcomes in patients receiving these therapies. The review's conclusions are framed as hypothesis-generating, and any clinical considerations offered are described as mechanism-based rather than evidence-based. This limits the paper's direct applicability to patient care.
Aesthetic surgery journal · Jun 2026DOI ↗ Review
This review synthesizes evidence from randomized controlled trials and high-quality meta-analyses on approved and investigational obesity medications, examining their effects beyond weight loss alone. Medications reviewed include phentermine-topiramate, naltrexone-bupropion, GLP-1 receptor agonists (liraglutide, semaglutide), and newer multiagonist agents (tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). The authors evaluated impacts across a broad range of obesity-related comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnea, polycystic ovary syndrome, osteoarthritis, muscle mass, depression, quality of life, food cravings, binge-eating disorders, substance use disorders, and neurodegenerative diseases. The review concludes that GLP-1-based and multiagonist therapies demonstrate beneficial effects across these conditions. Notably, the authors report that while many benefits appear to be mediated through weight reduction, accumulating evidence suggests weight loss-independent mechanisms, particularly for GLP-1 receptor agonist-based therapies. Key limitations include its reliance on synthesized rather than primary data and variability in evidence quality across the individual conditions reviewed.
The lancet. Diabetes & endocrinology · May 2026DOI ↗ Limited · human
This pharmacovigilance study investigated reports of dysesthesia (abnormal skin sensations, particularly burning sensations) associated with GLP-1 receptor agonists, including semaglutide, tirzepatide, exenatide, and others. The researchers conducted a disproportionality analysis using VigiBase — the WHO's global drug safety database — focusing on the High Level Term "Paraesthesia and dysesthesia," supplemented by a qualitative review of case narratives from the French Pharmacovigilance database and a broader literature review. The analysis found that exenatide was significantly associated with hypoesthesia and oral paraesthesia, while semaglutide and tirzepatide were associated with hyperaesthesia; semaglutide was also linked to dysesthesia and burning sensations specifically. The study suggests dysesthesia may be dose-dependent and more frequent with more potent agents used at higher doses. Many reported cases involved drug discontinuation followed by spontaneous resolution, and some rechallenge cases were documented. Key limitations include the inherent biases of spontaneous reporting systems (underreporting, confounding, notoriety bias), the inability to establish causality, and the absence of controlled comparison groups. The authors conclude that pharmacovigilance data reinforces signals already observed in clinical trials of semaglutide, tirzepatide, and retatrutide.
European journal of clinical pharmacology · May 2026DOI ↗ Review
This narrative review examines the relationship between diabetes mellitus (DM) and stroke, and evaluates the cerebrovascular potential of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide). The authors summarize evidence from large cardiovascular outcome trials (CVOTs), noting that agents such as semaglutide and liraglutide were associated with reductions in non-fatal stroke incidence, fewer hospitalizations, and improved neurological outcomes in patients with prior stroke or high cardiovascular risk. The review highlights that stroke reduction may represent a class effect of GLP-1 RAs, though differences between individual agents exist, attributed to variations in pharmacokinetics, receptor affinity, and study populations. Evidence in the acute stroke setting is described as preliminary, coming largely from early-phase or ongoing trials. The authors also discuss emerging agents—orforglipron, retatrutide, Maridebart cafraglutide, and CagriSema—as potential future options. Limitations acknowledged include the narrative (non-systematic) design, reliance on trial-level rather than individual patient data, and the absence of large-scale, long-term randomized trials specifically targeting post-stroke populations. The authors conclude that GLP-1-based therapies should currently be considered tools for long-term vascular risk reduction rather than established acute stroke treatments.
Pharmaceutics · May 2026DOI ↗ Review
This narrative review examines the potential role of incretin-based therapies in treating metabolic dysfunction-associated steatotic liver disease (MASLD), a condition strongly linked to metabolic syndrome and a leading cause of chronic liver disease. The authors highlight that no approved pharmacological treatments currently exist for MASLD and that progression to advanced fibrosis poses a significant clinical challenge. The review synthesizes evidence on GLP-1 receptor agonists, which the authors report have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, largely attributed to weight loss and improved insulin sensitivity. Dual agonists such as tirzepatide (GLP-1/GIP) are described as demonstrating superior hepatic and metabolic outcomes. Emerging agents including cotadutide (GLP-1/glucagon dual agonist) and retatrutide (GLP-1/GIP/glucagon triagonist) are presented as a novel frontier, with early clinical data suggesting potent hepatoprotective effects and favorable metabolic remodeling. The authors acknowledge that evidence on fibrosis progression remains limited. As a narrative review without systematic search methodology or meta-analysis, this paper is susceptible to selection bias and does not establish causality. It provides a useful synthesis of the current landscape but should be interpreted with appropriate caution.
Medicina (Kaunas, Lithuania) · May 2026DOI ↗ Insufficient
TRANSCEND-CKD (NCT05936151) is a double-blind, placebo-controlled Phase 2b mechanistic trial evaluating retatrutide — a triple agonist of the GIP, GLP-1, and glucagon receptors — in adults with overweight or obesity and chronic kidney disease (CKD). The publication describes the trial's rationale, design, and baseline characteristics of the 146 randomized participants (out of 367 screened). Participants had a mean age of 65.1 years, mean BMI of 35.7 kg/m², and mean measured GFR of 49.3 mL/min/1.73 m² (eGFR range 25–75). Roughly 38% had type 2 diabetes. Participants were randomized 1:1 to once-weekly retatrutide (maximum tolerated dose up to 12 mg) or matched placebo. The primary endpoint is change in measured GFR via iohexol clearance at 24 weeks; secondary endpoints include MRI-assessed kidney hemodynamics, volumes, and perirenal/renal sinus fat. The study is explicitly designed as a mechanistic precursor to the larger cardio-kidney outcomes trial TRIUMPH-Outcomes. Because this paper reports only design and baseline data — with no efficacy or safety outcomes yet — no conclusions about retatrutide's effects on kidney function can be drawn from it.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · May 2026DOI ↗ InsufficientPreprint
This study analyzed a large, publicly available independent testing dataset of 6,441 samples spanning fourteen peptide compounds sold through largely unregulated gray market channels directly to consumers. Compounds examined included BPC-157, semaglutide, tirzepatide, PT-141, TB-500, thymosin beta-4, and others marketed for purposes such as injury recovery, muscle growth, fat loss, and athletic performance. Researchers applied two quality acceptance frameworks — one approximating standards for 503A compounded medications and a stricter model reflecting FDA-approved drug production standards — to assess purity, measured abundance, and endotoxin burden. The study found that between 41.6% and 71.1% of samples failed to meet basic quality criteria depending on the framework applied, and measurable endotoxin contamination was detected in 15% of samples. Gray market peptides were consistently cheaper than FDA-approved alternatives, though cost differentials varied widely (e.g., 72.8% higher for tirzepatide vs. 3,850% higher for PT-141 when comparing FDA-approved options). The authors concluded that consumer-directed third-party testing improves transparency but captures only a fraction of the full safety profile relevant to patients self-administering injectable compounds. Key limitations include reliance on a secondary dataset not collected under controlled research conditions and the inability to assess many other safety dimensions beyond purity and endotoxin levels.
Unknown journal · Apr 2026DOI ↗ Animal only
This preclinical study investigated whether obesity could be reversed without activating the GLP-1 receptor (GLP-1R), which is commonly associated with adverse gastrointestinal side effects in current therapies. Using diet-induced obese (DIO) mice and rats, as well as GLP-1R knock-out (KO) mice, researchers tested selective, dual, and triple agonists targeting the GIP receptor (GIPR), glucagon receptor (GCGR), and GLP-1R in various combinations. Three independent experimental approaches — (1) administering the triagonist retatrutide to GLP-1R KO mice, (2) physically combining separate selective GIPR and GCGR agonists, and (3) testing a novel unimolecular GIPR:GCGR co-agonist called BWB3054 — all demonstrated meaningful reductions in body weight and improvements in blood glucose without meaningful GLP-1R engagement. BWB3054 showed potency at the mouse GIPR comparable to retatrutide, 4-fold reduced potency at the mouse GCGR, and more than 100-fold reduced potency at the mouse GLP-1R. Indirect calorimetry and pair-feeding studies were used to characterize mechanisms of weight loss. A key limitation is that all experiments were conducted in rodents, leaving the translatability of these findings to humans uncertain. The study raises the possibility that GLP-1R-independent obesity treatment strategies could avoid the GI tolerability issues seen with current agents.
Molecular metabolism · Apr 2026DOI ↗ Review
This narrative review synthesizes the evolution of incretin-based pharmacotherapies for metabolic disorders, drawing on literature from PubMed, Scopus, and Google Scholar up to July 2025. The authors trace the trajectory from DPP-4 inhibitors—noted for modest glycaemic benefits—through GLP-1 receptor agonists (GLP-1RAs) such as liraglutide and semaglutide, which pivotal trials have associated with meaningful weight loss and cardiometabolic protection, to next-generation agents. Dual GIP/GLP-1 agonist tirzepatide and triple agonist retatrutide are highlighted as demonstrating particularly substantial efficacy, with the review citing up to 24% body weight reduction alongside improvements in hepatic and inflammatory markers in included trials. Agents such as cotadutide and efinopegdutide are discussed in the context of expanding indications to MASLD and MASH. The authors acknowledge several limitations across the field: high cost and accessibility barriers, underrepresentation of low- and middle-income country populations in major trials, and pharmacogenomic variability that may modify therapeutic response. As a review, this paper does not generate new primary data. Its conclusions depend on the quality and representativeness of the underlying trials it synthesizes, and no independent meta-analytic pooling appears to have been conducted.
The Indian journal of medical research · Apr 2026DOI ↗ Review
This review examines the global burden of pediatric obesity and its cardiovascular consequences, drawing on data from PubMed, Scopus, and Springer databases. The authors report that over 381 million children worldwide are affected by obesity, and that childhood obesity substantially increases the risk of adult obesity and cardiovascular diseases (CVD) including atherosclerosis, coronary artery disease, hypertension, dysglycemia, dyslipidemia, arrhythmias, and stroke. The study identifies both genetic contributors (highlighted by genome-wide association studies) and lifestyle drivers such as physical inactivity, prolonged screen time, and poor diet. The authors evaluate public health frameworks including the WHO Global Action Plan on Physical Activity 2018–2030, as well as management strategies spanning lifestyle modification, pharmacotherapy (notably GLP-1 receptor agonists semaglutide and liraglutide), and bariatric surgery. They highlight data from the SURMOUNT-5 trial on tirzepatide and discuss emerging investigational agents including cagrilintide/semaglutide combination, orforglipron, danuglipron, and retatrutide. Gene therapy is noted as experimental. A key limitation is that this is a narrative review without systematic methodology or original data collection, limiting causal inference.
Clinical nutrition ESPEN · 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 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 ↗ Moderate · human
This network meta-analysis systematically evaluated the comparative efficacy and safety of four investigational glucagon receptor agonist (GRA)-based agents — retatrutide, cotadutide, mazdutide, and survodutide — in adults with type 2 diabetes, overweight, or obesity. Researchers searched PubMed, Cochrane, Embase, and Scopus, ultimately including 14 randomised controlled trials analyzed using frequentist network meta-analysis with random-effects models. Key outcomes included absolute and percent body weight change, HbA1c reduction, adverse events, and treatment discontinuation due to adverse events. The study found that retatrutide produced the greatest absolute weight reduction versus placebo (MD −13.44 kg), followed by survodutide (MD −10.74 kg) and mazdutide (MD −6.47 kg); cotadutide's effect did not reach statistical significance. Retatrutide also showed the largest HbA1c reduction, though only its effect was statistically significant among the agents. Regarding tolerability, mazdutide demonstrated the most favorable safety profile, while retatrutide and cotadutide were associated with comparatively lower tolerability. The authors acknowledge limitations inherent to network meta-analysis, including reliance on early- and mid-phase trial data and the absence of direct head-to-head comparisons between agents.
Endocrinology, diabetes & metabolism · 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 ↗ Animal only
This animal study investigated the anti-obesity effects of three GLP-1 receptor agonist peptides — semaglutide, tirzepatide, and retatrutide — in melanocortin 4 receptor knockout (MC4R KO) mice, a model of genetically driven obesity caused by disruption of the POMC-MC4R signaling pathway. All three compounds were administered for 21 days, after which body weight, body composition, metabolic markers, liver health, and gene expression were assessed. The study found that all three GLP-1 analogs produced statistically significant reductions in body weight, with tirzepatide showing the greatest effect (approximately 31.6%), followed by retatrutide (approximately 24.1%) and semaglutide (approximately 19.7%). All three agents reduced both fat and lean mass, improved plasma insulin levels and insulin resistance (HOMA-IR), lowered cholesterol, and reduced markers of liver damage (AST and ALT) as well as liver hypertrophy. Gene expression analysis showed suppression of fatty acid synthesis genes, but no significant effect on inflammatory gene expression. Energy expenditure was reduced by all agents; only tirzepatide significantly decreased the respiratory quotient. A key limitation is that this is a mouse model study, and findings may not directly translate to humans. The authors suggest MC4R KO mice are a valid model for studying obesity-related drug efficacy.
International journal of obesity (2005) · Feb 2026DOI ↗ Strong · human
This systematic review and meta-analysis pooled data from 10 randomized controlled trials (3,236 participants) to evaluate the efficacy and safety of incretin-based dual and triple receptor agonists — specifically tirzepatide, retatrutide, and mazdutide — in overweight or obese adults. The authors searched PubMed, the Cochrane Library, and Google Scholar through June 2025 and applied a random-effects model to pool outcomes. The study found that these agents were associated with statistically significant reductions in body weight (mean difference: −11.47 kg), waist circumference (−9.40 cm), glycated hemoglobin (−0.96%), and fasting plasma glucose (−26.89 mg/dL) compared to placebo. On the safety side, treatment was associated with a higher risk of any adverse event (RR 1.13), gastrointestinal adverse events (nausea, vomiting, diarrhea, constipation), treatment discontinuation due to adverse events (RR 1.96), and hypoglycemic episodes (RR 3.08). No significant difference in serious adverse events was observed. Limitations include the relatively small number of pooled trials, heterogeneity inherent across different agents and doses, and the restriction to placebo-controlled comparisons, which limits conclusions about comparative effectiveness between agents.
Cardiology in review · Feb 2026DOI ↗ Moderate · human
This systematic review and meta-analysis examined the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and heart rate (HR) changes in people with overweight or obesity who do not have diabetes. Researchers searched four major databases (PubMed, Web of Science, Embase, and Cochrane Library) and ultimately included 12 randomized controlled trials. Using both pairwise and network meta-analysis methods, the study calculated mean differences (MDs) in HR compared to placebo. Pairwise meta-analysis found that all analyzed GLP-1RAs — including liraglutide, semaglutide, orforglipron, oral semaglutide, tirzepatide, retatrutide, and the drug class overall — were associated with statistically significant increases in heart rate versus placebo. Network meta-analysis, which allows indirect comparisons across agents, suggested that orforglipron 36 mg was associated with the most pronounced HR increase, while tirzepatide 5 mg showed the least increase (and its result was not statistically significant). Key limitations include the indirect nature of network comparisons, variability in trial designs and follow-up durations, and the restriction to a non-diabetic population, which limits generalizability. The clinical significance of the observed HR increases was not fully addressed.
European journal of medical research · Jan 2026DOI ↗ Review
This perspective article examines retatrutide (LY3437943), a novel triple receptor agonist that simultaneously targets GLP-1, GIP, and glucagon receptors, positioning it as a significant advancement in obesity pharmacotherapy. The authors contextualize retatrutide within the broader evolution of incretin-based therapies, arguing that its multi-hormonal mechanism addresses limitations of existing GLP-1 and dual GIP/GLP-1 agonists. The article highlights Phase 2 trial findings, which reportedly demonstrated weight reductions comparable to bariatric surgery, along with potential benefits for metabolic comorbidities including non-alcoholic steatohepatitis (NASH) and cardiovascular disease. The authors frame retatrutide as a proof-of-concept for rational multi-agonist peptide engineering and advocate for broader scientific engagement, health equity considerations, and proactive policy planning in anticipation of wider clinical adoption. As a perspective/review piece, this paper synthesizes existing evidence rather than presenting original trial data, and does not provide head-to-head comparisons or long-term safety data. Its conclusions are largely interpretive, and the characterization of Phase 2 findings as surgery-comparable warrants cautious interpretation pending Phase 3 results and regulatory review.
Clinical pharmacology in drug development · Jan 2026DOI ↗ Moderate · human
This systematic review and meta-analysis evaluated the efficacy and safety of retatrutide — a novel triple agonist (GIP/GLP-1/glucagon receptor) — specifically in patients with type 2 diabetes and/or obesity comorbid with chronic kidney disease (CKD). Researchers conducted a comprehensive literature search and ultimately included eight randomized controlled trials. The study found that retatrutide was associated with a statistically significant mean reduction in HbA1c of -1.04% (95% CI: -1.42 to -0.67) and body weight reductions of up to -24.2%. A subgroup analysis suggested a dose-dependent pattern in glycemic outcomes, with lower doses appearing to produce greater HbA1c reductions than higher doses, though this finding warrants cautious interpretation. Secondary analyses indicated possible renoprotective effects, reflected by reductions in albuminuria. Gastrointestinal adverse events were the most commonly reported safety concern, consistent with the broader drug class. Key limitations include the small number of included studies (n=8), potential heterogeneity across trials, and the fact that CKD-specific data may have been drawn from subgroup analyses of broader trials rather than CKD-dedicated studies. The overall evidence base for retatrutide in CKD patients remains early-stage.