Review
This narrative review examines the expanding therapeutic landscape of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) beyond their established roles in glycemic control and the metabolic-cardiovascular-renal axis. The authors searched PubMed, Scopus, and Google Scholar for publications from 2014 to 2026, with over 80% of included studies published between 2020 and 2026. The review synthesizes findings across a broad range of conditions, reporting associations between GLP-1 RA use and potential benefits in substance use disorders, mental health disorders, neurodegenerative diseases, liver disease (including reduced hepatic steatosis and lower risk of hepatocellular carcinoma), genitourinary disorders, polycystic ovary syndrome (PCOS), male fertility and libido, prostate cancer, osteoarthritis, and sleep apnea. The authors note that GLP-1 RAs currently represent the most effective pharmacological agents for obesity treatment. Key limitations include the narrative (non-systematic) review design, which is susceptible to selection bias, and the authors' own acknowledgment that much of the supporting evidence is preliminary, requiring further large-scale, well-designed clinical trials to establish efficacy and safety across these emerging indications.
Journal of clinical medicine · Apr 2026DOI ↗ Review
This review examines the acute contractile effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on the human heart, with a focus on isolated atrial and ventricular cardiac preparations from both failing and non-failing hearts. The paper discusses how GLP-1R stimulation in cell cultures, neonatal cardiomyocytes, and adult atrial cardiomyocytes elevates adenylyl cyclase activity and increases cAMP levels, a key intracellular signaling pathway. The authors explore the expanding landscape of receptor agonists — including single GLP-1R agonists as well as dual and triple agonists targeting the glucagon receptor (GCGR) and/or the GIP receptor (GIPR) — in the context of treating type 2 diabetes, obesity, liver disease, and cardiovascular conditions. GLP-1R expression across different cardiac regions of the human heart is also reviewed. The paper critically evaluates existing experimental and clinical data, notes that several newer agents remain in early clinical development phases, and identifies gaps requiring further research. A key limitation is that the review synthesizes heterogeneous experimental and early-phase clinical data rather than presenting original controlled trial findings, limiting the strength of conclusions about cardiac efficacy or safety in humans.
Pharmaceutics · Apr 2026DOI ↗ Strong · human
This systematic review and network meta-analysis compared the weight-loss efficacy and safety of three FDA-approved agents—tirzepatide (a dual GIP/GLP-1 agonist), semaglutide, and liraglutide—in non-diabetic adults with obesity. Researchers searched four major databases through May 2025 and identified 15 Phase 3 RCTs encompassing 14,059 patients. Using a frequentist random-effects network meta-analysis, the authors found that all three agents produced statistically significant body weight reductions compared to placebo. Ranking by magnitude of effect, the highest tolerated dose of tirzepatide demonstrated the greatest weight reduction, followed by lower tirzepatide doses, then semaglutide, and finally liraglutide. On the safety side, tirzepatide and semaglutide were each associated with a higher risk of any adverse event compared to placebo, while liraglutide was not. The authors note that the analysis was limited to Phase 3 RCTs and did not assess long-term outcomes such as weight regain after discontinuation, metabolic endpoints, cost-effectiveness, or patient preferences, which they identify as priorities for future research.
Obesity (Silver Spring, Md.) · Apr 2026DOI ↗ Moderate · human
This systematic review and meta-analysis pooled data from three head-to-head randomized or controlled trials comparing tirzepatide (a dual GIP/GLP-1 receptor agonist) with semaglutide (a selective GLP-1 receptor agonist) in adults with obesity and/or type 2 diabetes. Studies were identified through searches of PubMed, Embase, and ScienceDirect up to February 2026. Using a random-effects model, the authors found that tirzepatide was associated with significantly greater weight reduction compared to semaglutide (pooled mean difference: −5.19 kg) and a higher likelihood of achieving ≥10% weight loss (pooled risk ratio: 1.50). No statistically significant differences were observed in overall adverse events or gastrointestinal events between the two agents; however, serious adverse events were reported more frequently with tirzepatide (risk ratio: 1.83). Key limitations include a very small number of included studies (n=3), substantial statistical heterogeneity in weight-related outcomes (I² >86%), and insufficient follow-up duration to draw conclusions about long-term cardiovascular safety. The authors note that further studies with longer follow-up are needed to confirm the cardiometabolic safety profile of tirzepatide relative to semaglutide.
Nepal journal of epidemiology · Apr 2026DOI ↗ In vitro
This in vitro study examined the effects of three incretin-based therapies — semaglutide (GLP-1 receptor agonist), tirzepatide (dual GLP-1/GIP agonist), and cagrilintide (amylin analogue) — on mitochondrial function in C2C12 skeletal muscle myotubes under both normal and lipotoxic conditions. Lipotoxicity was induced using palmitic acid (PA), which significantly reduced basal oxygen consumption rate and ATP production in treated cells. The study used Seahorse XFp metabolic flux analysis, mitochondrial DNA copy number quantification (qPCR), and oxidative phosphorylation complex protein expression (western blotting), with key findings replicated in primary human skeletal muscle cells. The researchers found that semaglutide and cagrilintide transiently reduced basal respiration in healthy myotubes, while tirzepatide demonstrated more sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions. The study's primary limitations include its reliance on cell culture models, meaning findings may not directly translate to whole-organism physiology, and the use of a single lipotoxic stimulus. The partial replication in human primary cells adds some translational relevance, but in vivo validation remains absent.
Journal of cachexia, sarcopenia and muscle · Apr 2026DOI ↗ Review
This review paper examines the role of amylin — a pancreatic hormone — in regulating food intake, body weight, and reward processing through its actions in the brain. The authors outline how early research focused on hindbrain regions as the primary sites where amylin suppresses feeding, but highlight more recent evidence pointing to mesolimbic brain structures (associated with reward and motivation) as additional key targets. The review discusses findings suggesting that amylin signaling in these reward-related areas influences not only consumption of palatable foods but also responses to drugs of abuse, raising important considerations for the development of amylin-based obesity therapies. The paper is contextualized within the broader landscape of obesity treatment, acknowledging the success of GLP-1 receptor agonists while arguing that amylin represents a complementary pharmacological avenue. As a narrative review, the paper synthesizes existing literature rather than presenting new experimental data, meaning its conclusions are only as strong as the individual studies it draws upon. It does not provide direct clinical trial evidence, and the breadth of findings discussed spans animal models and limited human data, which constrains the translational certainty of its conclusions.
Comprehensive Physiology · Apr 2026DOI ↗ Limited · human
This cross-sectional study conducted in Saudi Arabia (January–June 2025) investigated the frequency, characteristics, and predictors of hair loss among 254 adults using GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Ozempic), tirzepatide (Mounjaro), liraglutide (Saxenda), or liraglutide (Victoza) — primarily for weight loss. Data were collected via structured questionnaires covering demographics, clinical characteristics, and hair loss details such as timing, severity, and progression. The majority of participants were female (71.3%), with a mean age of approximately 33 years. The study found that overall hair loss prevalence did not differ significantly across GLP-1RA types (p = 0.116); however, severe hair loss was reported significantly more often among Mounjaro (43.4%) and Saxenda (42.9%) users. Female sex and Mounjaro use were identified as notable predictors of hair loss. The authors noted that the hair loss observed was generally non-scarring and potentially reversible, but associated with psychological distress and possible impacts on treatment adherence. Key limitations include the cross-sectional design (precluding causal inference), reliance on self-reported data, the single-country sample limiting generalizability, and the absence of a control group not using GLP-1RAs.
Journal of cosmetic dermatology · Apr 2026DOI ↗ Review
This review article provides a comprehensive overview of glucagon-like peptide-1 (GLP-1) receptor agonists, a class of incretin-based therapies used in the management of type 2 diabetes mellitus and obesity. The authors describe the multiple mechanisms of action of these agents, including glucose-mediated insulin stimulation, slowing of gastric emptying, glucagon inhibition, favorable shifts in the intestinal microbiome, and direct hypothalamic effects that promote satiety and weight loss. The review highlights findings from large-scale randomized controlled trials demonstrating that GLP-1 receptor agonists can reduce cardiovascular risk and slow progression to renal failure in high-risk individuals and those with type 2 diabetes. It also covers dual GLP-1 and glucose-dependent insulinotropic peptide (GIP) agonists. The authors note that adverse effects are predominantly gastrointestinal and raise concerns about potential loss of muscle and bone mass. Unresolved questions include long-term treatment adherence, weight regain following discontinuation, and the clinical significance of muscle and bone changes. Emerging research is exploring additional therapeutic applications. As a narrative review, it does not present original data, which limits its direct evidentiary weight.
The New England journal of medicine · Apr 2026DOI ↗ Review
This review examines the cardioprotective potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with autoimmune rheumatic diseases (ARDs), a population at elevated risk of premature cardiovascular death. The authors synthesize evidence from landmark randomized controlled trials in diabetes and obesity—where GLP-1RAs demonstrated cardiovascular, kidney, and metabolic benefits—alongside observational studies in ARD populations (including rheumatoid arthritis and systemic lupus erythematosus) that reported reductions in cardiovascular event risk comparable to those seen in broader populations. The review outlines proposed direct and indirect cardioprotective mechanisms: GLP-1RAs address type 2 diabetes and obesity as cardiovascular risk factors, reduce lipid levels by mitigating post-prandial hyperlipidemia, lower blood pressure via carotid body-mediated sympathetic suppression, and exhibit anti-atherogenic and anti-inflammatory properties observed in murine models. Anti-inflammatory effects are attributed to direct activation of GLP-1 receptors on gut intraepithelial lymphocytes and indirect modulation of myeloid cell inflammation through central neuronal GLP-1 receptor activation. The authors acknowledge remaining knowledge gaps and note that much mechanistic evidence derives from animal studies. Overall, they conclude existing evidence is supportive but not definitive for GLP-1RA cardioprotection in ARDs.
Rheumatology (Oxford, England) · Apr 2026DOI ↗ Review
This narrative review synthesizes evidence on how GLP-1-based therapies (liraglutide, semaglutide, tirzepatide, dulaglutide, exenatide) interact with the gut microbiome and influence metabolic dysfunction-associated steatotic liver disease (MASLD/MASH) in the context of type 2 diabetes mellitus (T2DM). The authors searched PubMed, Scopus, and ClinicalTrials.gov (2015–2026), ultimately including 33 studies (18 preclinical, 15 clinical) out of 363 identified. Preclinical findings suggest liraglutide normalized the Firmicutes/Bacteroidetes ratio and increased beneficial bacteria, while tirzepatide reduced hepatic steatosis and increased Akkermansia abundance in diabetic mice, and semaglutide improved gut barrier integrity in murine models. Clinically, tirzepatide achieved MASH resolution in 44–62% of patients in the phase 2 SYNERGY-NASH trial, and the FDA approved semaglutide for MASH with fibrosis in August 2025 based on the Phase 3 ESSENCE trial. A longitudinal study found baseline microbiome composition predicted glycemic response to semaglutide. Key limitations include the narrative (non-systematic) design, heavy reliance on preclinical data, and heterogeneous study populations. The authors conclude that personalized MASLD management informed by microbiome profiling warrants further dedicated clinical investigation.
Biomedicines · Apr 2026DOI ↗ Review
This narrative review synthesizes evidence from randomized controlled trials, meta-analyses, and observational studies through 2026 to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual incretin-based therapies on a range of ocular outcomes. The authors report that recent meta-analyses indicate an overall neutral long-term risk profile for diabetic retinopathy and macular edema with these agents. They describe a transient early worsening of diabetic retinopathy observed primarily in patients with advanced baseline disease undergoing rapid HbA1c reduction, framing this as a "metabolic transition phenomenon" rather than direct retinal toxicity—an interpretation supported by data from the SELECT trial, in which no increased ocular risk was found in a non-diabetic population. The review also notes observational signals suggesting possible protective associations with glaucoma and age-related macular degeneration, a potential safety concern regarding nonarteritic anterior ischemic optic neuropathy at low absolute incidence, and emerging evidence of benefit in ocular surface homeostasis and uveitis. Limitations include reliance on observational data for several signals and the inherent constraints of a narrative review design. The authors conclude that risk-stratified ophthalmic monitoring, aligned with a cited 2025 expert consensus, is preferable to routine treatment avoidance in high-risk diabetic patients.
Journal of obesity & metabolic syndrome · 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 emerging pharmacological approaches for managing obesity in patients with cardiovascular disease, with a focus on novel anti-obesity agents beyond the already-established semaglutide and tirzepatide. The authors surveyed the current landscape of investigational weight-lowering drugs, categorizing them by their primary mechanisms of action: reducing caloric intake, increasing basal metabolic rate, and increasing muscle mass. The review highlights that GLP-1 receptor agonists (GLP-1 RAs) have demonstrated both significant weight reduction and cardiovascular benefits, but notes a concern regarding muscle wasting associated with their use. The authors suggest that combination therapies using agents with complementary mechanisms may help mitigate this side effect. The review concludes that obesity treatment is likely to become more personalized over time and anticipates further cardiovascular benefits from pipeline agents. The authors also emphasize that the strongest evidence linking increased muscle mass and basal metabolic rate to improved cardiovascular health comes from diet and physical activity, positioning pharmacotherapy as a complement to—rather than a replacement for—healthy lifestyle changes. As a narrative review, this paper does not perform systematic synthesis or meta-analysis, and its conclusions reflect the authors' expert opinion rather than pooled quantitative data.
Biomedicines · Mar 2026DOI ↗ Review
This review paper systematically examines the patent landscape and therapeutic development trajectory of mazdutide, a dual GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist being investigated for obesity and type 2 diabetes. Using the Patentscope database, the authors analyzed 12 patent families filed between 2015 and 2025, covering composition-of-matter, process chemistry, formulation technologies, dosing regimens, and therapeutic applications. The review traces innovation from early peptide design work by Eli Lilly to formulation, clinical, and indication-expansion strategies later pursued by Innovent Biologics, including applications in obesity, type 2 diabetes, hyperuricemia, and adolescent obesity. The authors argue that mazdutide's development illustrates a "layered" intellectual property strategy — integrating molecular design, manufacturability, formulation stability, and clinical-use claims — as a model for securing durable market exclusivity for next-generation peptide therapeutics. Limitations include that this is a review and patent analysis rather than a clinical study, so it does not directly evaluate patient outcomes, safety, or comparative efficacy. The paper provides strategic and historical context for mazdutide's development rather than original experimental data.
Expert opinion on therapeutic patents · Mar 2026DOI ↗ Moderate · human
This systematic review and meta-analysis (PRISMA 2020, PROSPERO-registered) pooled three randomized controlled trials (N = 13,590 adults with type 2 diabetes) comparing once-weekly tirzepatide — a dual GIP/GLP-1 receptor agonist — against dulaglutide (a GLP-1 receptor agonist) over at least 26 weeks. The primary safety outcome was overall adverse event incidence, which the study found did not differ significantly between treatments (RR 1.04; moderate-certainty evidence). However, discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32; high-certainty evidence), suggesting a tolerability-persistence trade-off. Glycemic target achievement (HbA1c) was population-dependent: tirzepatide showed consistent benefit at the primary threshold in treatment-naïve patients receiving lower-dose dulaglutide, while the advantage narrowed in patients with established cardiovascular disease on higher-dose dulaglutide; heterogeneity was extreme at the strictest threshold. Weight-loss threshold achievement favored tirzepatide, though evidence certainty was very low due to substantial heterogeneity. Serious adverse events did not differ significantly. Key limitations include only three included trials, high heterogeneity for several outcomes, and restricted generalizability across patient subgroups. GRADE certainty ranged from very low to high across outcomes.
Healthcare (Basel, Switzerland) · Mar 2026DOI ↗ Moderate · human
This retrospective cohort study used the TriNetX global federated electronic health record (EHR) database to compare real-world cardiovascular outcomes between tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a GLP-1 receptor agonist) in non-diabetic adults treated for obesity. Patients who initiated either medication between November 2023 and August 2024 were included, with individuals having recent atherosclerotic events, prior heart failure, or treatment crossovers excluded. After 1:1 propensity score matching yielding 35,336 pairs, the study found that tirzepatide was associated with a statistically significantly lower incidence of the composite primary endpoint — all-cause death, acute coronary syndrome, stroke, or new-onset heart failure — at 12 months (1.90% vs. 2.18%; HR 0.86). This difference was primarily driven by a reduction in new-onset heart failure (both reduced and preserved ejection fraction). No significant differences were observed for all-cause mortality, acute coronary syndrome, or stroke individually. Tirzepatide also produced greater mean weight loss. Limitations include the retrospective observational design, reliance on EHR coding accuracy, inability to confirm medication adherence, short follow-up duration, and potential for residual confounding despite propensity matching.
Diabetes, obesity & metabolism · Mar 2026DOI ↗ Review
This narrative review synthesized evidence on injectable semaglutide for weight management specifically in non-diabetic adults, drawing on 27 studies (including RCTs, observational studies, and qualitative reports) identified through PubMed, Scopus, and Web of Science (2019–2025) using the SANRA framework. The authors found that, according to the included literature, semaglutide (2.4 mg) was associated with mean body weight reductions of approximately 14.9% in non-diabetic adults, compared to roughly 9.6% in diabetic populations. Beyond weight loss, the review reported improvements in cardiometabolic markers and quality-of-life measures. Gastrointestinal adverse effects were identified as the primary driver of treatment discontinuation. The review also highlighted practical barriers to real-world use, including high out-of-pocket costs, global supply constraints, and evidence of weight regain following cessation. Tirzepatide was used as a comparative benchmark. The authors conclude that semaglutide represents a meaningful advance in obesity pharmacotherapy but emphasize that its utility depends on integration into multimodal treatment strategies and resolution of structural access issues. Limitations include the narrative (non-systematic) design, potential for selection bias in study inclusion, and inability to pool effect sizes statistically.
Health science reports · Mar 2026DOI ↗ Limited · human
This pharmacovigilance study compared post-marketing adverse event reporting patterns for tirzepatide (a dual GIP/GLP-1 receptor agonist) against semaglutide and liraglutide (GLP-1 receptor agonists) using aggregated Individual Case Safety Reports (ICSRs) from the EudraVigilance database. Researchers applied pairwise disproportionality analyses using reporting odds ratios (RORs) at the System Organ Class (SOC) level, with false discovery rate correction and sensitivity analyses limited to serious and healthcare professional-reported cases. The study found that, compared with semaglutide, tirzepatide was associated with higher relative reporting for immune system disorders (ROR 1.97) and hepatobiliary disorders (ROR 1.71). Compared with liraglutide, tirzepatide showed higher reporting for musculoskeletal (ROR 2.02) and psychiatric disorders (ROR 2.14), but lower reporting for neoplasms (ROR 0.28). Eight SOCs remained significant across all analytical conditions. The authors emphasize that these findings are hypothesis-generating only, as disproportionality analyses cannot establish causality, do not adjust for exposure levels, and are subject to reporting biases inherent in spontaneous pharmacovigilance databases. Confirmation in exposure-adjusted studies is recommended.
International journal of molecular sciences · Mar 2026DOI ↗ Limited · human
This study characterizes PG-102, a bispecific Fc fusion protein that co-activates both GLP-1 and GLP-2 receptors, combining preclinical animal work with a Phase I human trial. In db/db mice (a model of advanced type 2 diabetes with hyperglycemia and catabolic weight loss), PG-102 demonstrated superior and more sustained glycemic control compared to semaglutide or tirzepatide while preserving body weight — an effect attributed to β-cell preservation and enhanced glucose uptake rather than acute insulin stimulation. Mechanistic experiments suggested that dual receptor engagement was necessary for these benefits, with PG-102 also promoting coordinated, delayed receptor internalization compared to monospecific agents. The Phase I randomized, double-blind, placebo-controlled trial enrolled 24 adults with overweight (BMI 25–30 kg/m²) across three dose cohorts, with 18 receiving PG-102 and 6 receiving placebo. The primary endpoint was safety and tolerability. Treatment-emergent adverse events occurred in 83.3% of PG-102 participants and 66.7% of placebo participants; gastrointestinal events were mild to moderate. No serious adverse events or treatment discontinuations were reported. Limitations include the small sample size, single-center design, overweight-only population, and lack of efficacy endpoints in the human portion of the study.
Nature communications · Mar 2026DOI ↗