Review
This review examines the ocular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual-incretin therapies, which are increasingly used for diabetes and obesity management. The authors synthesize experimental and clinical evidence across multiple ocular conditions. Preclinical data suggest plausible protective mechanisms, including antioxidant and neuroprotective effects on retinal and optic nerve tissues. In diabetic retinopathy, the review identifies transient early worsening as a key concern, attributed to rapid glycemic improvement rather than direct drug toxicity. A potential signal linking semaglutide to non-arteritic anterior ischemic optic neuropathy (NAION) is noted, though the authors characterize absolute risk as low and causality as unproven. Emerging associations are discussed for glaucoma, ocular surface diseases, and retinal vascular outcomes, while evidence on age-related macular degeneration and cataract is described as conflicting or preliminary. The authors conclude that ocular outcomes likely reflect an interplay of drug pharmacology, systemic metabolic changes, and individual patient factors rather than a uniform class effect. They suggest baseline ophthalmic assessment and individualized follow-up for high-risk patients, and call for prospective ophthalmology-focused trials. A key limitation is its reliance on heterogeneous and largely indirect evidence.
Vision (Basel, Switzerland) · May 2026DOI ↗ Review
This registry-based cross-sectional qualitative analysis examined the landscape of completed clinical trials investigating GLP-1 receptor agonists (GLP-1 RAs) for obesity, using data retrieved from ClinicalTrials.gov in October 2025. The authors identified 227 completed interventional studies and analyzed their design characteristics, research themes, and outcome domains. Liraglutide was the most studied agent (n = 86), followed by semaglutide and tirzepatide (n = 18 each) and exenatide (n = 15). Phase 3 and 4 trials predominated, though most studies enrolled fewer than 200 participants, suggesting relatively modest individual sample sizes. The authors reported a notable surge in completed trials after 2018, coinciding with the emergence of newer GLP-1 analogues. Primary outcomes were predominantly weight-related, but the synthesis identified a growing research focus on hepatic, cardiometabolic, and inflammatory endpoints. The study's key limitation is its registry-based, qualitative design — it does not synthesize individual-level patient outcome data or conduct meta-analysis, and therefore cannot draw conclusions about comparative efficacy or safety. Rather, it maps the structural and thematic evolution of the GLP-1 obesity research field. The authors conclude that the field is maturing beyond glycaemic and weight outcomes toward broader organ-specific endpoints.
Diabetes, metabolic syndrome and obesity : targets and therapy · May 2026DOI ↗ In vitro
This study investigated whether five FDA-approved glucagon-like peptide-1 receptor agonists (GLP-1RAs) — semaglutide, tirzepatide, liraglutide, and two others — could directly inhibit the aggregation of the 42-residue amyloid-β peptide (Aβ42), a key process implicated in Alzheimer's disease (AD). Using in vitro aggregation kinetics and microscopic analysis, researchers found that semaglutide, tirzepatide, and liraglutide inhibited Aβ42 aggregation, primarily by targeting the primary nucleation step — the initial formation of amyloid seeds. Semaglutide and tirzepatide delayed aggregation with submicromolar potency, while liraglutide showed the strongest suppression of primary nucleation and additionally modestly inhibited secondary nucleation. Liraglutide also altered fibril structure — producing less mature, more tortuous, and longer fibrils — and reduced the ability of fibrils to self-replicate (template). The study was conducted entirely in vitro (no cell, animal, or human data), which is a significant limitation for clinical translation. The authors conclude that certain GLP-1RAs can directly interfere with molecular steps of Aβ42 aggregation, and call for further studies to determine whether these mechanisms contribute to potential AD-protective effects observed in preclinical and clinical research.
Journal of the American Chemical Society · May 2026DOI ↗ Review
This narrative review, aimed at obstetricians and gynecologists, synthesizes current evidence on GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP agonists (e.g., tirzepatide) as they relate to women's health. The authors highlight that phase 3 trials have reported 15–21% body weight reduction with these agents, with tirzepatide showing greater efficacy than semaglutide. In women with polycystic ovary syndrome (PCOS), the authors cite meta-analyses finding improvements in insulin resistance, androgen levels, and ovulation rates. Regarding contraception, the review notes that tirzepatide's gastric-emptying delay has prompted manufacturer guidance about backup contraception around initiation and dose escalation. On pregnancy safety, the authors describe emerging human cohort data suggesting no significantly increased risk of major congenital malformations from inadvertent early pregnancy exposure, while noting that animal teratogenicity data still warrant caution. Perioperative guidance has shifted toward individualized risk-stratified approaches rather than blanket discontinuation. The authors call for formal pregnancy registries to address persistent knowledge gaps. As a review, this paper does not generate new primary data, and its conclusions are limited by the underlying evidence base, which in several areas remains preliminary or indirect.
Current opinion in obstetrics & gynecology · May 2026DOI ↗ Limited · humanPreprint
This observational cohort analysis describes weight-loss outcomes and adverse event rates in 503 overweight adults who completed six months of the "Trimsulin Weight Loss Program," a nutraceutical regimen combining two proprietary products (a powdered drink mix and a capsule) with a structured diet and exercise protocol. The authors compare their results descriptively — without inferential statistics — to published real-world data for the prescription GLP-1 receptor agonist semaglutide and the dual GIP/GLP-1 agonist tirzepatide. The study reports that Trimsulin participants experienced mean weight reductions of 7.3% at 3 months and 14.1% at 6 months, numerically exceeding the comparator figures drawn from a separate published cohort. Adverse events were self-reported by 4.8% of Trimsulin participants versus much higher rates cited for the pharmacological comparators. Key limitations are substantial: there is no randomization, no placebo or active control arm, no blinding, no direct head-to-head comparison, reliance on self-reported adverse events, a highly selected completer-only analysis (503 of 1,000+ enrollees), differing baseline BMI profiles across cohorts, and the absence of any inferential statistical testing. The program's dietary and behavioral components cannot be disentangled from any supplement effect. The authors acknowledge the need for randomized controlled trials. The paper is identified as a preprint.
Unknown journal · May 2026DOI ↗ Review
This narrative review evaluates whether incretin-based therapies — specifically GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide) — warrant consideration as first-line antihypertensive agents. The authors synthesize findings from recent large-scale trials demonstrating that these agents are associated with significant reductions in body weight, blood pressure, and adverse cardiovascular outcomes. Mediation analyses cited in the review suggest that weight loss accounts for a substantial portion of the observed blood pressure reductions; however, the authors also highlight putative direct mechanisms, including improvements in vascular function, renal sodium handling, and neurohumoral pathway modulation. The review notes that beneficial effects on blood pressure appear consistent across diverse patient populations, including those without established hypertension. A key limitation acknowledged by the authors is the absence of randomized controlled trials specifically designed with blood pressure as a primary endpoint. Based on the available evidence, the authors conclude that incretin-based therapies may have an emerging role in hypertension management guidelines, particularly for selected high-risk populations. As a review article, conclusions are dependent on the quality and interpretation of the underlying primary studies cited.
Current hypertension reports · May 2026DOI ↗ Limited · humanPreprint
This large-scale observational study used an EHR-linked body-composition "digital phenotyping" pipeline — incorporating large language model (LLM)-based data extraction — to compare lean body mass (LBM) changes in routine clinical care among adults initiating GLP-1 receptor agonists (GLP-1RAs). Of 670,422 first-episode GLP-1RA users (456,742 on semaglutide; 213,680 on tirzepatide), 7,965 had paired pre- and post-initiation body-composition measurements analyzable over 12 months. The study found that tirzepatide was associated with greater relative LBM loss than semaglutide at each time point assessed (3, 6, 9, and 12 months), with excess LBM losses ranging from approximately 1.1% to 2.0%. The authors also identified two GLP-1 "metabotypes": a "Depletive" metabotype (>20% total body weight loss with >5% LBM loss), which was more frequent with tirzepatide (10.3%) than semaglutide (6.7%), and a "Prime" metabotype (>10% total body weight loss with preserved LBM). Key limitations include the observational, real-world design; reliance on LLM-extracted EHR data; potential unmeasured confounding; and the relatively small subset with paired body-composition data relative to the overall cohort.
Unknown journal · May 2026DOI ↗ Moderate · human
This network meta-analysis (NMA) synthesized evidence from six randomized controlled trials (N = 4,642; durations 12–68 weeks) to compare novel amylin-based therapies (ABTs) — amycretin, eloralintide, and cagrilintide/semaglutide (CagriSema) — against placebo and established anti-obesity agents (semaglutide 2.4 mg, liraglutide 3.0 mg) in adults with overweight or obesity without diabetes. Using a frequentist random-effects framework, the study found that high-dose subcutaneous amycretin produced the largest estimated reduction in percent body weight versus placebo (mean difference approximately −24%), followed by high-dose eloralintide (−18%) and high-dose CagriSema (−17%), all exceeding reductions seen with semaglutide 2.4 mg (−11%) and liraglutide 3.0 mg (−6%). Similar ranking patterns emerged for absolute weight, BMI, waist circumference, and categorical weight-loss thresholds. Gastrointestinal adverse events — particularly nausea, vomiting, and constipation — were more frequent with high-dose ABTs, and only high-dose CagriSema significantly increased treatment-discontinuation due to adverse events. The authors acknowledge that the included trials are few, relatively short-to-medium term, and carry low certainty of evidence, characterizing findings as preliminary and requiring confirmation in larger trials.
Endocrinology, diabetes & metabolism · May 2026DOI ↗ Moderate · human
This observational study used two target-trial emulations to compare cardiovascular outcomes among commercially insured U.S. adults with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) who initiated tirzepatide, dulaglutide, or semaglutide between June 2022 and December 2024. Using propensity-score (PS) 1:1 matching to reduce confounding, the researchers formed two cohorts: 9,233 tirzepatide–dulaglutide pairs and 25,266 tirzepatide–semaglutide pairs. The primary outcome was a modified MACE composite (nonfatal myocardial infarction, nonfatal stroke, and all-cause death). The study found that tirzepatide initiators had a statistically significantly lower rate of modified MACE compared with dulaglutide initiators (HR 0.80; 95% CI 0.65–0.99), largely driven by reduced all-cause mortality (HR 0.60; 95% CI 0.43–0.83); tirzepatide was also associated with fewer pneumonia-related hospitalizations versus dulaglutide. No significant difference in modified MACE was observed between tirzepatide and semaglutide initiators (HR 1.03; 95% CI 0.90–1.17). Key limitations include the observational design, potential residual confounding, reliance on administrative claims data, and a relatively short follow-up window.
Diabetes care · May 2026DOI ↗ Limited · human
This pharmacovigilance study used the U.S. FDA Adverse Event Reporting System (FAERS) database (Q2 2022–Q2 2025) to examine whether specific GLP-1 receptor agonists (GLP-1 RAs) — exenatide, lixisenatide, liraglutide, dulaglutide, semaglutide, and tirzepatide — differ in their association with alopecia and reproductive or endocrine-related adverse events. Researchers identified 1,276 alopecia-related and 759 reproductive/endocrine-related cases, then applied disproportionality analyses using crude and adjusted reporting odds ratios (cROR/aROR) from logistic regression, controlling for potential confounders. Sensitivity analyses with positive and negative control drugs were used to validate signal robustness. The study found that semaglutide was significantly associated with disproportionate reporting of alopecia (aROR 1.23) and several hormonal conditions, including polycystic ovary syndrome (aROR 6.59) and menstrual abnormalities. By contrast, dulaglutide and tirzepatide showed negative or non-significant associations for several reproductive outcomes. Important limitations include the inherent biases of spontaneous reporting systems (e.g., underreporting, notoriety bias, inability to establish causation), lack of denominator data, and absence of clinical detail. The authors conclude that agent-specific differences in endocrine and dermatologic safety profiles may warrant personalised prescribing decisions and ongoing surveillance.
Diabetes/metabolism research and reviews · May 2026DOI ↗ Limited · human
This pharmacovigilance study examined safety signals associated with potentially counterfeit semaglutide products by conducting a descriptive and disproportionality analysis of Individual Case Safety Reports (ICSRs) submitted to the European pharmacovigilance database EudraVigilance between January 2018 and December 2025. Researchers identified 234 ICSRs linked to suspected counterfeit semaglutide, of which 73.5% involved female patients and 35.5% involved adults. Notably, 89.3% of reported suspected adverse drug reactions (ADRs) were classified as serious. The most commonly reported suspected ADRs were vomiting, nausea, and hypoglycemia. Disproportionality analysis revealed a statistically higher reporting frequency for hypoglycemia, product use in an unapproved indication, malaise, and drug ineffectiveness compared with reports involving non-counterfeit semaglutide. The authors suggest these signals may reflect contamination, incorrect active ingredients, or subtherapeutic dosing in counterfeit products. Limitations include the inherent biases of spontaneous pharmacovigilance reporting (underreporting, lack of denominator data, and inability to confirm causality), reliance on database classifications of "counterfeit," and the descriptive nature of the analysis. The study concludes that pharmacovigilance databases can play a useful role in detecting safety concerns related to counterfeit medicines, and calls for further research.
Frontiers in pharmacology · Apr 2026DOI ↗ Moderate · human
This study aimed to indirectly compare the efficacy and safety of injectable tirzepatide (a dual GIP/GLP-1 receptor agonist) with oral semaglutide (a GLP-1 receptor agonist) for weight management in adults with overweight or obesity but without type 2 diabetes. Because no head-to-head trial exists, researchers used multilevel network meta-regression (ML-NMR) to adjust for baseline differences in sex, ethnicity, and outcome measures between two pivotal trials: SURMOUNT-1 (tirzepatide, 72 weeks) and OASIS 1 (oral semaglutide, 68 weeks). After adjustment, the analysis found that tirzepatide at two of the three doses studied was associated with statistically significantly greater reductions in body weight and waist circumference compared with oral semaglutide. Tirzepatide was also associated with higher odds of achieving clinically meaningful weight-loss thresholds (≥5%, ≥10%, ≥15%, and ≥20% body weight reduction). Cardiometabolic outcomes and safety profiles were reported as improved or broadly comparable for tirzepatide versus oral semaglutide. Key limitations include the indirect nature of the comparison, differences in trial duration and populations, and the inability to fully control for all confounders across separate trials. The findings should be interpreted cautiously pending direct head-to-head evidence.
Diabetes, obesity & metabolism · Apr 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 ↗ Review
This paper argues that body image has been largely overlooked in research on glucagon-like peptide-1 receptor agonists (GLP-1s) such as semaglutide and tirzepatide, despite its central relevance to why people seek these treatments and how they psychologically adjust to the bodily changes that follow. Drawing on existing literature across body image, weight loss interventions, weight stigma, and cosmetic procedures, the authors conceptualise body image not simply as an outcome of GLP-1 use, but as a motivator, mediator, and moderator across the entire treatment trajectory. The paper identifies several critical research gaps, including the absence of prospective and longitudinal studies tracking body image before, during, and after GLP-1 use, as well as limited understanding of individual vulnerability factors and heterogeneity in psychological responses. The authors also highlight broader societal concerns, including the potential reinforcement of weight stigma, inequities in access to these medications, and the role of media representation. They call for body image-informed psychological support for people using GLP-1s, as well as professional education and training. As a narrative review, the paper does not present new empirical data and its conclusions are based on inference from adjacent literatures rather than direct evidence.
Body image · Apr 2026DOI ↗ Review
This narrative review compared tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a selective GLP-1 receptor agonist) across weight loss, glycemic control, cardiometabolic, and safety outcomes by synthesizing evidence from clinical trials, real-world observational studies, and cardiovascular outcome analyses. The authors found that in completed head-to-head randomized trials, tirzepatide consistently produced greater reductions in body weight and HbA1c compared with semaglutide in people with obesity or type 2 diabetes. Regarding cardiovascular outcomes, the review noted that semaglutide currently holds the most mature evidence for cardiovascular risk reduction, supported by the SUSTAIN-6, PIONEER-6, and SELECT trials. Tirzepatide's SURPASS-CVOT trial demonstrated non-inferiority to dulaglutide for cardiovascular outcomes along with improvements in cardiometabolic risk factors, but direct cardiovascular superiority data versus semaglutide remain limited. Real-world studies on cardiovascular outcomes were characterized as heterogeneous. The authors concluded that treatment selection should be individualized. Key limitations include the narrative (non-systematic) methodology, potential for selection bias in literature inclusion, and the absence of a completed direct head-to-head cardiovascular outcomes trial between the two agents.
Frontiers in medicine · Apr 2026DOI ↗ Limited · human
This large-scale observational study used a federated biomedical data platform to analyze 135,349 individuals treated with GLP-1 receptor agonists (GLP-1RAs) — specifically semaglutide (Wegovy) and tirzepatide (Zepbound) formulations — to characterize differences between "super responders" (>15% weight loss), "moderate responders" (5–15% weight loss), and a "minimal weight-loss" group. The study found substantial heterogeneity in weight-loss outcomes across patients receiving the same therapies. Notably, super responders to Zepbound showed reduced risk of developing certain comorbidities, including conditions at relative risks as favorable as 0.5 for osteoarthritis (P = .001), while Wegovy super responders showed an association with psoriasis (RR = 2.5, P = .03). The authors conclude that differences in weight trajectories likely reflect a combination of biological, behavioral, and social factors. Key limitations include the observational, retrospective design (which cannot establish causation), the reliance on federated real-world data (subject to coding variability), and lack of randomization. The authors call for prospective studies to develop more individualized weight-loss strategies.
Biology methods & protocols · Apr 2026DOI ↗ Limited · human
This real-world observational study examined weight trajectories in 4,182 patients during the 6 months following their last documented semaglutide or tirzepatide prescription, drawn from a federated health network. The study found that approximately two-thirds of the full cohort showed stable weight or continued weight loss after their final prescription. In a representative subset of 300 patients whose clinical notes were analyzed using a large language model (LLM), treatment discontinuation was confirmed in 119 patients (40%), and of those, 72% did not demonstrate weight regain. The study also noted that exercise counseling was documented more frequently among patients who maintained weight loss compared to those who experienced weight regain (26.2% vs. 14.7%; P = .04). Key limitations include the observational and retrospective design, reliance on documented prescriptions rather than confirmed medication use, potential incompleteness of clinical records, use of an LLM for data curation introducing possible inaccuracies, and the inability to establish causation. The authors acknowledge that further studies are needed to understand the mechanisms behind these real-world patterns of weight maintenance after GLP-1 receptor agonist discontinuation.
Biology methods & protocols · Apr 2026DOI ↗ Review
This systematic review (PRISMA-compliant, PROSPERO-registered) examined the association between GLP-1 receptor agonists (GLP-1 RAs) and hair loss by searching four major databases (PubMed, Embase, Scopus, Web of Science). Of 133 studies identified, 24 met inclusion criteria as primary articles. The review found that semaglutide and tirzepatide showed the highest reported incidence of hair loss and the strongest pharmacovigilance signals among GLP-1 RAs. The predominant subtypes reported were androgenetic alopecia and telogen effluvium, with telogen effluvium most frequently linked to tirzepatide—the agent associated with the greatest magnitude of weight loss. The authors noted that hair loss with semaglutide appeared dose-dependent, and that females were disproportionately affected. Rapid weight loss was identified as a potential contributing mechanism, especially for telogen effluvium. Other agents—liraglutide, dulaglutide, lixisenatide, and exenatide—had fewer studies and generally lower reported risk. Key limitations include the reliance on pharmacovigilance data and heterogeneous study designs, which preclude definitive causal conclusions. The authors call for large, prospective randomized trials to establish causality and temporal relationships.
Science progress · Apr 2026DOI ↗ InsufficientPreprint
This narrative review examines the pharmacogenomics of GLP-1 receptor agonists — principally semaglutide (Ozempic®/Wegovy®) and the dual GIP/GLP-1 agonist tirzepatide (Mounjaro®/Zepbound®) — with a focus on explaining the wide inter-individual variability in efficacy and tolerability observed in clinical practice. The authors synthesise evidence around key genetic loci, including GLP1R, GIPR, ARRB1, TCF7L2, and MC4R, and highlight a purported April 2026 genome-wide association study (GWAS) conducted by 23andMe (n=27,885) as the largest pharmacogenomic study of GLP-1 therapies to date. The review also surveys the competitive landscape among Novo Nordisk, Eli Lilly, 23andMe Research Institute, and PGxAI, and dedicates substantial attention to South Asian and Indian populations, arguing that their large diabetes burden and undercharacterised pharmacogenomic profiles represent a critical gap. The authors conclude that GLP-1 pharmacogenomics has advanced from exploratory science toward actionable clinical discovery. Limitations include the narrative (non-systematic) design, reliance on a preprint-stage GWAS of uncertain peer-review status, and the absence of prospective clinical validation data for genotype-guided prescribing.
Unknown journal · Apr 2026DOI ↗ Review
This review examines the current clinical development pipeline for metabolic dysfunction-associated steatotic liver disease (MASLD) and its more advanced form, MASH (metabolic dysfunction-associated steatohepatitis), with a particular focus on cardiovascular comorbidities. The authors highlight the strong bidirectional relationship between MASLD and cardiometabolic risk, arguing that effective treatments should address both hepatic and cardiovascular outcomes simultaneously. The review surveys a broad range of drug candidates and mechanisms, including incretin mimetics (e.g., semaglutide), thyroid hormone receptor-beta agonists (e.g., resmetirom), farnesoid X receptor agonists, PPAR agonists, de novo lipogenesis inhibitors, and fibroblast growth factor analogues. The authors note that the two FDA-approved therapies — resmetirom and semaglutide — have demonstrated reductions in major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality in MASH patients, with semaglutide also showing benefit in heart failure with preserved ejection fraction. However, the review emphasizes that cardiovascular outcome data for most other pipeline agents remain limited or absent. A key limitation is that this is a narrative review and does not involve primary data collection or meta-analytic methods.
Biomedicines · Apr 2026DOI ↗