Limited · human
This pharmacovigilance study analyzed reports submitted to the FDA Adverse Event Reporting System (FAERS) to compare biliary adverse events (AEs) across five GLP-1 receptor agonists (GLP-1RAs): semaglutide, tirzepatide, liraglutide, exenatide, and dulaglutide. After deduplication, 3,460 reports were included. Using semaglutide as the reference, the authors calculated proportional reporting ratios (PRR), reporting odds ratios (ROR), and Fisher exact tests across five biliary outcomes: cholelithiasis, cholecystitis, biliary colic, bile duct stone, and cholangitis. The study found that compared with semaglutide, exenatide and tirzepatide showed lower relative reporting for bile duct stone, while exenatide and dulaglutide showed lower relative reporting for biliary colic. Dulaglutide showed higher relative reporting for cholangitis. Exenatide, liraglutide, and tirzepatide all showed higher relative reporting for cholecystitis and cholelithiasis. Sensitivity and subgroup analyses were broadly consistent, though rarer outcomes lost statistical significance. Key limitations include the inherent biases of spontaneous reporting databases (underreporting, confounding by indication, and lack of denominator data), which preclude causal inference. The authors concluded that biliary AE reporting patterns differ meaningfully across agents within the GLP-1RA class.
Digestive diseases and sciences · May 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 · humanPreprint
This large pharmacovigilance study analyzed 20.3 million FDA FAERS adverse event reports (2004–2024) to investigate impaired gastric emptying (IGE) as a potential class-wide adverse effect of GLP-1 receptor agonists (GLP-1 RAs). Researchers identified 6,868 IGE reports across nine GLP-1 RA agents and applied the proportional reporting ratio (PRR) method with sensitivity analyses, supplemented by cross-national validation using 29 reports from Brazil's pharmacovigilance database. The study found that all nine agents exceeded established Evans signal detection criteria, with PRRs ranging from 4.4 (exenatide) to 83.9 (injectable semaglutide). Notably, oral and injectable semaglutide showed comparable PRRs, suggesting a systemic rather than route-dependent mechanism. Tirzepatide prescribed for type 2 diabetes showed a substantially higher PRR than the same drug prescribed for obesity, which the authors interpret as a possible effect of diabetic autonomic neuropathy. A pre-litigation signal analysis was also conducted to account for potential notoriety bias. Key limitations include the inherent constraints of spontaneous pharmacovigilance data—including reporting bias, lack of denominator data, and inability to establish causation—as well as the small cross-national validation sample (n=29). The authors conclude that findings support pre-treatment risk stratification discussions for gastroparesis in GLP-1 RA candidates.
Unknown journal · May 2026DOI ↗ Limited · humanPreprint
This large pharmacovigilance study extracted 412,643 adverse event reports for five GLP-1 receptor agonists (semaglutide, tirzepatide, liraglutide, dulaglutide, and exenatide) from the FDA Adverse Event Reporting System (FAERS) spanning 2004–2024, comparing disproportionality signals using proportional reporting ratios (PRR) and reporting odds ratios (ROR). The study identified 154 drug-event signals overall. The most notable finding was a strong gastroparesis signal for semaglutide (PRR 88.9, 95% CI 85.4–92.6), which the authors describe as substantially higher than prior published estimates and as robust across three pre-specified sensitivity analyses using different comparator groups. All five agents showed statistically significant gastroparesis signals. Gastroparesis reports were consistently female-predominant across all agents (female-to-male ratio 2.7–3.6×). Tirzepatide's adverse event profile was notably dominated by device-usability reports rather than clinical events. Case-fatality rates varied across agents (0.6% to 3.7%). Key limitations include inherent FAERS biases (underreporting, stimulated reporting, lack of denominator data, and confounding by indication), which preclude causal inference or incidence estimation. The authors acknowledge the preprint status of this work.
Unknown journal · May 2026DOI ↗ Moderate · human
This systematic review and network meta-analysis (NMA) evaluated the comparative efficacy of pharmacological interventions—at specific dosages—for improving liver fibrosis in adults with metabolism-associated steatotic liver disease (MASLD) and fibrosis stages F1–F3. Researchers searched three databases through July 2025, identifying 13 randomized controlled trials encompassing 3,871 patients and 12 distinct drug regimens. Using both direct comparisons and network meta-analysis, the study found that six interventions—resmetirom (two doses), survodutide, and tirzepatide (three doses)—were significantly more effective than placebo at achieving NASH resolution without worsening fibrosis. Surface Under the Cumulative Ranking (SUCRA) analysis ranked survodutide 6 mg/week highest, followed by tirzepatide 15 mg/week; emricasan 10 mg/day ranked lowest. The authors concluded that survodutide, efruxiferimin, resmetirom, and denifanstat showed the most promise for this population, while emricasan was not supported. Limitations include the moderate number of included trials, potential heterogeneity across study populations and outcome definitions, and the indirect nature of many NMA comparisons, which may limit the precision of the relative effect estimates.
Journal of translational medicine · May 2026DOI ↗ Insufficient
This brief report, authored for nurse practitioners (NPs), examines the clinical and regulatory challenges arising from patient-driven "microdosing" of GLP-1 receptor agonists (semaglutide and tirzepatide) in the context of FDA restrictions on compounded versions following resolution of drug shortages. The authors describe how affordability barriers push patients toward subtherapeutic dosing strategies, unregulated "research-grade" peptides purchased online, and unsupervised sources such as medical spas. The paper outlines specific safety concerns associated with these practices, including pen manipulation, medication sharing, compounded vials, and dosing errors, as well as the side effect profiles encountered. It also explores how provider weight bias may inadvertently drive patients toward unregulated alternatives and offers practical stigma-reduction strategies for clinical encounters. The authors discuss the legal risks of compounded "copies" and acknowledge a narrow legitimate role for compounding in patients with documented allergies. As a brief report rather than an empirical study, the paper does not present original data or a systematic review; its conclusions are based on regulatory context, clinical observation, and expert opinion. Its primary value lies in synthesizing emerging practice-relevant issues for NPs navigating a rapidly evolving regulatory environment.
Journal of the American Association of Nurse Practitioners · May 2026DOI ↗ Review
This narrative review examines the role of lifestyle interventions before, during, and after treatment with second-generation obesity management medications (OMMs), specifically semaglutide and tirzepatide. The authors note that these agents have demonstrated weight losses of approximately 15–20% in recent trials, prompting a reconsideration of how lifestyle programs should be integrated into obesity care. The review identifies several emerging concerns in the literature, including lean mass loss, nutritional deficiencies, gastrointestinal side effects, and significant weight regain following medication discontinuation. The authors argue that lifestyle modification remains the foundation of obesity treatment but that the focus may need to shift from weight reduction toward broader health promotion in the context of highly effective pharmacotherapy. Key lifestyle strategies discussed include protein intake and physical activity to preserve muscle mass, and dietary approaches to manage gastrointestinal side effects. The review also explores pre-treatment lifestyle programs as potential prerequisites for pharmacotherapy while cautioning that such requirements could limit access and reinforce weight stigma. Limitations include the narrative (non-systematic) design, lack of primary data, and the rapidly evolving evidence base. The authors conclude that optimal timing, frequency, and content of lifestyle interventions alongside OMMs remain unclear and warrant further research.
Current atherosclerosis reports · May 2026DOI ↗ Review
This review article argues that GLP-1 receptor agonists (GLP-1 RAs) — such as semaglutide and tirzepatide — should be understood as catalysts for, rather than replacements of, lifestyle intervention in cardiometabolic care. The authors propose the guiding principle "lifestyle first and lifestyle always, but not lifestyle only," acknowledging that GLP-1 RAs have produced meaningful clinical benefits including substantial weight loss, improved glycemic control, and reduced cardiovascular and renal risk. However, the authors contend that pharmacotherapy alone cannot address the full spectrum of cardiometabolic risk drivers, including sarcopenia, physical deconditioning, poor sleep, psychological stress, and social determinants of health. The article highlights that discontinuation of GLP-1 RAs without structured lifestyle support is commonly associated with weight regain. Key lifestyle pillars emphasized include high-quality nutrition, regular physical activity (including resistance training), restorative sleep, stress management, and social connectedness. The authors advocate for integrated, interprofessional care models combining pharmacologic and lifestyle strategies, supported by systemic and policy-level change. As a narrative review, the paper does not present original data, conduct a systematic literature search, or include a meta-analysis, which limits the directness of its evidentiary contribution.
American journal of lifestyle medicine · May 2026DOI ↗ Moderate · human
This systematic review and meta-analysis synthesized evidence from three placebo-controlled randomized controlled trials (total n = 258) examining semaglutide in adults with schizophrenia spectrum disorders (SSDs). The authors conducted a preregistered search, pooled outcomes using random-effects meta-analysis, and assessed evidence certainty using GRADE criteria. The included trials tested semaglutide over 26–36 weeks. The study found that, compared to placebo, semaglutide was associated with statistically significant reductions in body weight (approximately −11.3 kg), BMI (approximately −3.6 kg/m²), HbA1c (approximately −0.37%), and fasting glucose. On the safety side, semaglutide was associated with meaningfully higher risks of abdominal pain, vomiting, and constipation, consistent with the known gastrointestinal profile of GLP-1 receptor agonists; no elevated risk of serious adverse events was observed. The authors note that the overall evidence base is limited by a small number of trials, modest combined sample size, and relatively short follow-up durations. No trials of tirzepatide in this population were identified. The authors conclude that semaglutide shows promise as an adjunctive metabolic treatment in SSDs but call for larger, longer trials.
BJPsych open · May 2026DOI ↗ Review
This systematic review examined the clinical outcomes of GLP-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 receptor agonists in children and adolescents (aged 6–19 years) with overweight or obesity, with or without type 2 diabetes. Researchers searched PubMed, Scopus, and ClinicalTrials.gov following PRISMA 2020 guidelines, ultimately analyzing 15 studies (12 interventional, 3 observational) comprising 1,448 participants across six agents: liraglutide, exenatide, semaglutide, dulaglutide, tirzepatide, and lixisenatide. Study durations ranged from 6 to 68 weeks. The review found that BMI reductions varied across agents and study designs, with semaglutide trials reporting reductions of up to –16.1%. A key finding was the substantial heterogeneity in how concomitant lifestyle interventions were reported—ranging from general dietary advice to structured multidisciplinary programs—making it impossible to isolate the independent contributions of pharmacological versus behavioral components. The authors conclude that while GLP-1 RAs appear to be a promising therapeutic option in this population, the evidence base is limited by inconsistent lifestyle co-intervention reporting. They call for standardized reporting frameworks (e.g., TIDieR), validated behavioral measures, and factorial or stratified study designs to disentangle drug and lifestyle effects in future pediatric trials.
Nutrients · 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 review examines the evolution of GLP-1–based pharmacotherapies for obesity, tracing the discovery of glucagon-like peptide-1 (GLP-1) and assessing the clinical efficacy of GLP-1 receptor agonists (GLP-1RAs), with particular focus on semaglutide. The authors explore proposed central mechanisms by which GLP-1RAs may reduce appetite and body weight. A substantial portion of the review addresses the "paradox" surrounding glucose-dependent insulinotropic polypeptide receptor (GIPR) targeting: both dual GLP-1R/GIPR agonism (as seen with tirzepatide) and GLP-1R agonism combined with GIPR antagonism (as seen with maridebart cafraglutide) appear to yield favorable metabolic outcomes. The authors note a lack of evidence that GIPR agonism or antagonism alone produces meaningful anorectic effects in humans, raising mechanistic questions about how GIPR modulation enhances GLP-1RA efficacy. The review concludes by exploring additional explanations for why dual-targeting compounds appear to outperform semaglutide monotherapy. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, and its conclusions are dependent on the quality and scope of the studies reviewed.
Annual review of nutrition · May 2026DOI ↗ Limited · human
This single-arm pragmatic trial examined psychosocial outcomes in 180 adults with obesity (mean age 44.1 years; 91% female; 81% white; mean weight 102.6 kg) enrolled in a telemedicine program (WeightWatchers Clinic) who received semaglutide or tirzepatide alongside an adjunctive virtual behavioral intervention tailored for patients on long-acting incretin therapy. Psychosocial measures—including depression (PHQ-8), perceived stress (Perceived Stress Scale), well-being (WHO-5), weight bias internalization (WBIS-2F), and weight-related quality of life (IWQOL-Lite)—were collected at baseline, 12 weeks, and 24 weeks. Wilcoxon signed-rank tests with False Discovery Rate correction were used; an intent-to-treat analysis using last observation carried forward (LOCF) was also performed. The study found statistically significant improvements from baseline to 24 weeks across all five psychosocial outcomes. Key limitations include the absence of a control group, a predominantly white and female sample limiting generalizability, and the inability to separate medication effects from behavioral intervention effects. The findings suggest an association between the combined telehealth and behavioral approach and improved psychosocial outcomes, but causality cannot be established.
Obesity science & practice · 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 ↗ Limited · human
This retrospective pharmacovigilance study analyzed the FDA Adverse Event Reporting System (FAERS) from Q1 2004 through Q2 2025 to identify risk factors for drug-related impaired gastric emptying (IGE), a recognized contributor to perioperative pulmonary aspiration risk. Researchers identified 731 drugs associated with IGE reports. Among the most frequently reported were antidiabetic agents, particularly five GLP-1 receptor agonists (GLP-1RAs): semaglutide, dulaglutide, tirzepatide, exenatide, and liraglutide. The study employed disproportionality analysis, logistic regression, LASSO regression, and time-to-onset analysis to characterize these associations. Multi-factor analysis identified female sex and younger age as patient-level risk factors for drug-related IGE. Key limitations include the inherent biases of spontaneous adverse event reporting (underreporting, confounding by indication, lack of denominator data), the inability to establish causality, and incomplete clinical information in FAERS records. The authors suggest findings may help clinicians identify patients at elevated risk for drug-related IGE and inform perioperative fasting and anesthetic planning, particularly given the growing clinical use of GLP-1RAs.
Frontiers in pharmacology · May 2026DOI ↗ Limited · human
This review evaluated the potential role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in managing lipedema, a chronic disorder marked by disproportionate subcutaneous fat accumulation, pain, inflammation, and fibrosis, for which liposuction remains the primary treatment. Authors searched PubMed through March 2026 using terms related to lipedema, GLP-1 RAs, tirzepatide, inflammation, and insulin resistance. Of 13 publications identified, only two specifically examined GLP-1 RAs in lipedema, and just one provided direct patient-level evidence: a small uncontrolled case series of 5 patients treated with exenatide that reported improvements in pain and limb volume. Additional translational evidence suggested GLP-1 RAs, particularly tirzepatide, may influence inflammatory and fibrotic pathways relevant to lipedema. The authors concluded that GLP-1 RAs have not been proven to directly affect lipedema progression, but may offer adjunctive benefit through weight reduction and metabolic improvement. Key limitations include the very small evidence base, absence of controlled trials in lipedema populations, and reliance on indirect evidence from obesity and fibroinflammatory research. The review highlights a significant gap in rigorous clinical data for this patient population.
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] · May 2026DOI ↗ Limited · human
This retrospective cohort study used the TriNetX Research Network — a large federated database — to examine whether GLP-1 receptor agonists (GLPs: semaglutide, tirzepatide, liraglutide, dulaglutide, exenatide, albiglutide, and lixisenatide) were associated with reduced postoperative inflammatory complications (IC) in patients undergoing dermatologic surgery. The study population included patients who underwent Mohs Micrographic Surgery or wide local excisions for melanoma or nonmelanoma skin cancer. Outcomes tracked over one month included wound disruption, hematoma, post-procedure infection, skin and subcutaneous tissue infection, and other procedural complications. After adjusting for demographics and proinflammatory comorbidities using hazard ratios and 95% confidence intervals, the study found that GLP use was associated with a statistically significant reduction in all measured IC categories compared with non-GLP users. Semaglutide and tirzepatide showed the largest individual reductions. Limitations include the retrospective, observational design — which cannot establish causation — along with potential residual confounding, database coding inaccuracies, and inability to control for medication adherence or surgical technique variability.
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] · May 2026DOI ↗ Review
This scoping review examined the relationship between glucagon-like peptide-1 receptor agonists (GLP-1RAs) — a class of medications used for type 2 diabetes and weight management — and hair loss (alopecia). Researchers searched PubMed for relevant articles published through April 2026. The review found conflicting evidence overall: some data suggested an association between GLP-1RA use (particularly semaglutide and tirzepatide) and telogen effluvium (a stress-related, diffuse hair shedding) as well as androgenic alopecia, with risk potentially tied to longer treatment duration, greater magnitude of weight loss, and higher doses. Proposed biological mechanisms included weight loss-induced physiological stress, changes in dermal white adipose tissue, and hormonal shifts, though the authors note their relative contributions remain poorly understood. Conversely, a smaller subset of literature indicated possible improvement in inflammatory forms of alopecia, especially in patients with underlying metabolic dysfunction. Key limitations include the scoping design's reliance on heterogeneous existing literature, absence of original clinical trial data, and the difficulty of disentangling drug effects from weight-loss effects. The authors conclude that dermatology practitioners should be aware of this association and consider patient counseling and monitoring.
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] · May 2026DOI ↗ Review
This review examines the potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) — including exenatide, semaglutide, dulaglutide, and the dual GLP-1R/GIP-R agonist tirzepatide — as pharmacological treatments for alcohol use disorder (AUD). The authors synthesized data from preclinical rodent and non-human primate studies, registered clinical trials, observational/pharmacoepidemiologic studies, and social media reports. In animal models, multiple GLP-1RAs were found to reduce alcohol consumption, alcohol-seeking behavior, alcohol-induced locomotor stimulation, reward memory, and relapse drinking, while also appearing to blunt alcohol's activation of the mesolimbic dopamine system. In the limited available human data, clinical trials of exenatide, semaglutide, and dulaglutide reported reductions in alcohol consumption, and pharmacoepidemiologic studies observed decreased rates of alcohol-related events among AUD patients prescribed GLP-1RAs or tirzepatide. The authors conclude that the GLP-1 system appears to be involved in AUD-related processes and that GLP-1RAs represent a promising but still tentative treatment avenue. Key limitations include the small number of human trials, heterogeneous study designs, and reliance on observational data for most clinical findings.
International journal of molecular sciences · 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 ↗