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 ↗ 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 ↗ Strong · human
This systematic review and meta-analysis pooled data from four randomized controlled trials (n = 5,023 adults with overweight or obesity) to evaluate the efficacy and safety of cagrilintide — a long-acting amylin analogue — and its combination with semaglutide (CagriSema) versus placebo. The primary outcome was percent change in body weight. The authors followed PRISMA 2020 and AMSTAR 2 guidelines and used Cochrane RoB 2 for bias assessment, with random-effects models throughout. Key findings: cagrilintide alone was associated with a mean body weight reduction of approximately 6.1% versus placebo (95% CI: −8.0% to −4.1%), and CagriSema with approximately 6.0% (95% CI: −10.6% to −1.3%). CagriSema also significantly reduced waist circumference and HbA1c; cagrilintide alone showed modest blood pressure improvements without significant glycemic effects. Adverse events were more frequent with active treatment, though discontinuation rates were comparable to placebo. Notable limitations include the small number of pooled trials (n = 4) and potential heterogeneity across study populations and durations. The authors conclude that both therapies show clinically meaningful weight loss and acceptable tolerability, positioning them as emerging options in obesity pharmacotherapy.
Journal of diabetes and metabolic disorders · May 2026DOI ↗ In vitro
This study describes the computational design and preliminary laboratory characterization of SR18, a rationally engineered 18-amino acid peptide candidate intended to act as a GLP-1 receptor (GLP-1R) agonist for potential use in Type 2 diabetes (T2DM). The researchers used in silico methods—including molecular docking and 1-microsecond molecular dynamics (MD) simulations—to design SR18 to be resistant to DPP-4 cleavage and to retain key amino acids that interact with GLP-1R, similar to endogenous GLP-1 and approved drugs like Semaglutide and Liraglutide. In laboratory experiments, circular dichroism confirmed that synthesized SR18 adopts a stable α-helical conformation across various solvent conditions. Dynamic light scattering, cytotoxicity, and hemolytic assays suggested acceptable basic pharmaceutical and safety properties for a lead peptide candidate. Computational analyses indicated that SR18 may bind GLP-1R with comparable or favorable affinity relative to GLP-1 and Semaglutide. Limitations include the absence of any cell-based receptor activation assays, animal studies, or human data; the evidence remains entirely in silico and in vitro. No conclusions about clinical efficacy can be drawn at this stage.
Frontiers in pharmacology · 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 structured narrative review synthesized contemporary evidence (January 2020–August 2025) on injectable peptides used in orthopaedics and sports medicine, drawing from PubMed/MEDLINE, Embase, and Web of Science. The authors identified five functional peptide classes: GLP-1 receptor agonists (e.g., semaglutide), collagen-derived injectables, regenerative peptides (e.g., BPC-157, thymosin derivatives), growth hormone secretagogues (e.g., CJC-1295, ipamorelin, tesamorelin), and related compounds. The review found that GLP-1 receptor agonists were the only class supported by reproducible randomized evidence for musculoskeletal benefit—specifically symptomatic improvement in knee osteoarthritis—attributing this primarily to weight loss and putative anti-inflammatory effects rather than proven structural cartilage modification. Collagen-derived preparations showed only preliminary signals from small, single-center prospective studies. All remaining classes were deemed investigational, carrying unresolved safety profiles, significant product quality concerns, and widespread antidoping restrictions. Risk of bias was appraised for included human trials. The authors concluded that clinical use of injectable peptides should be restricted to approved agents for established indications or rigorously designed research protocols, and that clinicians should counsel athletes about uncertain efficacy, safety risks, and antidoping consequences. The study was assigned Level V evidence and a predominantly Grade C strength of recommendation.
JBJS reviews · 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 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 ↗ Limited · human
This retrospective observational study analyzed GLP-1 receptor agonist (GLP-1 RA) prescription records from the LUX MED private healthcare network in Poland between 2018 and 2025. Among 42,423 patients with more than one prescription, the study characterized how frequently patients switched between GLP-1 RA agents and identified factors associated with switching. The primary analysis used a discrete-time hazard model at the prescription-transition level, with subcutaneous semaglutide as the reference comparator. The study found that nearly 30% of patients switched agents at least once, and over 14% switched two or more times. After adjusting for switching opportunity and calendar time, liraglutide was associated with substantially lower odds of switching compared to subcutaneous semaglutide, while oral semaglutide and dulaglutide did not differ significantly. Temporal analyses revealed episodic peaks in switching and accelerating uptake of tirzepatide following its market entry. Key limitations include the retrospective, observational design; the lack of data on reasons for switching (e.g., tolerability, cost, availability); restriction to a single private-sector network; and the inability to establish causality. The authors characterize findings as hypothesis-generating.
Acta diabetologica · May 2026DOI ↗ Limited · human
This report examines the transfer of semaglutide into human breast milk in mothers using subcutaneous (injectable) semaglutide. The study found that semaglutide was undetectable in the breast milk of mothers receiving the drug via subcutaneous injection, and breastfed infants whose mothers used this route did not experience adverse effects. The report also highlights an important safety consideration regarding oral formulations of semaglutide (e.g., Rybelsus): these contain the absorption enhancer salcaprozate sodium (SNAC), which may be transferred into breast milk and potentially accumulate in nursing infants, raising concerns about the oral route during lactation. The report concludes that only injectable forms of semaglutide appear to be appropriate for use during breastfeeding based on currently available data. Limitations include the likely small number of mother-infant pairs studied and the observational nature of the data, which precludes definitive causal conclusions. Long-term infant outcomes were not assessed.
Unknown journal · May 2026Source ↗ Review
This narrative review synthesizes current evidence on glucagon-like peptide-1 (GLP-1)-based therapies—primarily semaglutide and tirzepatide—for the management of obesity-related heart failure with preserved ejection fraction (HFpEF). Drawing on PubMed and Scopus literature published between January 2020 and March 2026, the authors incorporated randomized trials, pooled analyses, mechanistic studies, and observational data. The review describes how obesity-related HFpEF arises from a complex interplay of excess lipids, chronic inflammation, and metabolic dysregulation, which also interact with GLP-1 pathways. According to the authors, GLP-1-based therapies demonstrated meaningful improvements in symptoms, exercise capacity, and quality of life in this population, with benefits attributed to weight reduction, decreased systemic inflammation, and improved congestion indices. Tirzepatide was additionally associated with reductions in heart failure-related complications. Proposed mechanisms include coordinated effects on metabolism, inflammation, hemodynamics, and cardiac remodeling. The authors note that evidence for improvements in morbidity appears stronger than evidence for reductions in mortality. Key limitations include the narrative (non-systematic) review methodology, potential selection bias in study inclusion, and the absence of long-term mortality data. The authors conclude that further research is needed to clarify long-term outcomes, refine patient selection, and guide clinical integration.
Journal of clinical medicine · May 2026DOI ↗