Limited · human
This cross-sectional pharmacovigilance study analyzed 142,705 adverse event (AE) reports for GLP-1 receptor agonists (GLP-1 RAs) from the FDA Adverse Event Reporting System (2015–2025), focusing on 4,090 reports linked to obesity indications. The authors found gastrointestinal events were most common, 76% of reports involved female patients, and most events onset within 0–30 days. Semaglutide showed a distinct distribution including a higher proportion of late-onset events (≥360 days), while tirzepatide showed negative reporting odds ratios for several gastrointestinal events. Strong disproportionality signals were identified for biliary, pancreatic, renal, and coagulation events. Separately, the study constructed herb-compound-target-AE networks using HERB 2.0 and the Comparative Toxicogenomics Database, applying graph convolutional network (GCN) modeling to identify herbal candidates—including Liquorice Root, Mulberry Leaf, Dahurian Angelica Root, Danshen Root, and Ginkgo Leaf—potentially associated with GLP-1 RA AE profiles. GCN performance was moderate (AUC-ROC 0.666–0.798). The authors explicitly note findings are exploratory and hypothesis-generating, with results limited by spontaneous reporting biases and computational modeling constraints. Independent experimental and clinical validation is required before any clinical application.
Scientific reports · Jun 2026DOI ↗ Limited · human
This narrative review examined the clinical potential of tirzepatide — a dual agonist of the GLP-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) — specifically in type 1 diabetes mellitus (T1DM), a population distinct from the type 2 diabetes and obesity contexts in which tirzepatide is already established. Researchers searched PubMed/MEDLINE, Scopus, and Google Scholar through March 2026. Across the reviewed studies, tirzepatide was associated with reductions in HbA1c of up to 0.9%, body weight reductions of up to 23.4% (up to 9.0 kg/m² BMI reduction), increases in continuous glucose monitoring time-in-range (TIR) of up to 18.0% (primarily driven by reductions in time above range), and decreases in daily insulin requirements of up to 38 units/day. The authors noted that glycemic and weight benefits appeared to be partly, but not exclusively, mediated by weight loss. Key limitations acknowledged include that most available studies are observational in design, enrolled participants with overweight or obesity, and that randomized controlled trials in T1DM populations are still needed to confirm these findings.
Expert review of clinical pharmacology · Jun 2026DOI ↗ Limited · human
This retrospective federated cohort study used the TriNetX US Collaborative Network to examine whether GLP-1-based therapy (semaglutide or tirzepatide) was associated with lower rates of ICD-10-documented heart failure (HF) or respiratory failure (RF) in non-diabetic adults with rheumatoid arthritis (RA) and obesity (BMI ≥30 kg/m²). Patients were required to have baseline disease-modifying antirheumatic drug (DMARD) use, and those with diabetes or overlapping systemic autoimmune diseases were excluded. After propensity score matching on 68 covariates (1:1), 3,483 patients remained per cohort. The study found that GLP-1-based therapy was associated with a substantially lower hazard of first post-landmark composite HF or RF events during days 91–365. In absolute terms, the primary composite occurred in 0.7% of GLP-1 users versus 1.8% of never-users, corresponding to roughly one fewer event per 100 patients. Heart failure and respiratory failure analyzed separately showed directionally consistent lower hazards, though individual event counts were small. The authors acknowledge that the findings are hypothesis-generating only, are limited by the retrospective, administrative-data design and potential residual confounding, and require prospective validation before informing clinical practice.
Clinical rheumatology · Jun 2026DOI ↗ Limited · human
This prospective, matched controlled study used continuous glucose monitoring (CGM) via FreeStyle Libre to characterize glycaemic patterns during Ramadan 2025 in 54 adults with insulin-treated diabetes. Three matched groups of 18 participants each were compared: type 2 diabetes on basal-bolus insulin alone (BB), type 2 diabetes on basal-bolus insulin plus adjunctive semaglutide or tirzepatide (BB+), and type 1 diabetes on basal-bolus insulin. CGM data were collected over 28 days pre-Ramadan and 29 days during Ramadan. The study found that dysglycaemia was predominantly driven by the post-iftar (meal-breaking) period. The BB group showed marked deterioration in glycaemic control during non-fasting hours. In contrast, the BB+ group demonstrated significantly better time-in-range (74.4% vs. 36.8%), a lower glucose management indicator (6.9% vs. 8.3%), and an approximately 61% reduction in post-iftar glucose excursions, without increased hypoglycaemia or treatment discontinuations. Limitations include a relatively small matched sample size, a single Ramadan observational period, and non-randomized group assignment, which may introduce residual confounding despite matching.
Diabetes research and clinical practice · Jun 2026DOI ↗ Limited · humanPreprint
This retrospective, propensity-score matched observational study used de-identified federated U.S. electronic health record (EHR) data to examine real-world associations of semaglutide (n=1,424) and tirzepatide (n=578) use in adults with type 1 diabetes (T1D) compared to 1:1 matched T1D controls (n=2,002) who did not receive these agents, over a study period from 2018–2025. Neither drug is approved for T1D. The study found that both agents were associated with statistically significant reductions in total daily insulin dose, HbA1c, and body weight at 12 and 24 months compared to controls. Greater insulin reductions were observed in semaglutide users who achieved higher weight loss or dose escalation. The pre-vs-post safety analysis identified predominantly gastrointestinal adverse events; DKA, severe hypoglycemia, pancreatitis, and retinopathy did not increase significantly overall, though patients with >30% insulin dose reduction had higher DKA rates. Semaglutide and tirzepatide exposure was associated with lower all-cause mortality and major adverse cardiovascular events versus matched controls. Key limitations include the observational design, EHR data quality constraints, off-label prescribing confounding, and preprint status, meaning findings have not yet undergone peer review.
Unknown journal · Jun 2026DOI ↗ Limited · human
This case report describes the use of tirzepatide — a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist — in a 31-year-old woman diagnosed with Smith-Magenis syndrome (SMS), a rare neurodevelopmental disorder associated with intellectual disability, behavioral dysregulation, and hyperphagia-driven obesity. The patient had a lifelong history of obesity and aggressive behaviors that had not responded adequately to standard management. Following initiation and titration of tirzepatide, the authors report that the patient achieved approximately 9.4% body weight loss (~7.3 kg) over 10 months, along with improvements in fasting glucose levels. Caregivers also noted behavioral benefits, including reduced food-seeking behavior and impulsivity, and quantitative analysis reportedly showed a significant reduction in aggression. The treatment was described as well tolerated. The authors hypothesize that tirzepatide may engage both metabolic and central nervous system pathways relevant to the SMS phenotype. Key limitations include the single-patient design, the absence of a control condition, and the inherent difficulty in attributing behavioral improvements to tirzepatide alone in a complex neurodevelopmental disorder.
JCEM case reports · Jun 2026DOI ↗ Limited · human
This retrospective cohort study used the TriNetX Global Research Network to examine whether GLP-1 receptor agonist (GLP-1 RA) use was associated with a reduced risk of total knee arthroplasty (TKA) in adults with knee osteoarthritis (OA) diagnosed between 2010 and 2024. Patients exposed to GLP-1 RAs (either any agent or newer agents—semaglutide or tirzepatide) were propensity score matched to unexposed controls, balancing for age, sex, race, musculoskeletal diagnoses, obesity-related conditions, BMI, and healthcare access proxies. Matched cohort sizes ranged from approximately 13,000 to 42,000 patients depending on the exposure class and treatment duration analyzed (1 or 3 years). The primary outcome was cumulative TKA incidence at 1, 3, 5, and 8 years, estimated via Kaplan-Meier curves and Cox proportional hazards models. The study found that GLP-1 RA use was associated with significantly lower TKA incidence across all subgroups, with larger reductions observed with longer treatment durations and with newer-generation agents. The authors suggest the findings are consistent with possible disease-modifying activity beyond weight loss, but acknowledge that as a retrospective observational design, causality cannot be established, and prospective randomized trials are needed.
Regional anesthesia and pain medicine · Jun 2026DOI ↗ Limited · human
This observational pharmacovigilance study analyzed Individual Case Safety Reports (ICSRs) from the European EudraVigilance (EV) database to investigate whether GLP-1 receptor agonists (semaglutide, liraglutide, exenatide, lixisenatide, dulaglutide) and the dual GLP-1/GIP agonist tirzepatide are disproportionately associated with thyroid cancer-related adverse events. The study retrieved 34,956 ICSRs reported between January 2022 and September 2024. Most adverse events affected adult and elderly female patients, with gastrointestinal disorders being the most commonly reported category. Using disproportionality analysis (Reporting Odds Ratio, ROR), the study found that semaglutide had a statistically significantly lower probability of thyroid cancer-related adverse event reporting compared to tirzepatide (ROR = 0.54, 95% CI 0.37–0.81). The authors acknowledge key limitations inherent to pharmacovigilance databases, including reporting bias, confounding by indication, and the inability to establish causality. They conclude that findings must be interpreted cautiously and that further prospective studies are needed to clarify whether a true causal relationship exists between GLP-1 RAs and thyroid cancer risk.
Pharmacological reports : PR · May 2026DOI ↗ 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 ↗ 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 ↗ 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 ↗ 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 ↗ 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 ↗ 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 · 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 ↗ Limited · human
This case series describes two patients with severe obesity who developed moderate-to-severe cutaneous allodynia — a condition where normally non-painful stimuli such as touch or mild temperature change cause pain — while being treated with the dual GLP-1/GIP receptor agonist tirzepatide for weight management. In both cases, the onset of allodynia was temporally linked to dose escalation, occurring at higher doses, and resolved upon discontinuation of the drug. The allodynia varied between static and dynamic types across the two patients. The authors reviewed the tirzepatide U.S. prescribing information and found no prior documentation of skin pain or allodynia as an adverse event, though a prior FDA Adverse Event Reporting System (FAERS) pharmacovigilance analysis had identified rare allodynia signals across six GLP-1RAs. The authors assert this is the first case series specifically reporting allodynia with tirzepatide. Key limitations include the very small sample size (n=2), absence of a control group, and the inherent inability to establish causality from case reports alone. The temporal association and resolution upon drug withdrawal do, however, provide a suggestive signal warranting further investigation.
The American journal of case 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 ↗