Limited · human
This retrospective, real-world study used the TriNetX federated database to compare oncologic outcomes in postmenopausal women aged ≥50 with obesity (BMI ≥30) and stage 0–III breast cancer, across three groups: GLP-1 receptor agonist (GLP-1RA) users, bariatric surgery patients, and those receiving both interventions. Two propensity score–matched analyses (1:1) adjusted for age, BMI, tumor stage, receptor status, adjuvant therapy, and comorbidities. Study 1 (n=3,438 matched per group) found that GLP-1RA users had a lower instantaneous mortality risk (HR 0.57, 95% CI 0.45–0.73) and lower locoregional recurrence (LRR) rate (1.8% vs. 4.7%; HR 0.52) compared to bariatric surgery alone, despite similar 10-year overall survival (87% vs. 83%). Study 2 (n=1,129 matched per group) found that combined bariatric surgery plus GLP-1RA therapy was associated with higher 10-year overall survival (91% vs. 80%; HR 0.44) and lower LRR (2.5% vs. 5.8%; HR 0.52) versus surgery alone. The authors hypothesize potential anti-inflammatory, insulin-modulating, or other metabolic mechanisms beyond weight loss. Key limitations include the observational design, potential residual confounding, lack of GLP-1RA dose/duration data, and inability to establish causality.
Annals of surgery · Jun 2026DOI ↗ Limited · human
This pharmacovigilance study analyzed over 58 million adverse event reports from the FDA Adverse Event Reporting System (FAERS, 2004–2025) and cross-validated findings against the Canada Vigilance Adverse Reaction Online Database (CVARD) to identify drugs associated with delayed gastric emptying and gastroesophageal reflux. Using three signal-detection algorithms — Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Bayesian Confidence Propagation Neural Network (BCPNN) — the study screened 50 drugs and found 20 with positive signals across all three methods. GLP-1 receptor agonists showed the strongest associations, with semaglutide exhibiting the highest signal for impaired gastric emptying (ROR: 80.27). Other drug classes flagged included insulin formulations (notably insulin degludec), bisphosphonates, angiotensin receptor blockers, and trofinetide. Weibull time-to-onset analysis further characterized temporal patterns, ranging from very early onset (trofinetide, median ~6.6 days) to markedly delayed onset (immunoglobulin G, median ~535 days). Key limitations include the inherent reporting biases of spontaneous pharmacovigilance databases, inability to establish causality, and potential confounding by indication or co-medications. The authors suggest findings should inform enhanced pharmacovigilance and clinical monitoring strategies.
Limited · human
This case report describes a woman in her 50s who developed Boerhaave's syndrome (spontaneous full-thickness esophageal perforation) in the context of GLP-1 receptor agonist (GLP-1 RA) use — specifically semaglutide restarted abruptly at the maximum weekly dose after several months off therapy. She presented with vasopressor-dependent shock, respiratory failure, pneumomediastinum, and bilateral pleural effusions. An esophagram confirmed a contained esophageal perforation. Initial management included endoscopic stent placement, nasojejunal feeding, and chest tube drainage with early improvement. Two months later she was readmitted with necrotizing pneumonia, esophagopleural fistula, stent migration, and abscess, requiring left thoracotomy, decortication, abscess drainage, lung wedge resection, and intercostal muscle flap repair. At 10-month follow-up, the esophagus had healed on endoscopy. The authors propose that GLP-1 RA–induced gastroparesis contributed to forceful emesis and transmural rupture. Key limitations include the inherent inability to establish causality from a single case, and the absence of a control group or systematic population-level data linking GLP-1 RAs to esophageal perforation.
Journal of cardiothoracic surgery · Jun 2026DOI ↗ Limited · human
This retrospective cohort study examined how the timing of preoperative semaglutide discontinuation affects short-term surgical outcomes in patients undergoing aesthetic lipoabdominoplasty. Eighty non-diabetic patients were divided into four groups: those who continued semaglutide until the day of surgery (Group A), those who discontinued 2 weeks prior (Group B), those who discontinued 4 weeks prior (Group C), and semaglutide-naïve controls (Group D). Groups were matched for age, BMI, and surgical technique, and 30-day postoperative complications were tracked. The study found that Group A had the highest complication rate at 45%, encompassing wound dehiscence, infection, and seroma formation. Group B showed a moderate reduction (30%), while Group C's complication rate (10%) was comparable to the control group (10%). Gastrointestinal intolerance and prolonged drain duration were also more common among patients with recent or ongoing semaglutide use. No reoperations or readmissions were recorded. The authors concluded that a 4-week preoperative discontinuation window effectively normalizes complication rates. Key limitations include the retrospective design, small sample size (n=80 across four groups), and the absence of randomization, blinding, or long-term follow-up.
Aesthetic plastic surgery · Jun 2026DOI ↗ 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 clinical trial examined whether short-term meal replacement therapy (MRT) could reduce liver fat and improve metabolic markers in adolescents with severe obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Seventeen participants aged 12–17 years (mean BMI ~40 kg/m²; mean hepatic fat fraction ~15.6%) completed a 4–8 week MRT program targeting a ~500 kcal/day caloric deficit and at least 5% BMI reduction. Liver fat was measured using magnetic resonance spectroscopy (MRS) at baseline and follow-up. The study found a mean 5.6% absolute reduction in BMI and a statistically significant decrease in hepatic fat fraction, along with improvements in insulin sensitivity, glucose area under the curve, and leptin levels. No significant change in alanine aminotransferase (ALT) was observed. Key limitations include the very small sample size (n=17), absence of a control group, and the short intervention duration, all of which substantially restrict generalizability. The authors conclude that MRT was associated with reductions in liver fat and metabolic improvements in this population and call for larger, controlled trials to assess MRT as part of a broader multimodal treatment strategy for adolescent MASLD.
Childhood obesity (Print) · Jun 2026DOI ↗ Limited · human
This observational matched case-control study used high-field (7 T) ¹H/³¹P magnetic resonance spectroscopy (MRS) to examine skeletal muscle metabolism in newly diagnosed, treatment-naïve people with multiple sclerosis (PwMS) compared to matched healthy controls. Gastrocnemius muscle was assessed both at rest (static MRS) and during post-exercise recovery (dynamic ³¹P-MRS), alongside systemic metabolic profiling via an oral glucose tolerance test (OGTT) measuring glucose, insulin, and GLP-1. The study found that PwMS showed lower resting carnosine levels, elevated pre-exercise inorganic phosphate (Pi), a trend toward a reduced phosphocreatine-to-Pi ratio, and significantly prolonged post-exercise phosphocreatine (PCr) recovery — all indicators of mitochondrial energetic impairment. PwMS also demonstrated a blunted GLP-1 response during OGTT despite preserved insulin sensitivity. Notably, higher PCr levels correlated with greater GLP-1 response only in PwMS, suggesting a muscle-systemic metabolic link specific to the disease. The authors conclude that skeletal muscle mitochondrial dysfunction is detectable at MS onset, even before significant systemic metabolic disruption occurs. Limitations include relatively small sample size, a single muscle group assessed, and the cross-sectional design precluding causal inference.
Scientific reports · Jun 2026DOI ↗ Limited · human
This systematic review and meta-analysis examined whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) — medications commonly used for type 2 diabetes and obesity — are associated with an increased risk of diabetic macular edema (DME). Researchers searched five major databases through October 2025 and ultimately included 13 retrospective cohort studies (published 2021–2025) drawn from large real-world databases, all involving patients with diabetes who did not have DME at baseline. Using random-effects models, the study found that the pooled incidence proportion of new-onset DME among GLP-1RA users was approximately 14%. Compared with mixed antihyperglycemic therapies, GLP-1RA use was not significantly associated with increased DME risk (HR: 0.81, 95% CI: 0.52–1.26). GLP-1RAs were associated with a higher relative risk of DME compared to SGLT-2 inhibitors (HR: 1.50, 95% CI: 1.17–1.94), but not compared to DPP-4 inhibitors. The authors rated the overall certainty of evidence as very low, citing high statistical heterogeneity (I² = 99.8%), reliance on retrospective observational designs with inherent confounding risks, and variability across database sources. The study concluded that current evidence does not support a clear overall increased DME risk with GLP-1RA use but called for prospective studies to better characterize comparative retinal safety.
Canadian journal of ophthalmology. Journal canadien d'ophtalmologie · Jun 2026DOI ↗ Limited · human
This retrospective cohort study examined whether a documented GLP-1 receptor agonist prescription history (within one year before surgery) was associated with differences in one-year patient-reported outcomes (PROMs), patient satisfaction, and complication rates following primary total hip arthroplasty (THA). Researchers analyzed 12,749 patients who underwent THA at a single tertiary medical center between 2016 and 2022, of whom 145 had a prior GLP-1 prescription. Multivariable logistic regression was used to adjust for confounders. The study found no statistically significant difference between GLP-1 users and non-users in achieving clinically meaningful improvements in hip pain and function (PASS and MCID thresholds) or patient satisfaction at one year. However, GLP-1 prescription history was associated with reduced odds of 90-day hospital readmission (OR 0.47) and a higher rate of 90-day medical complications (9.66% vs. 6.01%). No significant differences were observed in length of stay, 90-day emergency visits, or two-year implant complication rates. The authors caution that the small exposed cohort (n=145) limits statistical power, and the retrospective, single-center, observational design precludes causal inference. Confounding by indication (e.g., GLP-1 users having more metabolic comorbidities) may also influence results.
Hip international : the journal of clinical and experimental research on hip pathology and therapy · 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 post hoc analysis of the RECAP study examined how combination therapy with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) and a glucagon-like peptide-1 receptor agonist (GLP-1RA) affected blood pressure (BP) control in Japanese patients with type 2 diabetes (T2D) and hypertension. Of 643 T2D patients in the original study, 431 with baseline hypertension were analyzed. Patients were grouped by which drug class was initiated first (GLP-1RA-preceding, n=207; SGLT2i-preceding, n=224). The study found that the rate of achieving the target office BP of less than 130/80 mmHg increased significantly from 25.4% after single-agent therapy to 33.3% after combination therapy was established. Office BP declined from 141.8/82.4 mmHg at baseline to 131.7/79.4 mmHg following combination therapy, and home systolic BP also decreased significantly. Propensity score-based inverse probability weighting analysis revealed no significant difference in BP outcomes based on which drug class was initiated first. Key limitations include the post hoc, non-randomized design, the single-ethnicity Japanese population, and potential residual confounding despite statistical adjustment.
Hypertension research : official journal of the Japanese Society of Hypertension · 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
Two single-dose pharmacokinetic studies investigated whether renal or hepatic impairment affects how the body processes cagrilintide, a long-acting amylin agonist in development for weight management and type 2 diabetes (also studied in combination with semaglutide as "CagriSema"). In each study, adult participants were grouped by organ function (normal, mild, moderate, or severe impairment) and received a single subcutaneous dose of cagrilintide. The renal study enrolled 33 participants and the hepatic study enrolled 32. The primary measure was total drug exposure (AUC₀–∞), with secondary measures including peak concentration (Cmax) and time to peak (tmax). Both studies found that cagrilintide exposure was broadly similar across all impairment levels; estimated AUC ratios relative to normal function ranged from approximately 0.99 to 1.23, with overlapping confidence intervals. No serious adverse events, study withdrawals, or deaths occurred, and no increase in adverse events was observed with worsening organ impairment. The authors concluded that dose adjustment may not be necessary in these populations. Key limitations include small group sizes, single-dose design, and the inability to generalize to steady-state conditions or combined therapies.
Clinical pharmacokinetics · Jun 2026DOI ↗ Limited · human
This qualitative study explored the lived experiences of 30 U.S. adults who were currently taking or had previously taken GLP-1 receptor agonists (GLP-1 RAs) for any indication, recruited via ResearchMatch and snowball sampling across 15 states. Semi-structured video interviews conducted in mid-2025 were analyzed using inductive thematic analysis. Researchers identified eight themes grouped under two domains. The first domain—patient-reported benefits and trade-offs—included reductions in "food noise," appetite, and psychological hunger; recognition that GLP-1 RAs are not standalone weight loss solutions; a wide spectrum of adverse effects; and willingness to tolerate significant side effects and logistical burdens to achieve weight loss goals. The second domain—social, clinical, and structural context—highlighted perceived stigma tied to prescription indication, highly variable clinical support and patient education, prohibitive costs and access barriers, and the value patients placed on shared peer experiences. The study concludes that participants viewed GLP-1 RAs as facilitators of, rather than replacements for, lifestyle change, and that inconsistent clinical support points to a need for standardized patient education guidelines. Key limitations include a small, non-random sample and potential self-selection bias inherent to qualitative recruitment methods.
JAMA network open · 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 ↗