S791 Comparative Risk of Gastrointestinal Adverse Events Among GLP-1 Receptor Agonists: A Real-World Multicenter Study

Introduction: GLP-1 receptor agonists (GLP-1 RAs) have transformed the management of type 2 diabetes and obesity. However, concerns remain regarding gastrointestinal (GI) adverse effects, including gastroparesis, pancreatitis, and gallstone formation. Comparative real-world data across individual agents remain limited. Our aim was to compare the incidence of GI adverse events among patients prescribed different GLP-1 RAs using a large, multicenter electronic health record (EHR) database. Methods: This retrospective cohort study used TriNetX, a U.S. research network of 90+ healthcare systems. Adults (≥18 years) with type 2 diabetes (ICD-10 E11) initiating semaglutide, liraglutide, or exenatide from January 2018 to December 2023 were included. Patients with prior gastroparesis, pancreatitis, cholelithiasis, pancreatic cancer, cirrhosis, or GLP-1 RA use in the prior year were excluded. Cohorts were matched 1:1:1 using propensity scores, adjusting for age, sex, body mass index, HbA1c, diabetes duration, comorbidities (chronic kidney disease, inflammatory bowel disease, gallbladder disease, alcohol use), and medications (metformin, insulin, SGLT2 inhibitors, proton pump inhibitors). Primary outcomes: new-onset gastroparesis, acute pancreatitis, and cholelithiasis. Cox models estimated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Results: There were 42,313 eligible patients: semaglutide (n = 19,870), liraglutide (n = 14,621), exenatide (n = 7,822). After matching, 7,000 patients per group (21,000 total) were retained with balanced covariates. Median follow-up: 14.3 months. Gastroparesis: semaglutide 4.2%, liraglutide 3.1%, exenatide 2.3%. Semaglutide vs exenatide: aHR 1.68 (1.29–2.18), P < 0.001. Semaglutide vs liraglutide: aHR 1.42 (1.17–1.74), P = 0.003. Pancreatitis: semaglutide 2.1%, liraglutide 1.7%, exenatide 1.4%. Semaglutide vs exenatide: aHR 1.41 (1.07–1.86), P = 0.015. Cholelithiasis: liraglutide 6.9%, semaglutide 5.1%, exenatide 4.3%. Liraglutide vs exenatide: aHR 1.47 (1.12–1.91), P = 0.004. Liraglutide vs semaglutide: aHR 1.33 (1.01–1.76), P = 0.038. Highest risks were observed in females with BMI ≥30 and diabetes >10 years. Kaplan-Meier curves showed early divergence by 6 months. Conclusion: GI adverse event risk differs across GLP-1 RAs. Semaglutide showed higher risk for gastroparesis and pancreatitis; liraglutide had the highest cholelithiasis risk. These findings support individualized therapy based on patient-specific GI risk.