Comparative Safety of GLP-1 Receptor Agonists Across Gastrointestinal, Renal and Pancreatic Systems

Objectives: to assess the safety profile of Gastrointestinal (GIT), renal, and pancreatic effects of GLP-1 and dual receptor agonists. Methods: Disproportionality analyses were performed on FDA Adverse Event Reporting System (FAERS) data following each drug's approval for weight management. Signals were identified using Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR) with 95% confidence intervals (CIs). Results: Among GIT AEs, semaglutide (n = 12,321; 1.65%) showed the strongest signals (PRR 3.97, ROR 14.21), exceeding liraglutide (n = 5972, 0.45%, PRR 2.76, ROR 5.01) and tirzepatide (n = 4056, 3.48%, PRR 1.64, ROR 1.90). For renal and pancreatic outcomes, liraglutide demonstrated the highest overall signal (PRR 4.91, ROR 5.35), particularly for acute pancreatitis (PRR 18.9, ROR 19.4) and pancreatic carcinoma (PRR 18.6, ROR 19.5). Semaglutide showed stronger associations with diabetic ketoacidosis (DKA) (PRR 5.86, ROR 5.9) and acute kidney injury (AKI) (PRR 1.25, ROR 1.25). Tirzepatide demonstrated weaker or absent signals across most outcomes. Conclusions: This study revealed that semaglutide was most associated with GIT events, while liraglutide showed stronger renal and pancreatic signals. Novel associations with DKA and AKI were observed, warranting clinical vigilance. Findings should be cautiously interpreted given surveillance limitations, emphasising the need for large-scale real-world studies to confirm safety profiles.