Cohort Study: Risk of Gallstones and Biliary Complications With Glucagon‐Like Peptide‐1 Receptor Agonists in Type 2 Diabetes

Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are widely prescribed for type 2 diabetes mellitus (T2DM) because of their benefits in glycemic control, weight reduction, and cardiovascular outcomes. This study evaluated the risk of gallbladder disease among diabetic patients treated with GLP‐1 RAs. Methods A retrospective cohort analysis was performed using the TriNetX research network. Adults ≥ 18 years with T2DM who received GLP‐1 RAs were identified and compared with matched controls. Propensity score matching (1:1) was used to balance baseline characteristics. Outcomes included cholelithiasis/choledocholithiasis, cholecystitis, pancreatitis, endoscopic retrograde cholangiopancreatography (ERCP), and cholecystectomy. Subgroup analyses were performed according to GLP‐1 RA agents. Results A total of 156,376 patients were included; 43,077 patients were in the GLP‐1 RA cohort and 113,299 patients were in the control group. After matching, 39,140 patients remained in each group. At two years, patients with GLP‐1 RA use had higher rates of cholelithiasis/choledocholithiasis (aOR 1.44, 95% CI 1.24–1.65), whereas rates of cholecystectomy were non‐significant. By three years, GLP‐1 RA use remained associated with higher rates of cholelithiasis/choledocholithiasis (aOR 1.43, 95% CI 1.24–1.63), cholecystitis (aOR 1.45, 95% CI 1.14–1.83), and cholecystectomy (aOR 1.54, 95% CI 1.17–2.02). There were no significant differences in the rates of pancreatitis or ERCP. Semaglutide and dulaglutide demonstrated higher cholelithiasis, whereas liraglutide and exenatide were not associated with a significant increase. Conclusion GLP‐1 RAs use in patients with T2DM was associated with modestly higher rates of cholelithiasis/choledocholithiasis, cholecystitis, and cholecystectomy, whereas there were no significant differences in rates of pancreatitis or ERCP.