GLP-1 Receptor Agonists Increase Gallstone and Biliary Complication Risk in Type 2 Diabetes Patients

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are cornerstone therapies for Type 2 Diabetes Mellitus (T2DM), offering significant benefits in glycemic control, weight reduction, and cardiovascular outcomes. Despite these advantages, concerns have emerged regarding their potential impact on gallbladder health, particularly the risk of cholelithiasis (gallstones) and related complications. Rapid weight loss, a known effect of GLP-1 RAs, is a recognized risk factor for gallstone formation. This study aimed to systematically evaluate the incidence of gallbladder disease among diabetic patients using GLP-1 RAs compared to matched controls, addressing a critical safety profile aspect.

Researchers conducted a retrospective cohort analysis using the TriNetX research network, identifying adults aged ≥18 years with T2DM who initiated GLP-1 RAs. A total of 156,376 patients were initially included, with 43,077 in the GLP-1 RA cohort and 113,299 in the control group. Propensity score matching (1:1) was applied to balance baseline characteristics, resulting in 39,140 patients in each group. Primary outcomes assessed over two and three years included cholelithiasis/choledocholithiasis, cholecystitis, pancreatitis, endoscopic retrograde cholangiopancreatography (ERCP), and cholecystectomy. Subgroup analyses differentiated risks among specific GLP-1 RA agents like semaglutide, dulaglutide, liraglutide, and exenatide.

At the two-year mark, patients on GLP-1 RAs exhibited significantly higher rates of cholelithiasis/choledocholithiasis with an adjusted odds ratio (aOR) of 1.44 (95% CI 1.24-1.65). However, rates of cholecystectomy were not statistically significant at this time point. Extending the observation to three years, the association between GLP-1 RA use and gallbladder issues became more pronounced across multiple outcomes. There were no significant differences observed in the rates of pancreatitis or ERCP at either time point. Specific GLP-1 RAs showed varying risk profiles; semaglutide and dulaglutide were associated with higher rates of cholelithiasis, whereas liraglutide and exenatide did not show a significant increase. This suggests a potential agent-specific effect on biliary complications. The overall findings highlight a consistent, albeit modest, elevation in gallbladder disease risk. > At three years, GLP-1 RA use was associated with significantly 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).