To compare the 1-year risk of biliary/pancreatic adverse events among patients with obesity and type 2 diabetes treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus dipeptidyl peptidase-4 inhibitors (DPP-4i), and to directly compare tirzepatide with semaglutide. Methods: We conducted a retrospective propensity score-matched cohort study using the TriNetX Global Collaborative Network. Adults with obesity and type 2 diabetes without prior biliary or pancreatic disease were included. Two prespecified comparisons were performed: GLP-1RA (semaglutide or tirzepatide) versus DPP-4i, and tirzepatide versus semaglutide. The primary outcome was incident cholelithiasis at 1 year. Secondary outcomes included cholecystitis, cholangitis, acute pancreatitis, and cholecystectomy. Hazard ratios (HRs) were estimated using Cox proportional hazards models. Results: After matching, 281,283 patients were included in each GLP-1RA and DPP-4i cohort, and 242,876 patients in each tirzepatide and semaglutide cohort. Compared with DPP-4i, GLP-1RA therapy was associated with lower risks of cholelithiasis (1.02% vs. 1.16%; HR 0.92, 95%CI 0.87-0.96), cholecystitis (HR 0.88, 95%CI 0.79-0.98), cholangitis (HR 0.46, 95%CI 0.36-0.58), acute pancreatitis (HR 0.68, 95%CI 0.61-0.76), and cholecystectomy (HR 0.51, 95%CI 0.38-0.69). In the head-to-head comparison, semaglutide was associated with higher risks of cholelithiasis (HR 1.11, 95%CI 1.05-1.18) and cholecystitis (HR 1.22, 95%CI 1.10-1.37) compared with tirzepatide, while risks of pancreatitis, cholangitis, and cholecystectomy did not differ significantly. Conclusions: In this large real-world study, GLP-1RA therapy was associated with lower risks of biliary and pancreatic events compared with DPP-4i. Tirzepatide demonstrated a modestly more favorable biliary safety profile than semaglutide, supporting the overall hepatobiliary safety of contemporary GLP-1-based therapies.
