S26 Risk of Biliary Diseases in Patients Treated With GLP-1 vs GLP-1/GI Receptor Agonists: A Real-World Comparative Analysis of Semaglutide and Tirzepatide

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide and the dual glucose-dependent insulinotropic polypeptide/GLP-1 RA tirzepatide, are increasingly prescribed for diabetes and obesity. However, their role in promoting biliary disease is under-investigated. We aimed to compare the risk of biliary disease between GLP-1 RAs and GLP-1/glucose-dependent insulinotropic polypeptide therapies. Methods: We performed a retrospective cohort study using the TriNetX Research Network (Cambridge, MA), a federated network of de-identified electronic health records. Adults (≥18 years) who initiated and continued subcutaneous semaglutide or tirzepatide between 2006 and 2025 were included. Patients with pre-existing biliary disease or prior cholecystectomy were excluded. Propensity score matching (1:1) was used to balance cohorts by age, sex, BMI, diabetes status, and baseline lipid profile. The primary outcome was new biliary disease (ICD-10 codes for cholelithiasis, cholecystitis, cholangitis, and biliary pancreatitis). Secondary outcomes included cholecystectomy and endoscopic retrograde cholangiopancreatography. Cox regression models estimated relative risk. Results: Baseline characteristics for tirzepatide (n = 63,878) and semaglutide (n = 119,588) users are shown in Table 1 [Tables presented at ACG annual meeting]. After matching (n = 63,057 per group), tirzepatide users had significantly lower risk of cholelithiasis (0.86% vs 1.48%; RR 0.58, P < 0.0001), cholecystitis (0.24% vs 0.45%; RR 0.54, P < 0.0001), choledocholithiasis (0.16% vs 0.34%; RR 0.47, P < 0.0001), and other gallbladder complications (0.37% vs 0.65; RR 0.57, P < 0.0001). Biliary pancreatitis was numerically lower (0.04% vs 0.06%; RR 0.65, P = 0.08) but not statistically significant. Among those with biliary disease, cholecystectomy occurred in 20% of tirzepatide users vs 21% of semaglutide users (RR 0.97, P = 0.71), and endoscopic retrograde cholangiopancreatography was performed in 2.72% vs 3.45% (RR 0.79, P = 0.32), with no significant differences. Conclusion: Tirzepatide is associated with a significantly lower risk of biliary disease compared to Semaglutide, including lower rates of cholecystitis and choledocholithiasis. While procedural interventions were numerically reduced in the tirzepatide group, differences were not statistically significant. These findings suggest a more favorable biliary safety profile for tirzepatide among GLP-1-based therapies.