Guts, Glucose, and Gallbladders: The Protective Role of GLP-1/GIP Receptor Agonists Against Biliary Complications in Patients with Type 2 Diabetes and Inflammatory Bowel Disease.

: Patients with type 2 diabetes mellitus (T2DM) and inflammatory bowel disease (IBD) face elevated risk of hepatobiliary complications. The biliary safety of GLP-1 and dual GLP-1/GIP receptor agonists in this population is uncertain. : We conducted a retrospective cohort study using the TrinetX LIVE global health research network. Adults (≥18 years) with coexisting T2DM and IBD were assigned to exposure (semaglutide or tirzepatide) or comparator (no GLP-1/GIP therapy) cohorts. The index was first prescription (or matched date). Primary outcomes-cholelithiasis, cholecystitis, choledocholithiasis, and cholangitis-were identified by ICD-10 codes. Propensity score matching (1:1 greedy nearest neighbor; caliper 0.1 SD) balanced demographics, comorbidities, GI surgeries, and antidiabetic medications. : After propensity score matching, 32,052 patients were included (16,026 per cohort), achieving excellent covariate balance with standardized mean differences < 0.1 for nearly all variables. GLP-1/GIP agonist use was associated with significantly lower risks of multiple biliary complications. Cholelithiasis occurred in 3.5% of GLP-1/GIP users compared with 6.3% of nonusers (risk ratio [RR] 1.81, 95% CI 1.64-2.00; hazard ratio [HR] 1.27, 95% CI 1.14-1.41; < 0.001). Cholecystitis similarly occurred less frequently among users (0.8% vs. 2.2%; RR 2.74, 95% CI 2.24-3.34; HR 1.85, 95% CI 1.50-2.27; < 0.001). Choledocholithiasis was also reduced in the GLP-1/GIP cohort (0.6% vs. 1.5%; RR 2.72, 95% CI 2.14-3.46; HR 1.90, 95% CI 1.48-2.44; < 0.001). Cholangitis events were rare in both groups (0.1% vs. 0.2%) with no significant difference on survival analysis (HR 1.07, 95% CI 0.58-1.97; = 0.08). : In adults with T2DM and IBD, GLP-1 and dual GLP-1/GIP receptor agonists are associated with substantially reduced risks of gallstone-related complications. These real-world data support the gastrointestinal safety of GLP-1-based therapy in a high-risk population and suggest possible biliary protective effects warranting prospective, agent-specific studies.