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.

Background

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.

Methods

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.

Results

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; p < 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; p < 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; p < 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; p = 0.08).

Conclusions

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.