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Biliary and Pancreatic Safety of Incretin-Based Therapies in Obesity and Type 2 Diabetes: A Propensity-Matched Real-World Comparison of Tirzepatide, Semaglutide, and DPP-4 Inhibitors

Year: 2026

Type: article

Abstract: 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.

Source: Journal of Clinical Medicine

DOI: 10.3390/jcm15208027

Authors: Wissam Ghusn, Sasha-Jane Abi-Aad, Maria Daniela Hurtado

Institutions: Mayo Clinic, Saint Louis University, Mayo Clinic in Florida

Language: English

Topic: Diabetes Treatment and Management

Subfield: Endocrinology, Diabetes and Metabolism

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,137