Risk of Acute Pancreatitis and Biliary Events After Initiation of Incretin-Based Medications in Patients With Type 2 Diabetes

OBJECTIVE: Patients with type 2 diabetes (T2D) are at increased risk of acute pancreatitis (AP) and biliary events. Evidence remains mixed regarding the association between incretin-based therapies, such as glucagon-like peptide 1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase 4 inhibitors (DPP-4is), and these outcomes. We examined the association between incretin medication use and risk of incident AP or biliary disease in patients with T2D. RESEARCH DESIGN AND METHODS: Using Medicare Fee-for-Service (FFS) and two U.S. commercial claims databases (2014-2021), we identified three pairwise cohorts of propensity score (PS)-based fine stratification-weighted patients aged ≥18 years (≥65 years in Medicare FFS) with T2D without prior AP or biliary disease who initiated treatment with GLP-1RAs versus sodium-glucose cotransporter 2 inhibitors (SGLT2is), DPP-4is versus SGLT2is, or GLP-1RAs versus DPP-4is. PS was estimated using 92 covariates. Weighted hazard ratios (HRs) with 95% CIs for hospitalization because of AP and biliary events were estimated using Cox models. RESULTS: Each cohort included >1.2 million patients. After weighting, GLP-1RA and DPP-4i initiators had similar risk of AP compared with SGLT2i initiators (HR 1.01; 95% CI 0.90-1.13 and HR 1.00; 95% CI 0.85-1.15, respectively). However, both GLP-1RA and DPP-4i initiators showed a modestly increased risk of biliary disease compared with SGLT2i initiators (HR 1.15; 95% CI 1.05-1.26 and HR 1.22; 95% CI 1.03-1.46, respectively), equivalent to fewer than one additional event per 1,000 person-years. There was no difference in risk of AP (HR 1.08; 95% CI 0.95-1.22) or biliary disease (HR 0.95; 95% CI 0.86-1.04) between GLP-1RAs and DPP-4is. CONCLUSIONS: In patients with T2D, GLP-1RAs and DPP-4is were associated with a small increase in risk of biliary disease, but not of AP, compared with SGLT2is.