Diabetes CareSide Effects & SafetyCohortDecember 1, 2025

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

Fang YE, Paik JM, Ortega-Montiel J, Tesfaye H, Wexler DJ, Patorno E

Key Finding

Popular diabetes medications GLP-1 agonists and DPP-4 inhibitors carry a small 15-22% increased risk of gallbladder problems but don't increase pancreatitis risk compared to SGLT-2 inhibitors.

What This Study Found

This massive study followed over 1.2 million patients with type 2 diabetes in three different comparisons, like running three separate horse races to see which medications are safest for the pancreas and gallbladder. Think of the pancreas and gallbladder as two neighbors who both get upset by diabetes - researchers wanted to know if incretin-based medications (GLP-1 agonists like Ozempic and DPP-4 inhibitors) made either neighbor angrier than SGLT-2 inhibitors (like Jardiance). The good news about pancreatitis: it was essentially a dead heat - no meaningful difference between any of the medications, like three runners crossing the finish line at exactly the same time. However, the gallbladder story was different. Both GLP-1 agonists and DPP-4 inhibitors showed a modest increased risk of biliary events (gallstones, gallbladder inflammation) compared to SGLT-2 inhibitors - but we're talking about less than one additional person per 1,000 having problems each year, which is like finding one extra defective light bulb in a batch of 1,000.

Statistics Decoded

HR 1.01 for GLP-1 pancreatitis risk means virtually identical to the comparison group - like two cars going the same speed. HR 1.15 for GLP-1 biliary risk means 15% higher chance of gallbladder problems, while HR 1.22 for DPP-4 inhibitors means 22% higher risk. The confidence intervals (0.90-1.13, 1.05-1.26) tell us we're reasonably sure the true effect lies within these ranges - none crossed into scary territory. The phrase 'fewer than one additional event per 1,000 person-years' means if you followed 1,000 people for a year, less than one extra person would develop gallbladder problems compared to the safer medication.

Why This Matters

This provides reassuring evidence for the millions taking these popular diabetes medications - pancreatitis fears appear unfounded, and the slight gallbladder risk is small enough that it shouldn't drive treatment decisions for most patients.

Original Abstract

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. 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. 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. 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.