Glucagon-like Peptide-1 Receptor Agonists Are Not Associated with Increased Risk of Acute Pancreatitis or Pancreatic Complications, Including Pancreatic Cancer, in Type 2 Diabetes: A Global Propensity-Matched Cohort Study

Introduction: Association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and pancreatitis and its long-term complications remains controversial. Using a global electronic health record database, we evaluated pancreatic outcomes following GLP-1 RA initiation in adults with type 2 diabetes mellitus (T2DM). Methods: Adults aged ≥18 years who were alive at the index date; T2DM patients initiating GLP-1 RAs between 2013 and 2025 were identified in the TriNetX network and compared with patients initiating sodium–glucose cotransporter-2 inhibitors (SGLT2i). Sensitivity analyses included comparisons with other second-line diabetes therapies, excluding dipeptidyl peptidase-4 inhibitors, and analyses were restricted to U.S.-based health care organizations. Patients with pre-existing pancreatic conditions were excluded. Cohorts were propensity score-matched for treatment indications, pancreatitis risk factors, and demographics. Kaplan–Meier and Cox proportional hazard models evaluated acute pancreatitis (overall and biliary), chronic pancreatitis, pancreatic pseudocyst, and pancreatic cancer. Results: After matching, 291,152 patients were included in each cohort. GLP-1 RA initiation was not associated with an increased hazard of overall acute pancreatitis compared with SGLT2i initiation (HR 1.095; 95% CI 0.996–1.204), with concordant Kaplan–Meier analyses. A modest, etiology-specific increase in biliary acute pancreatitis was observed in the primary comparison (HR 1.276; 95% CI 1.010–1.612) but was not consistent across sensitivity analyses. No differences were observed in the risks of pancreatic pseudocyst (HR 0.729; 95% CI 0.525–1.014) or pancreatic cancer (HR 1.069; 95% CI 0.940–1.215). Results were similarly consistent in sensitivity analyses. Conclusion: GLP-1 RAs are not associated with an increased risk of acute pancreatitis, pancreatitis-related complications, or pancreatic cancer in T2DM adults; a modest biliary pancreatitis signal was observed, but was not consistent across sensitivity analyses.