GLP-1 Receptor Agonists Initiation and Risk of Acute Pancreatitis and Pancreatic Cancer: A Real-World Comparative Study

Background Glucagon-like peptide 1 receptor agonist (GLP-1RA) medications are widely used in managing type 2 diabetes because of their cardio-renal-metabolic benefits. However, concerns persist regarding their potential association with acute pancreatitis (AP) and pancreatic cancer. This study’s objective was to examine the association of GLP-1RAs with the risk of AP and pancreatic cancer. Methods This retrospective propensity score-matched cohort study used Veterans Health Administration national data during fiscal years 2006 to 2021. Using a new-user active comparator design, we included veterans who initiated either GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP-4i) medication, the latter as an active comparator. The primary outcomes were incident AP and pancreatic cancer. We excluded patients with a history of pancreatitis, pancreatic tumors, pancreatic congenital anomalies, and alcohol use. Secondary analysis included adjusting for confounders that may have been introduced during the follow-up period, such as gallbladder diseases, and post hoc analysis restricted analysis to people who had normal serum lipase during follow-up. Results We matched 88,972 pairs of GLP-1RA and DPP-4i users on all characteristics. AP was diagnosed in 214 (0.24%) DPP-4i users versus 273 (0.31%) GLP-1RA users (OR 1.28; 95% CI, 1.07-1.53), and pancreatic cancer was diagnosed in 154 (0.17%) DPP-4i users versus 211 (0.24%) GLP-1RA users (OR 1.37; 95% CI, 1.11-1.69). Secondary and post hoc analyses showed results consistent with the primary analysis. Conclusions GLP-1RAs are associated with a modest but statistically significant increase in the risk of AP and pancreatic cancer compared to DPP-4i. Clinical significance GLP-1RA use is associated with modestly increased odds ratio of acute pancreatitis and pancreatic cancer. Whereas the increased risk seems modest compared to their benefits as shown in the literature, vigilance is recommended, specifically, when GLP-1RAs are used for off label indications.