Comprehensive pharmacovigilance assessment of pairwise drug–drug interactions and acute pancreatitis in the FDA adverse event reporting system: focus on incretin-based drugs

Background Drug-induced pancreatitis remains a clinically important condition owing to its severity and relevance to pharmacotherapeutic risk management. Incretin-based antidiabetic agents, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, are associated with an increased risk of acute pancreatitis (AP). However, the extent to which concomitant medication modifies AP has not yet been systematically elucidated. We conducted a comprehensive systematic drug–drug interaction (DDI) assessment involving GLP-1 RA and DPP-4 inhibitors using the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS). Methods Disproportionality analyses were conducted using the FAERS data (JAPIC FAERS) from the fourth quarter of 1997 to the first quarter of 2024. Crude reporting odds ratios (cRORs) were calculated to assess the association between individual drugs and AP. DDI signals for 1:1 concomitant use involving GLP-1 RAs or DPP-4 inhibitors were comprehensively evaluated using the Ω shrinkage measure, with Ω 025 as the signal detection criterion. Ω 025 were analyzed for all pooled cases, and temporal trends were assessed across six multi-year periods using a period-stratified analysis. Results Elevated cRORs for AP were observed for several agents, including GLP-1 RAs, DPP-4 inhibitors, and other antidiabetic medications. Pairwise DDI analyses of GLP-1 RAs or DPP-4 inhibitors with other drugs identified positive interaction signals in 308 drug pairs in pooled analyses. Period-stratified analyses narrowed the findings to 11 drug pairs with consistent signals across ≥3 of 6 periods, including dulaglutide–atorvastatin (four periods). However, no concomitant drug combinations involving GLP-1 RAs or DPP-4 inhibitors were identified as being robustly associated with increased AP reporting. Conclusion Period-stratified analysis helped mitigate false-positive signals identified in the pooled DDI analyses. Drug pairs exhibiting recurrent weak AP signals warrant continued pharmacovigilance and further evaluation.