Pancreatic and biliary safety signals of GLP-1 receptor agonists and tirzepatide: a disproportionality analysis of FAERS reports

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Abstract

[BACKGROUND] The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide is increasing rapidly worldwide, and the pancreatic and biliary safety of these drugs has been a concern. This study was based on the US Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate the pancreatic and biliary adverse event reporting signals of liraglutide, semaglutide, tirzepatide and dulaglutide. [OBJECTIVES] To describe the reporting patterns of pancreatic and biliary adverse events for liraglutide, semaglutide, dulaglutide, and tirzepatide, and to identify signals in both organ systems within a single framework. [DESIGN] Retrospective disproportionality analysis of individual case safety reports. [METHODS] FAERS data from Q3-2009 through Q3-2025 were extracted, and deduplicated ICSRs were used as the unit of analysis. Reporting odds ratios (RORs) and information components (ICs) were computed at composite and Preferred Term levels; signals required the lower 95% confidence bound for the ROR to exceed 1 and IC025 to exceed 0. Metformin and sodium-glucose cotransporter-2 inhibitors were included as contextual benchmarks. Analyses were stratified by brand (diabetes/obesity indication), sex, age, and reporter type, and time to onset was examined. [RESULTS] A disproportionality signal for pancreatic adverse events was observed for all four study drugs, but the control drugs metformin and SGLT2i also showed positive signals. For biliary events, all four study drugs showed signals, whereas the two control drugs showed no signals. After stratification by brand, the pancreatic signal remained for brands with diabetes indications, while the signal was weaker for brands with obesity indications. After excluding the cases of biliary tract co-reporting, the pancreatic signal still existed. Median time to onset ranged from 85.5 to 136 days for pancreatic events and from 146.5 to 320 days for biliary events. [CONCLUSION] Both GLP-1RAs and tirzepatide are associated with disproportionate reporting of pancreatic and biliary adverse events in FAERS. Signals are influenced by indication, reporting behavior, and time effects and cannot be used to estimate incidence or prove causality. These signals suggest the need for further validation in real-world cohort studies.

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