Serious adverse events, hospitalization, and mortality associated with icosapent ethyl: a pharmacovigilance analysis using the FDA adverse event reporting system

Background Icosapent ethyl (IPE) was FDA-approved in 2012 for severe hypertriglyceridemia, with its indication expanded following the landmark REDUCE-IT trial (2018) to cardiovascular risk reduction in high-risk statin-treated patients. While post-marketing surveillance has identified atrial fibrillation and bleeding as significant adverse effects, serious outcomes — hospitalization and death — remain insufficiently characterized in real-world populations. Purpose To evaluate disproportionate reporting of serious outcomes — hospitalization and death — associated with icosapent ethyl in FAERS, with comparison to other lipid-lowering therapies and assessment of temporal trends following REDUCE-IT publication. Methods This retrospective pharmacovigilance study queried publicly available FAERS data from January 2012 through the most recent available reporting year. We extracted reports of serious adverse events, hospitalizations, and deaths associated with icosapent ethyl and four comparator lipid-lowering drug classes: statins, fibrates, PCSK9 inhibitors, and other omega-3 fatty acids. Reporting odds ratios (RORs) with 95% confidence intervals were calculated against all other drugs in the database. To assess the impact of the 2018 REDUCE-IT publication, reports were stratified into pre- (2012–2018) and post-publication (2019–2026) epochs with RORs calculated independently for each period. SDRs were defined as drug–event pairs with a lower bound of the 95% CI of the ROR exceeding 1 and a minimum of five reports. Results Icosapent ethyl showed consistently reduced serious adverse event signals across the full study period (ROR 0.237, 95% CI: 0.221–0.256) and both epochs (2012–2018: ROR 0.103; 2019–2026: ROR 0.274), mirrored by other omega-3 fatty acids (ROR 0.481) and PCSK9 inhibitors (ROR 0.181). Statins and fibrates showed elevated and increasing signals (statins: ROR 3.671 to 5.715; fibrates: ROR 3.923 to 6.498). For mortality, IPE showed a reduced overall signal (ROR 0.495, 95% CI: 0.427–0.574) with temporal attenuation (2012–2018: ROR 0.096; 2019–2026: ROR 0.668), echoed by other omega-3 fatty acids (ROR 0.178 to 0.559). Statins maintained a reduced mortality signal (ROR 0.753 to 0.848). Fibrates were the only comparator with an elevated late-period signal (ROR 1.637, 95% CI: 1.496-1.792). PCSK9 inhibitors showed the lowest stable signal (ROR 0.163, 95% CI: 0.156–0.170). Conclusion IPE demonstrated serious adverse event reporting patterns similar to other omega-3 fatty acids and PCSK9 inhibitors, and markedly lower than statins and fibrates. For mortality, IPE occupied an intermediate position among lipid-lowering therapies. Post-REDUCE-IT attenuation of the mortality signal likely reflects indication expansion to higher-risk populations and increased prescribing volume rather than a true safety change, underscoring the need for controlled epidemiological studies with appropriate denominators.