Icosapent ethyl–induced lipoprotein remodeling and its impact on cardiovascular disease risk markers in normolipidemic individuals

Abstract

BACKGROUND. Icosapent ethyl (IPE), an ethyl ester of eicosapentaenoic acid (EPA), reduces cardiovascular disease (CVD), but the mechanism remains elusive. We examined the effect of IPE supplementation on lipoprotein subclasses, lipidomes, and pro-atherogenic properties. METHODS. Using 3 independent metabolomic platforms, we examined the effect of high-dose IPE supplementation for 28 days on fatty acid profiles, lipoprotein subclasses, lipidomes, and proatherogenic properties in normolipidemic volunteers (n = 38). RESULTS. IPE supplementation increased lipoprotein EPA on average 4-fold within 7 days, returning to baseline after a 7-day washout. Notably, the incorporation displayed marked interindividual variance, negatively correlating with baseline levels. We identified persistent participantspecific lipoprotein fingerprints despite uniform IPE-induced lipidome remodeling across all lipoprotein classes. This remodeling resulted in reductions in saturated, monounsaturated, and n-6 polyunsaturated fatty acids, resulting in reduced clinical risk markers, including triglyceride, remnant cholesterol, and apolipoprotein B (apoB) levels and 10-year CVD risk score. Of the proatherogenic properties tested, IPE significantly reduced apoB lipoprotein binding to proteoglycans, which correlated with lower apoB particle concentration, cholesterol content, and specific lipid species in LDL, including phosphatidylcholine 38:3 previously associated with CVD. CONCLUSION. These findings highlight IPE’s rapid, uniform remodeling of lipoproteins and reduced proteoglycan binding, likely contributing to previously observed CVD risk reduction. Persistent interindividual lipidome signatures underscore the potential for personalized therapeutic approaches in atherosclerotic CVD treatment.