Remodelling of plasma lipoproteins by icosapent ethyl -supplementation and its impact on cardiovascular disease risk markers in normolipidemic individuals

BACKGROUND AND AIMS Icosapent ethyl (IPE), an ethyl ester of eicosapentaenoic acid (EPA), can reduce cardiovascular disease (CVD). We examined the effect of IPE-supplementation on lipoprotein subclasses, lipidomes and atherogenic properties. METHODS Normolipidemic volunteers received daily 3.9g of IPE for 28 days. Using three independent metabolomic platforms, the fatty acid and lipoprotein profiles in plasma, and lipidomes of isolated VLDL, LDL and HDL, were determined. Aggregation propensity of LDL and the proteoglycan-binding of apoB-containing plasma lipoproteins, and the cholesterol efflux– inducing capacity of HDL were determined. RESULTS IPE-supplementation increased plasma EPA concentrations by 4-fold with consequent reductions in saturated, monounsaturated, and n-6 polyunsaturated fatty acids. This resulted in reduction of multiple clinical risk markers, including triglyceride-, remnant cholesterol-, and apoB-levels, and 10-year CVD risk score. IPE induced uniform alterations across all lipoprotein classes. However, intrinsic interindividual differences in lipoprotein lipidomes outweighed IPE-induced changes. IPE did not alter LDL aggregation propensity or HDL-mediated cholesterol efflux but reduced the affinity of apoB-lipoproteins for proteoglycans. This correlated with decreased apoB-particle concentration and cholesterol content, alongside changes in specific lipid species in LDL, notably phosphatidylcholine 38:3 previously associated with CVD. CONCLUSIONS IPE-supplementation rapidly increases circulating EPA, which integrates equally into all lipoprotein classes. Reduced proteoglycan binding of apoB-lipoproteins likely contributes to the known IPE-induced reduction in CVD risk. Features associated with increased lipoprotein proteoglycan-binding included characteristics of metabolic syndrome, and specific lipid species. The data underscore persistence of distinct interindividual lipoprotein signatures despite extensive IPE-induced remodelling, highlighting the need for personalised approaches in ASCVD-treatment. STRUCTURED GRAPHICAL ABSTRACT Graphical Abstract: The figure summarizes the study design and the main findings of this study. CVD, cardiovascular disease; EPA, eicosapentaenoic acid; FA fatty acid; IPE, icosapent ethyl; LDL, low-density lipoprotein; NMR, nuclear magnetic resonance (spectroscopy). Figure created with BioRender.com .