(VP027) COMPARING THE EFFECTS OF OMEGA-3 FATTY ACIDS AND DIFFERENT PLACEBO OILS ON RATES OF APO-B CONTAINING LIPOPROTEIN OXIDATION IN VITRO

Background: Oxidized lipoproteins lead to vascular inflammation and lipid deposition during the progression of atherosclerosis. The omega-3 fatty acid (n3-FA) EPA administered as icosapent ethyl (IPE) reduced cardiovascular (CV) events (REDUCE-IT) compared to mixed n3-FA formulations (STRENGTH). These discordant outcomes have raised questions about placebo choice (pharmaceutical grade mineral versus corn oil). We compared the effects of n3-FAs and placebo oils on rates of oxidation in different sized human ApoB particles where these fatty acids are transported.

METHODS AND RESULTS: ApoB particles VLDL and sdLDL were isolated from human plasma by isopycnic centrifugation, separated into test samples of 100 µg/mL and incubated at 37°C for 30 min with pharmaceutical grade mineral oil (MO), corn oil (CO), docosahexaenoic acid (DHA) or EPA at concentrations (10 µM) comparable to treatment levels (4 g/d). All samples then underwent copper-induced oxidation (20 µM) monitored by formation of malondialdehyde (MDA). After 4 hours, sdLDL and VLDL oxidation increased 15-fold and 57-fold compared to vehicle, respectively, and unaffected by treatment with either MO or CO. By contrast, EPA significantly inhibited sdLDL and VLDL oxidation by 75% and 94%, respectively (p < 0.001). DHA exhibited antioxidant activity only at 2 hours and at a level less than EPA; the antioxidant effect of DHA was eliminated by 4 hours. No effects on oxidation rates with either MO or CO were observed even at a supra-pharmacologic concentration.

Conclusion: EPA had potent antioxidant effects in ApoB particles over time compared to DHA and different placebo oils. The potent LDL antioxidant benefits of EPA may explain, in part, reduced vascular ischemic events in clinical outcome trials using IPE compared to DHA containing formulations, independent of placebo oil choice.