Is serum EPA level key to omega-3 benefit in ASCVD?

The contrasting results of the REDUCE-IT¹ and STRENGTH² trials of omega-3 fatty acids in ASCVD continue to be hotly debated, with differences in the type and dose of agents and placebos used in the studies among the suggested reasons.^3,4

Presenting the case for using omega-3 fatty acids for CV prevention, Professor Gabriel Steg (Hôpitaux de Paris, France, and REDUCE-IT investigator), highlighted the robust benefits of icosapent ethyl (IPE) 2 g bd in the REDUCE-IT study, with a 25% reduction in CV events, and the positive correlation between achieved serum levels of eicosapentaenoic acid (EPA) and reduction in CV risk.

“The EPA levels that were achieved on average in both REDUCE-IT and STRENGTH may be substantially lower than what is needed and, when looking at the curves, my feeling is that we really need to achieve a daily serum EPA level of 150-200 μg/mL to see a benefit. If we only achieve less than 100 μg/mL, as was seen in STRENGTH, that may be the reason we don’t see a benefit,” he said.

Presenting the case against using omega-3 fatty acids for CV prevention, Dr Stephen Nicholls (Monash Victorian Heart Institute, Victoria, Australia, and STRENGTH investigator) pointed out that, even in patients in the top tertile of achieved EPA (>88.6 μg/mL), in the STRENGTH trial, no reduction in CV events was seen. He agreed with other speakers that differences in physiological effects between EPA and docosahexaenoic acid (DHA), a combination of which was used in STRENGTH, may be important as EPA may offer more vascular protection than DHA.  

Antioxidant effects of EPA

New data presented at the congress suggested that the antioxidant effects of EPA and its effects on macrophage activity may contribute to the CV benefits seen in REDUCE-IT.^3,4 In one study, EPA significantly reduced lipid oxidation in model membranes in a concentration-dependent way.^5,6

Multilamellar vesicles (MLVs) were reconstituted from binary mixtures of 1,2-Dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) and cholesterol and a 0.5 C/P mole ratio; MLVs were subject to time-dependent autoxidation in air at 37°C.  Lipid hydroperoxide formation was then continuously monitored as a function of added inhibitors, including EPA and/or atorvastatin active metabolites (ATM) or rosuvastatin.

At 10 µM, the combination of EPA/ATM and EPA/rosuvastatin reduced lipid oxidation by 86% and 75%, respectively (p<0.001). The antioxidant activity of the EPA/ATM combination was more potent than that of EPA/rosuvastatin by 59% (p<0.01) due, in part, to the more potent activity of ATM separately, which reduced lipid hydroperoxide levels by 72% compared to rosuvastatin alone (p<0.001). Comparative investigations examining the anti-oxidant activity of DHA were not reported.

EPA effects on murine macrophage activity

In a second study, EPA reduced lipopolysaccharide (LPS)-induced murine macrophage activation, cyclooxygenase-1 (COX-1) levels and nitric oxide synthase (iNOS) activity in a concentration-dependent manner distinct from that of colchicine.⁶ EPA (10, 20, 40 µM) reduced LPS-induced nitrite production in activated murine macrophages by 77% (p<0.001) compared to LPS-alone. The reduction in nitrite production with EPA at its lowest concentration was similar to diclofenac, while colchicine (0.5, 1.0, 5.0, 10.0 µM) reduced nitrite production only at its highest concentration (35%, p<0.05). Both EPA and colchicine reduced IL-1β release (40% and 30%, respectively, p<0.001) and TNF release (31% and 29%, respectively p<0.001). After 24 hours, EPA also reduced COX-1 levels by 52% (p<0.01) but COX-1 was not detected in colchicine samples. The researchers concluded that the beneficial effects of EPA on macrophage activation may contribute to the reduced CV risk of EPA treatment demonstrated in some cardiovascular outcome trials. No studies with DHA were reported.

References

1. Bhatt DL, Steg PG, Miller M et al; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22
2. Nicholls SJ, Lincoff AM, Garcia M et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. 2020 Dec 8;324(22):2268-2280.
3. Doi T, Anne Langsted A, Nordestgaard BG. A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs. Eur Heart J. 2021 Dec 14;42(47):4807-4817
4. Steg PG, Blatt DL. The reduction in cardiovascular risk in REDUCE-IT is due to eicosapentaenoic acid in icosapent ethyl. Eur Heart J 2021 Dec 14;42(47):4865-4866.  
5. Sherratt S, Libby P, Bhatt DL, Mason RP, Eicosapentaenoic Acid (Epa) Combined With High Intensity Statins Reduce Lipid Oxidation In Model Membranes. Presented at ACC.22, April 2-4 2022, Washington DC, USA. Session 1276, Poster 082
6. Sherratt S, Libby P, Bhatt DL et al. Eicosapentaenoic Acid (Epa) Reduces J774 Macrophage Activation And Cyclooxygenase (Cox-1) Expression. Presented at ACC.22, April 2-4 2022, Washington DC, USA. Session 1108, Poster 03