New Omega-3 Fish Oils: Icosapent Ethyl (Vascepa^®), Omega-3 Carboxylic Acids (Epanova^®)

The marine omega-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to reduce hepatic VLDL production and secretion and increase TRLs clearance, with good safety profiles.^[97] Beyond TG lowering, omega-3 fatty acids (OM3FAs) possess pleiotropic effects, including lowering blood pressure, decreases in platelet aggregation, suppression of inflammation, and improvement of endothelial function.^[98] Lipid guidelines and scientific statements have recommended OM3FAs in hypertriglyceridemic patients for the prevention of ASCVD,^[94,99,100] whereas recent evidence has raised questions about their beneficial effect on ASCVD, from earlier studies showing risk reductions and later studies showing no CV benefits.^[101–104] However, the 2017 American Heart Association scientific advisory still recommends omega-3 supplementation for patients with prevalent coronary heart disease (CHD) on the basis of a ≈ 10% reduction in CHD mortality.^[105] It noted a concern about insufficient dosage (≈ 1 g/day) in previously published RCTs of omega-3 supplementation. Indeed, the most recently reported negative CVOT of OMFAs, the ASCEND (A Study of Cardiovascular Events in Diabetes) study, was also conducted using a low dosage (< 1 g/day), in diabetic patients without established CV disease.^[106] Given these issues, phase 3 RCTs of icosapent ethyl and Epanova were designed with higher dosages of omega-3 supplementation (2 or 4 g/day): REDUCE-IT (Reduction of Cardiovascular Events with EPA–Intervention Trial) trial with Vascepa^{® [107]} and the STRENGTH (Statin Residual Risk Reduction with Epanova in High CV Risk Patients with Hypertriglyceridemia) trial with Epanova^®.^[108] In particular, these trials were designed to enroll specifically TG-targeted subjects with LDL-C < 100 mg/dl and 150/180 ≤ TG < 500 mg/dl receiving statins, to assess whether TG-lowering reduces CV outcomes (Table 2). Both Vascepa^® (icosapent ethyl) and Epanova^® (omega-3 carboxylic acids) are the FDA-approved omega-3 in free fatty acid form for severe hypertriglyceridemia (≥ 500 mg/dl). Vascepa^® contains only the purified EPA ethyl ester, while Epanova^® contains 50–60% EPA and 15–25% DHA along with other potentially active OM3FAs.^[109] Recently, the results of the REDUCE-IT trial have been reported, in which LDL-C levels were well controlled (median baseline LDL-C 75 mg/dl).^[110] After a median follow-up of 4.9 years, icosapent ethyl treatment (4 g/day) demonstrated an approximately 25% relative risk reduction for CV events, with an acceptable safety profile in the population described above. This result could reconfirm the concern about the insufficient dosage of OM3FAs. In addition, the consistently observed benefits in patients with attained TG levels of < 150 or ≥ 150 mg/dl suggested an involvement of some biological effects of icosapent ethyl other than lowering TG levels. The inconsistent association between the observed reductions of median TG levels (45 mg/dl in the icosapent arm) and those of relative CV risk (25%) in the trial could support involvement of other factors, given recent findings by Mendelian randomization studies: a 200 mg/dl or greater TG reduction is required to generate comparable benefits on CV outcomes to those of a 38.7 mg/dl LDL-C reduction.^[111] The baseline TG levels in the REDUCE-IT trial (median 216 mg/dl) should be noted given the current indication of icosapent ethyl: severe hypertriglyceridemia (≥ 500 mg/dl). The results of the REDUCE-IT trial may have the potential to expand the indication. In addition, the incremental benefits on top of statins in the REDUCE-IT trial strongly highlight the importance of OM3FAs, given the magnitude of CV risk reductions. This could change clinical practice in this field. Meanwhile, the results of the STRENGTH trial are keenly awaited.