Median baseline LDL-C levels were 74 mg/dL and 76 mg/dL, respectively. Increased EPA lipid composition from carotid plaque specimens and increased circulating EPA/arachidonic acid ratio have been observed following EPA treatment. Most trials involving n-3 FA mixtures utilized daily doses close to 1g. At 12 weeks, treatment with icosapent ethyl reduced TG levels in a dose-dependent manner, respectively. The icosapent ethyl group had a 19.7% (−44.5 mg/dL) greater reduction in TG level at 1 year compared to placebo. Greater rate of statin use in later trials, therefore, may have tempered the detectable effect of the lower doses of n-3 PUFA in more recent trials involving mixture formulation.Since the publication of REDUCE-IT, several clinical practice guidelines, including those of the American Diabetes Association (ADA), National Lipid Association (NLA) and the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS), have endorsed the use of icosapent ethyl in their recommendations to further reduce ASCVD risk in select patients. Individuals in the icosapent ethyl 4g/day and 2g/day groups had at 21.5% (p<0.0001) and 10.1% (p=0.0005) decrease in TG levels from baseline compared to placebo. First, EPA trials have employed higher doses therapy. Second, particularly in REDUCE-IT, selection of patients with elevated TGs resulted in a study population with likely substantial residual risk beyond elevated LDL-C and thus are less likely to be attenuated by statins alone. The median baseline TG levels were 216.5 mg/dL and 216.0 mg/dL in the icosapent ethyl and placebo groups, respectively. EPA inhibits platelet aggregation under some ex vivo conditions. Furthermore, while there was a significant reduction in the primary composite outcome, subgroup analyses from JELIS, there was not a significant reduction observed in individual endpoints except reduction in unstable angina.Moreover, in the ANCHOR trial, 702 patients with TG level ≥200 and <500 mg/dL who were on stable statin regimens (with or without ezetimibe) with LDL-C ≥ 40 and < 100 mg/dL were randomized to receive either icosapent ethyl 4g/day, 2g/day or placebo. “The additional data presented showing very early timing of benefit and consistent statistically significant substantial benefit as early as 11 months, coupled with the interim EVAPORATE analysis showing early changes in most plaque measurements at 9 months, allow for advancing insight into the connectivity between the mechanism of action and clinical outcomes of icosapent ethyl,” said REDUCE-IT and … What set the REDUCE-IT trial apart was likely the utilization of a higher dose of purified EPA formulation in combination with strategic patient selection that reflects mounting evidence supporting elevated triglycerides (TGs) as an important marker of increased residual ASCVD risk.Individuals included in REDUCE-IT had either established ASCVD or diabetes mellitus with additional ASCVD risk factors, had elevated fasting TG levels but relatively well-controlled LDL-C levels on maximally tolerated statin therapy (~93% of the patients were on either moderate or high-intensity statin therapy). For instance, while the GISSI-P trial showed positive results, the study population was mostly not on statin at baseline. Despite Win, Issues Raised by EMDAC Members The advisory committee grappled with numerous issues throughout the daylong meeting, including whether to only approve icosapent ethyl … EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles. The median follow-up period was 4.9 years.REDUCE-IT results also demonstrated that icosapent ethyl exerted a significant long-term effect on lipids and inflammatory markers. Mechanism of Action. At last visit, the icosapent ethyl group had a reduction in TG level of 21.6% (−45.0 mg/dL) from baseline compared with a reduction of 6.5% (−13.0 mg/dL) for placebo. However, … Treatment with EPA resulted in a modest but significant reduction in TG levels (9% from baseline in the EPA group vs 4% in controls, p<0.0001) with no differences in the reduction of LDL-C. The modestly higher rate of bleeding events with icosapent ethyl suggests that there may be an antithrombotic mechanism of action. There are several potential reasons why EPA trials have more consistently shown cardioprotective effects on outcomes compared with trials using EPA plus DHA beyond differences in biochemical properties of the two types of n-3 PUFAs. Meanwhile, there was a reduction by 12.6% in hs-CRP with icosapent ethyl compared with an increase in 29.9% (0.4 mg/L) with placebo.The efficacy of icosapent ethyl in the reduction of ASCVD risk is built upon a confluence of evidence, culminating in the REDUCE-IT trial.
However, there are also likely important pleiotropic effects such as anti-inflammatory properties may play a role. This differs from other trials, involving both primary and secondary prevention populations, which included participants with relatively normal TGs.