The following are key points to remember about this statement from the National Lipid Association on use of icosapent ethyl (IPE):

1. The National Lipid Association now makes a Class I recommendation for use of IPE (4 g/d) to reduce cardiovascular risk in patients
   • ≥45 years of age with clinical atherosclerotic cardiovascular disease (ASCVD) or
   • ≥50 years of age with diabetes mellitus requiring medication and ≥1 additional risk factor;
   • already on high-intensity or maximally tolerated statin therapy;
   • with fasting triglycerides 135-499 mg/dL; and
   • with or without ezetimibe.
2. Additional risk factors are defined as
   • men ≥55 years of age or women ≥65 years of age;
   • cigarette smoker or stopped within 3 months;
   • treated or untreated hypertension;
   • high-density lipoprotein cholesterol (HDL-C) ≤40 mg/dl in men or ≤50 mg/dl in women;
   • high-sensitivity C-reactive protein (hs-CRP) >3.0 mg/dL;
   • creatinine clearance <60 mL/min and >30 mL/min;
   • retinopathy;
   • microalbuminuria or macroalbuminuria; and
   • ankle-brachial index <0.9 without symptoms of intermittent claudication.
3. IPE now joins ezetimibe and PCSK9 inhibitors for use as an adjunct to statins for ASCVD risk reduction.
4. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) Trial served as the main basis for review of IPE for ASCVD risk reduction by the National Lipid Association. REDUCE-IT results were published in the New England Journal of Medicine on January 3, 2019.
5. REDUCE-IT was a randomized, double-blind, placebo-controlled trial of high-dose IPE in 8,179 select patients. Primary composite endpoint occurred in 17.2% of IPE-treated patients versus 22.0% of placebo-treated controls (hazard ratio 0.75; p < 0.001).
6. The 39.9% median reduction in hs-CRP in REDUCE-IT suggests that an anti-inflammatory effect, in addition to changes in plasma lipids, may be a mechanism of benefit in cardiovascular risk reduction. Other potential mechanisms are also explored.
7. The statement describes additional evidence supporting the new recommendation: observational studies, results from prior randomized controlled trials, JELIS (Japan EPA Lipid Intervention Study), epidemiologic and Mendelian randomization studies, and prior meta-analyses.
8. The paper also discusses the central role of low-density lipoprotein cholesterol and non-HDL-C as a root cause of atherosclerosis and the identification of hypertriglyceridemia as a marker of increased residual ASCVD risk in statin-treated patients.
9. The statement reviews endorsements regarding treatment with IPE from other professional organizations, including the American Diabetes Association, European Society of Cardiology, and European Atherosclerosis Society.
10. Several ongoing trials (STRENGTH [Outcomes Study to Assess Statin Residual Risk Reduction With Epanova in High CV Risk Patients With Hypertriglyceridemia], EVAPORATE [Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy], OMEMI [Omega-3 Fatty Acids in Elderly Patients With Acute Myocardial Infarction], and PROMINENT [Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes]) may shed light on mechanisms of benefit from IPE and other therapies.

Keywords: Hypertriglyceridemia, Lipids, Cholesterol, HDL, Cholesterol, LDL, Eicosapentaenoic Acid, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Primary Prevention, Triglycerides, Diabetes Mellitus

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