Mechanisms Responsible for the Benefit on Cardiovascular Risk in the REDUCE-IT Trial
By Kevin C Maki, PhD
Recently, we learned of the impressive topline results from the Reduction of Cardiovascular Events with Eicosapentaenoic Acid (EPA) – Intervention Trial (REDUCE-IT), which showed that Vascepa® (icosapent ethyl or EPA ethyl esters) lowered major adverse cardiovascular events (MACE) by nearly 25% (p < 0.001) when added to statin therapy in patients with hypertriglyceridemia at high cardiovascular risk.1 This is great news, since residual hypertriglyceridemia is common in statin-treated patients.2 Moreover, other relatively inexpensive evidence-based therapies such as ezetimibe have been shown to have only a modest effect on MACE risk (~10%) when added to statin therapy, consistent with the anticipated effect based on the degree of low-density lipoprotein cholesterol (LDL-C) lowering. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors offer greater LDL-C reduction, but at a much higher cost.
The topline results from REDUCE-IT were a surprise to many who had concluded, based mainly on results from studies of omega-3 fatty acid interventions at low dosages in groups that did not have elevated average levels of triglycerides (TG), that omega-3 fatty acids were ineffective for lowering cardiovascular disease risk.3-7 I am looking forward to seeing the full set of results from REDUCE-IT, which will be presented at the 2018 American Heart Association Scientific Sessions and, hopefully, simultaneously published in a peer-reviewed journal. These should provide more insight into the nature of the event reduction and possible lipid and non-lipid related drivers of the MACE reduction.
We know from the development program for Vascepa that it produces significant reductions in TG and TG-rich lipoprotein cholesterol levels. In the ANCHOR trial, 4 g/d of Vascepa lowered the TG level by 21.5% relative to placebo in hypertriglyceridemic patients (median baseline TG 259 mg/dL) on statin therapy.8 In REDUCE-IT, the median baseline TG concentration was 216 mg/dL. Therefore, if we assume a similar percentage reduction in TG, that would be 0.215 x 216 = 46.4 mg/dL.
There are several mechanisms through which long-chain omega-3 fatty acid interventions, (including EPA) may affect cardiovascular risk, of which TG lowering is only one. Others include reducing myocardial fibrosis, lowering blood pressure and heart rate, reducing platelet activation and anti-inflammatory effects.9,10 Also, the physiologic effects of EPA, docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA; an intermediate in the conversion of EPA to DHA) are not identical, so we cannot assume that the effects will be identical for interventions that vary in the proportions of these fatty acids. However, my view is that a large fraction of the benefit in REDUCE-IT is likely to be attributable to TG lowering based on two lines of evidence.
First, a meta-analysis conducted by my colleagues and I of the effects of TG-lowering drug therapies showed a modest effect overall (12% risk reduction in 10 trials), but larger effects in subgroups with TG ≥150 mg/dL (18% risk reduction), especially if accompanied by low high-density lipoprotein cholesterol (HDL-C; 29% risk reduction).11,12 The subjects in REDUCE-IT all had elevated TG and a large percentage likely also had low HDL-C.
Second, a meta-regression by Jun et al. showed that each 0.1 mmol/L (8.85 mg/dL) reduction in TG with fibrate therapy was associated with a reduction of 5% in MACE risk.13 The approximate reduction in TG relative to placebo of 46.4 mg/dL in REDUCE-IT would therefore be expected to produce 5.24 units (46.4/8.85 = 5.24) of 5% MACE reduction, i.e., 1 - 0.955.24= 0.236 or 23.6% MACE reduction. The biologic plausibility of a benefit being attributable to TG reduction is supported not only by evidence from prior randomized, controlled trials of TG-lowering drug therapies (albeit in subgroups), but also by studies showing that genetic variants associated with reduced TG (and TG-rich lipoprotein cholesterol) are associated with lower cardiovascular risk.
My colleagues and I view the results from REDUCE-IT as a major positive development for patient care. We eagerly anticipate the full REDUCE-IT results, as well as those from additional studies that, we hope, will provide greater insight into the mechanisms responsible for reduced MACE risk in the REDUCE-IT trial.
- Amarin Corporation. REDUCE-IT™ cardiovascular outcomes study of VASCEPA® (icosapent ethyl) capsules met primary endpoint. September 24, 2018. Available at https://investor.amarincorp.com/news-releases/news-release-details/reduce-ittm-cardiovascular-outcomes-study-vascepar-icosapent.
- Fan W, Philip S, Granowitz C, et al. Prevalence and predictors of residual hypertriglyceridemia according to statin use in US adults. J Clin Lipidol. 2018;12:530-531.
- Maki KC, Dicklin MR. Omega-3 fatty acid supplementation and cardiovascular disease risk: glass half full or time to nail the coffin shut? Nutrients. 2018;10:864.
- Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: Meta-analysis of 10 trials involving 77,917 individuals. JAMA Cardiol. 2018;3:224-234.
- Alexander DD, Miller PE, Van Elswyk ME, et al. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017;29:15-29.
- Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177.
- The ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018 [Epub ahead of print].
- Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR 101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110:984-992.
- Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58:2047-2067.
- Mozaffarian D, Prineas RJ, Stein PK, Siscovick DS. Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans. J Am Coll Cardiol. 2006;38:478-484.
- Maki KC, Guyton JR, Orringer CE, et al. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10:905-914.
- Maki KC, Dicklin MR. Do triglyceride-lowering drugs decrease risk of cardiovascular disease? Curr Opin Lipidol. 2017;28:374-379.
- Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875-1884.