Targeting hypertriglyceridemia to mitigate cardiovascular risk: A review

Abstract

A causal relationship between elevated triglycerides and cardiovascular disease is controversial, as trials of triglyceride-lowering treatments have not shown significant impact on cardiovascular outcomes. However, hypertriglyceridemia is associated with atherogenesis and risk for acute cardiovascular events that persist despite optimal statin treatment. Although most trials of triglyceride-lowering treatments have been negative, in trials of niacin and fibrates, subgroup analyses in patients with higher baseline triglycerides and lower HDL-C levels suggest reduced incidence of cardiovascular endpoints. The REDUCE-IT trial demonstrated that addition of purified prescription eicosapentaenoic acid (icosapent ethyl) 4 ​g/day in high-risk patients with triglyceride levels 135-499 ​mg/dL and optimized statin treatment significantly reduced cardiovascular events versus placebo (hazard ratio 0.75; 95% confidence interval 0.68-0.83; P ​< ​0.001). Benefit was seen regardless of baseline and on-treatment triglyceride levels, suggesting that other effects of eicosapentaenoic acid besides triglyceride reduction may have played a role.

Keywords: Eicosapentaenoic acid; Icosapent ethyl; REDUCE-IT; Triglycerides.

Fig. 1

Hazard Ratios of Clinical Endpoints for the Japan EPA Lipid Intervention Study (JELIS). Superscript 1 and 2 indicate primary and secondary prevention endpoints, respectively [60]. ∗P ​< ​0.05. Reprinted from The Lancet, 369, Yokoyama M, Origasa H, Matsuzaki M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis, 1090–1098. Copyright 2007, with permission from Elsevier.

Fig. 2

Absolute Risk Reduction (ARR) in REDUCE-IT Endpoints. Percentages were calculated by taking absolute differences in endpoint rates between icosapent ethyl and control groups [ARR = (n/N)placebo – (n/N)icosapent ethyl]. Primary composite endpoint events: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. Key secondary composite endpoint events: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke [14]. ∗P ​< 0.05; ∗∗P ​≤ ​0.01; ∗∗∗P ​< 0.001 [14].

Fig. 3

Cellular and Molecular Mechanisms of Atherosclerosis and Role of EPA. Mechanisms are depicted in the illustration; effects of EPA are listed to the right indicating increases (↑) or decreases (↓). LDL is subject to oxidative modification, progressing from mm-LDL to ox-LDL. Monocytes attach to endothelial cells, migrate into the subendothelial space, and differentiate into macrophages. Ox-LDL cholesterol uptake leads to foam cell formation. Interactions between macrophage foam cells, Th1 cells, and Th2 cells establish a chronic inflammatory process. Cytokines secreted by lymphocytes and macrophages exert both pro- and anti-atherogenic effects on each of the cellular elements of the vessel wall. SMCs migrate from the medial portion of the arterial wall, proliferate, and secrete extracellular matrix proteins that form a fibrous plaque [75,76]. ACAT, acyl CoA:cholesterol acyltransferase; Apo E, apolipoprotein E; CCR, C–C chemokine receptor; CD, clusters of differentiation; CS, connecting segment; EPA, eicosapentaenoic acid; EPA/AA, eicosapentaenoic acid/arachidonic acid ratio; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; LDL, low-density lipoprotein; LO, lipoxygenase; Lp-PLA₂, lipoprotein-associated phospholipase A₂; MCP, monocyte chemotactic protein; mm-LDL, minimally modified LDL; MMP, matrix metalloproteinase; ox-LDL, oxidized LDL; RLP-C, remnant-like lipoparticle cholesterol; SMC, smooth muscle cell; Th, T helper; VCAM, vascular cell adhesion molecule. Adapted with permission from Atherosclerosis, 242(1), Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis, 357–366, copyright 2015, with permission from Elsevier [75].

Fig. 4

Biosynthetic Cascades and Actions of Selected Lipid Mediators Derived From Arachidonic Acid (AA), Eicosapentaenoic Acid (EPA), and Docosahexaenoic Acid (DHA). COX, cyclooxygenase; HDHA, hydroxy-docosahexaenoic acid; HETE, hydroxyeicosatetraenoic acid; LO, lipoxygenase; LT, leukotriene; LX, lipoxin; MaR, maresin; PD, protectin; PG, prostaglandin; Reproduced with permission from Serhan CN, Petasis NA. Resolvins and protectins in inflammation resolution. Chem Rev. 2011; 111(10):5922–5943, copyright 2011 American Chemical Society [78].