Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite significant advances in management . Elevated low-density lipoprotein cholesterol (LDL-C) levels are a well established risk factor for ASCVD, and randomized trials of primary and secondary prevention cohorts have consistently proved that reduction of LDL-C levels decreases the incidence of cardiac events . However, even among patients with optimal LDL-C levels, residual risk persists, requiring research into the role of other dyslipidemias in contributing to the progression of ASCVD [3,4]. Mounting epidemiological and clinical evidence has implicated triglyceride elevation as an independent risk factor for increased cardiovascular events, suggesting that hypertriglyceridemia represents one component of residual ASCVD risk . The U.S. National Health and Nutrition Examination Survey estimates that from 2011 to 2014, approximately 25% of adults had high triglyceride levels (>150 mg/dl). The prevalence of hypertriglyceridemia is expected to continue to increase, tracking with the triple epidemic of obesity, metabolic syndrome, and diabetes .
Multiple meta-analyses suggest that incremental elevations in triglycerides increase the risk of future ASCVD [7–10]. Mendelian randomization studies, which may minimize concerns about confounding and reverse causation, support a causal relationship between hypertriglyceridemia and ASCVD events [11,12]. A recent study utilizing genetic risk scores in the lipoprotein lipase (LPL) and low-density lipoprotein receptor (LDLR) genes found that triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants conferred independent cardiovascular risk reduction. Moreover, the degree of risk reduction for both types of variants was proportional to the absolute change in the apolipoprotein-B (apoB), a large protein that provides the macromolecular scaffold for atherogenic lipoproteins that carry both triglycerides and LDL-C [13▪▪]. These new data reaffirm our biological understanding that apoB-containing lipoproteins less than 70 nm in diameter freely flux across the arterial wall, where the cholesterol and triglyceride content of these lipoproteins can trigger oxidation, inflammation, and subsequent atherosclerotic plaque formation . Cumulatively, these findings suggest that treatment of hypertriglyceridemia may be an important therapeutic pathway for reduction of residual risk [15▪▪].
CURRENT THERAPEUTIC OPTIONS
Beyond a healthy diet and weight loss, the mainstay of treatment for hypertriglyceridemia has historically included fibrates, niacin, and omega-3 fatty acids (OM3FA). Although effective at reducing triglyceride levels, these interventions have not consistently shown benefit, and the data supporting such therapies for ASCVD risk reduction have been mixed, especially in the statin era (Fig. 1).
Fibrates primarily reduce triglyceride levels, modestly increase HDL-C levels, and have historically been the first medication class used to treat isolated hypertriglyceridemia. Fibrates showed most promise in the VA-HIT trial (Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial), a randomized, placebo-controlled study of gemfibrozil 1200 mg/day versus placebo intended to evaluate whether triglyceride-lowering and HDL-increasing therapy in a statin-naïve secondary prevention cohort would decrease the incidence of further atherosclerotic events. In 2531 men followed for a median of 5.1 years, gemfibrozil treatment led to a relative risk reduction in the primary endpoint of death or nonfatal myocardial infarction (MI) by 22% (95% confidence interval (CI) 7–35%; P = 0.006), as well as the combined secondary endpoint of cardiovascular death, nonfatal MI, or stroke by 24% (95% CI 11–36%; P < 0.001) . Subsequently, in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study, fenofibrate 200 mg/day versus placebo in 9795 patients with type 2 diabetes mellitus (T2DM) and no prior statin use resulted in no significant reduction in the primary outcome of total coronary events (hazard ratio 0.89, 95% CI 0.75–1.05; P = 0.16), though a post-hoc analysis of data did suggest that patients with both elevated triglyceride levels and low HDL-C levels were at the highest baseline risk and received the greatest potential clinical benefit from the treatment [17,18]. Finally, in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid trial, the addition of 160 mg/day fenofibrate to simvastatin 40 mg/day in 5518 individuals with T2DM provided no benefit towards the primary outcome of major fatal or nonfatal cardiovascular events (hazard ratio 0.92, 95% CI 0.79–1.08; P = 0.32). A prespecified subgroup of patients with baseline triglycerides in the highest tertile and HDL-C in the lowest tertile demonstrated a trend towards a 31% reduction in the primary outcome (P = 0.032) .
Niacin has been used for decades to treat dyslipidemia because of its ability to decrease atherogenic apo-B-containing lipoproteins and increase HDL-C levels in circulating blood. AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High triglyceride: Impact on Global Health Outcomes) was a trial of 3414 patients with established cardiovascular disease, low HDL-C, and elevated triglycerides randomized to extended-release niacin 1500–2000 mg/day versus placebo. All participants in both arms also received simvastatin 40–80 mg/day. The trial was stopped early after 36 months because of a lack of efficacy for the primary composite cardiovascular endpoint (hazard ratio 1.02, 95% CI 0.87–1.21; P = 0.79) . In the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) trial, 25 673 individuals with ASCVD on background statin therapy were randomized to niacin 2 g/day with laropiprant 40 mg/day (a prostaglandin inhibitor that reduces niacin-related flushing) versus placebo. At a median follow-up of 3.9 years, the treatment group had no significant reduction in the primary endpoint of major vascular events (hazard ratio 0.96, 95% CI 0.90–1.03; P = 0.29) but had significant increases in serious adverse events related to the treatment . There was also no benefit for the primary endpoint seen in the subgroup of patients who had the combination of high triglyceride levels and low HDL-C levels.
In addition to fibrates and niacin, OM3FA have been demonstrated to produce significant reductions in triglyceride levels when added to high-intensity statin therapy. However, when evaluated in primary and secondary prevention trials, the results of OM3FA in reducing ASCVD events have been inconsistent [22–24]. GISSI-P (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Prevenzione), an open-label, randomized trial investigating the effect of 1 g/day OM3FA [mixed eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] in patients with recent MI, found that low-dose OM3FA significantly reduced the incidence of the primary combined efficacy endpoint of death, nonfatal MI, and stroke by 10% (hazard ratio 0.90, 95% CI 0.82–0.99; P = 0.048) . However, only 5% of patients were statin-treated at baseline, as data on the efficacy of statins in this population was still in question at the initiation of this study. JELIS (Japan EPA Lipid Intervention Study) randomized 18 645 patients to treatment with a combination of low-dose statin and 1.8 g/day EPA ethyl ester, a highly purified OM3FA, or statin alone (placebo group). The EPA treatment group experienced a 19% reduction in ASCVD events (hazard ratio 0.81, 95% CI 0.69–0.95; P = 0.011) , with consistent benefits present across both primary prevention and secondary prevention cohorts. The subgroup of JELIS patients with higher baseline triglyceride levels (≥150 mg/dl) and lower HDL-C levels (<40 mg/dl) derived further benefit with a 53% reduction in ASCVD events (hazard ratio 0.47, 95% CI 0.23–0.98; P = 0.043) . Recently, contemporary placebo-controlled trials of low-dose, mixed OM3FA, such as ASCEND (A Study of Cardiovascular Events in Diabetes)  and VITAL (VITamin D and OmegA-3 TriaL) , have been unable to replicate the same degree of protection in their primary composite cardiac endpoints. In fact, a prior meta-analysis of GISSI-P, JELIS, and eight other trials (n = 77 917) failed to show any significant reduction in fatal or nonfatal coronary heart disease or any major vascular events [30▪]. However, the trials included in this analysis used heterogeneous sources of OM3FA, such as mixed DHA and EPA preparations, making interpretation of the results challenging. Many of these studies also utilized low-dose OM3FA (≤1 g) preparations, which are inadequate for substantial sustained triglyceride lowering.
REDUCTION OF CARDIOVASCULAR EVENTS WITH ICOSAPENT ETHYL-INTERVENTION TRIAL
REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial) was a randomized, placebo-controlled trial evaluating whether 4 g/day of icosapent ethyl (a highly purified ethyl ester of EPA) would lower the incidence of cardiovascular events when compared with placebo in 8179 patients at risk for ASCVD. To address specifically the question of whether icosapent ethyl offered any additional benefit beyond statin therapy, patient enrollment included those already on statin therapy with optimal LDL-C levels (41--100 mg/dl) and persistently elevated fasting triglycerides (135--499 mg/dl) . Participants were followed for a median of 4.9 years for the primary composite endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. In a time-to-first event analysis, treatment with icosapent ethyl demonstrated a 25% relative risk reduction in the primary endpoint (hazard ratio 0.75, 95% CI 0.68–0.83; P = 0.00000001) [32▪]. The magnitude of ASCVD risk reduction was consistent across a host of secondary endpoints, including the key secondary endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke (hazard ratio 0.74, 95% CI 0.65–0.83; P = 0.0000006). When incorporating the totality of second, third, and subsequent ischemic events among trial participants, icosapent ethyl was further shown to provide a 30% reduction in event burden over this study period (hazard ratio 0.70, 95% CI 0.62–0.78, P = 0.00000000036) [33▪,34]. Icosapent ethyl treatment resulted in a higher incidence of atrial fibrillation or flutter (3.1 versus 2.1%, P = 0.004), though overall, the treatment arm demonstrated a significant 28% reduction in stroke [35▪]. There was also a trend towards more serious bleeding events in the icosapent ethyl group (2.7 versus 2.1%, P = 0.06), though no significant differences in fatal or intracranial bleeding.
Despite elevated triglycerides serving as a key marker of residual risk and allowing for recruitment into the study, the benefit observed with icosapent ethyl was similar across baseline fasting triglyceride levels (≥150 versus <150 mg/dl or ≥200 versus <200 mg/dl). Additionally, on-treatment triglyceride levels at 1 year after randomization did not predict benefit, as patients with triglycerides less than 150 mg/dl and triglycerides at least 150 mg/dl were found to have near-equal reductions in the primary and key secondary endpoints. Furthermore, though the trial was not designed or powered to examine subgroups, patients in all three tertiles of baseline triglycerides demonstrated significant benefit from icosapent ethyl . Lastly, the difference in triglycerides between the two treatment groups would be expected to explain less than a 10% relative risk reduction instead of the witnessed 25% relative risk reduction for the primary composite endpoint . Taken together, these data suggest that at least some of the effect of icosapent ethyl that resulted in a lower risk of ischemic events may be explained by mechanisms other than a reduction of triglycerides.
POTENTIAL MECHANISMS OF ACTION
The mechanisms governing the benefit of icosapent ethyl observed in REDUCE-IT are an area of active investigation. It is likely that icosapent ethyl exerts several pleiotropic effects that together reduce ischemic endpoints. In addition to lowering triglycerides, icosapent ethyl is known to lower apoB levels, a marker for circulating atherogenic lipoproteins. Treatment with icosapent ethyl also decreases the levels of lipoprotein-associated phospholipase A2, a key facilitator of LDL-C oxidation and the progression of atherosclerosis. Furthermore, higher bleeding rates in patients randomized to icosapent ethyl over placebo are indicative of a possible underlying antithrombotic effect. With regards to inflammation, levels of high-sensitivity C-reactive protein fall by approximately 20% after 12 weeks of treatment [38–40] and several studies now provide evidence that EPA stabilizes coronary plaque whenever assessed by both intravascular ultrasound and optical frequency domain imaging [41–44]. One randomized trial assessing the effect of 1.8 g/day EPA in a cohort of patients with reperfused acute MI noted a significant decrease in the incidence of ventricular arrhythmias within the first month, indicating a possible antiarrhythmic effect . Icosapent ethyl may also produce a modest blood pressure reduction as well .
CLINICAL APPLICATION AND ONGOING TRIALS
Residual risk as reflected by hypertriglyceridemia despite optimal LDL-C levels remains an important consideration for reduction of future ischemic events. The recent findings from REDUCE-IT offer promise for further preventive care in this subset of high-risk patients [47▪]. Other trials of EPA are ongoing that may reinforce the relative risk reduction provided by tested formulations and doses of EPA in the studied patient populations. RESPECT-EPA (Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy -- Statin and Eicosapentaenoic Acid) is currently following approximately 3900 patients with established ASCVD, on a statin, randomized to 1.8 g/day EPA versus no EPA for the primary endpoint of major adverse cardiac events . Additionally, the EVAPORATE (Effect of Vascepa on Progression of Coronary Atherosclerosis in Persons With Elevated Triglycerides (200–499) on Statin Therapy) trial has randomized approximately 80 patients with elevated triglycerides, LDL-C ≤115 mg/dl on appropriate statin therapy, and at least one angiographic stenosis, to icosapent ethyl 4 g/day versus placebo. In EVAPORATE, patients will be followed for 18 months for the progression of low-attenuation plaque volume as measured by multidetector computed tomography angiography, with a planned interim analysis at 9 months . This latter trial will provide important imaging-derived data that should lend mechanistic insights and build upon prior open-label Japanese studies such as the CHERRY (Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography) trial that have already shown benefits of EPA on plaque progression .
Currently, icosapent ethyl is approved by the U.S. Food and Drug Administration to treat adult patients with triglycerides of 500 mg/dl or greater, with the goal of preventing acute pancreatitis. The results of REDUCE-IT support the use of 2 g twice daily of icosapent ethyl as an adjunctive treatment to patients already on a statin with persistently elevated triglycerides and residual risk for ASCVD, though the benefits are likely because of additional mechanisms beyond just triglyceride lowering. Physicians should be aware of the recently updated American Diabetes Association guidelines, which support the use of icosapent ethyl in both primary and secondary prevention of ASCVD, with a level ‘A’ grade of scientific evidence . Furthermore, it should be noted that these same guidelines explicitly state that other formulations of OM3FA lack similarly compelling evidence for cardiovascular risk reduction and should not be used. DHA, the other primary OM3FA, has alternate tissue distributions as well as distinct effects on membrane structure, lipid dynamics, rates of lipid oxidation, and signal transduction pathways [51▪▪]. As prior negative OM3FA studies utilized lower doses of OM3FA, varying ratios of EPA and DHA, and even unregulated dietary fish oil supplements, the results of REDUCE-IT should not be extrapolated to other OM3FA products.
The STRENGTH (A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs With Hypertriglyceridemia) trial, a randomized controlled trial of 13 086 primary and secondary prevention patients on a statin with LDL-C less than 100 mg/dl, elevated triglycerides (180–499 mg/dl), and low HDL-C comparing 4 g/day OM3FA (combined DHA+EPA) with placebo is ongoing . To reassess the role of fibrates in the subset of patients with high triglycerides, the PROMINENT trial (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes) will study 10 000 patients internationally with T2DM, effective LDL-C lowering therapy, triglycerides 200–499 mg/dl, and low HDL randomized to 0.2 mg pemafibrate twice daily versus placebo . Both trials will assess a composite cardiovascular endpoint and are expected to complete in 2020 and 2022, respectively. Whether these studies can reproduce the cardioprotective effects of icosapent ethyl remains to be seen.
Despite current efforts at optimal medical management of ASCVD, hypertriglyceridemia remains an important contributor to residual risk for ischemic events. Prior trials attempting to lower triglyceride levels have been unable to show consistent efficacy in reducing major adverse cardiac events, possibly because of inadequate dose of the treatment drug, the formulation tested, and/or improper patient selection. Icosapent ethyl, a highly purified eicosapentaenoic acid, has been rigorously demonstrated to decrease residual risk for total ischemic events in patients with ASCVD or with T2DM and other risk factors who had been receiving statin therapy.
The authors would like to thank Dr. Steven Ketchum, Chief Scientific Officer of Amarin Pharma, Inc., for proofreading the galley proofs. Amarin Pharma, Inc., paid for open access for this article.
Financial support and sponsorship
Conflicts of interest
D.L.B. was the Chair and PI of REDUCE-IT and discloses the following relationships -- Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda. The other authors have nothing to disclose.
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