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.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Benjamin EJ, Muntner P, Alonso A, et al. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation 2019; 139:e56–e528.
2. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease
. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis
Society Consensus Panel. Eur Heart J 2017; 38:2459–2472.
3. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388:2532–2561.
4. Xiao C, Dash S, Morgantini C, et al. Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol. Diabetes 2016; 65:1767–1778.
5. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015; 36:774–776.
6. Ford ES, Li C, Zhao G, et al. Hypertriglyceridemia
and its pharmacologic treatment among US adults. Arch Intern Med 2009; 169:572–578.
7. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 western prospective studies. Circulation 2007; 115:450–458.
8. Varbo A, Benn M, Tybjærg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013; 61:427–436.
9. Watts GF, Ooi EM, Chan DC. Demystifying the management of hypertriglyceridaemia. Nat Rev Cardiol 2013; 10:648–661.
10. Nordestgaard BG, Benn M, Schnohr P, Tybjærg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007; 298:299–308.
11. Musunuru K, Kathiresan S. Surprises from genetic analyses of lipid risk factors for atherosclerosis
. Circ Res 2016; 118:579–585.
12. Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nature Rev Genet 2017; 18:331–344.
13▪▪. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019; 321:364–373.
This study leverages Mendelian randomization to analyze the magnitude of risk reduction provided by specific triglyceride-lowering variants and LDL-C-lowering variants. A key finding was the discovery that the effect sizes were proportional to the net reduction of apo-B-containing lipoproteins.
14. Boren J, Williams KJ. The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis
: a triumph of simplicity. Curr Opin Lipidol 2016; 27:473–483.
15▪▪. Ganda OP, Bhatt DL, Mason RP, et al. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia
management. J Am Coll Cardiol 2018; 72:330–343.
This review clearly discusses one large component of residual risk for ASCVD, atherogenic dyslipidemia, and describes our current understanding of the origins, mechanisms of action, and treatment modalities available to correct this strong risk factor for further ischemic events. It describes the total body of triglyceride-lowering trials to a greater extent than discussed here.
16. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341:410–418.
17. Keech A, Simes RJ, Barter P, et al. Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366:1849–1861.
18. Scott R, O’Brien R, Fulcher G, et al. FIELD Study Investigators. Effects of fenofibrate treatment on cardiovascular disease
risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009; 32:493–498.
19. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362:1563–1574.
20. Boden WE, Probstfield JL, et al. AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255–2267.
21. Landray MJ, Haynes R, et al. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203–212.
22. 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; 92:15–29.
23. Siscovick DS, Barringer TA, Fretts AM, et al. American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Epidemiology and Prevention; Council on Cardiovascular Disease
in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease
: a science advisory from the American Heart Association. Circulation 2017; 135:e867–e884.
24. Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med 2002; 112:298–304.
25. Valagussa F, Franzosi MG, Geraci E, et al. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999; 354:447–455.
26. Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007; 369:1090–1098.
27. Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis
28. Bowman L, Mafham M, et al. ASCEND Study Collaborative Group. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018; 379:1540–1550.
29. Manson JE, Cook NR, Lee IM, et al. VITAL Research Group. Marine n-3 fatty acids and prevention of cardiovascular disease
and cancer. N Engl J Med 2019; 380:23–32.
30▪. Aung T, Halsey J, Kromhout D, et al. Omega-3 Treatment Trialists’ Collaboration. Associations of omega-3 fatty acid supplement use with cardiovascular disease
risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol 2018; 3:225–234.
In this study, the authors compile the results of 10 individual randomized controlled trials assessing omega-3 fatty acid supplementation on future cardiovascular disease risk. The authors investigate the differing eligibility criteria, treatment formulations, and outcomes measures that begin to explain the discrepancies between trial results.
31. Bhatt DL, Steg PG, Brinton EA, et al. REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl
-Intervention Trial. Clin Cardiol 2017; 40:138–148.
32▪. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl
. N Engl J Med 2018; 380:11–22.
This study describes the results of REDUCE-IT. In patients who were already on statin therapy with goal LDL-C levels but elevated triglycerides, treatment with icosapent ethyl provided a 25% relative risk reduction for the primary composite cardiovascular endpoint. The primary data suggest the benefit was because of additional mechanisms beyond triglyceride lowering.
33▪. Bhatt DL, Steg PG, Miller M, et al. REDUCE-IT Investigators. Effects of Icosapent ethyl
on total ischemic events: from REDUCE-IT. J Am Coll Cardiol 2019; 73:2791–2802.
This study provides an important follow-up to the results of REDUCE-IT and analyzes the treatment and control groups for second, third, and fourth or more occurrences of ischemic events. The data demonstrate that icosapent ethyl significantly reduced total ischemic burden over the study period.
34. Granger CB, Nelson AJ, Pagidipati NJ. Risk of total events with icosapent ethyl
: can we reduce it? J Am Coll Cardiol 2019; 73:2803–2805.
35▪. Bhatt DL. REDUCE-IT. Eur Heart J 2019; 40:1174–1175.
This commentary summarizes the key findings from REDUCE-IT and brings attention to other notable trends in the data, such as the suggestion of lower all-cause mortality.
36. Bhatt DL, Steg PG, Miller M, et al. Reduction in first and total ischemic events with icosapent ethyl
across baseline triglyceride tertiles. J Am Coll Cardiol 2019; 74:1159–1161.
37. Bowman L, Hopewell JC, Chen F, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017; 377:1217–1227.
38. Bays HE, Ballantyne CM, Kastelein JJ, et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multicenter, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] Trial). Am J Cardiol 2011; 108:682–690.
39. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol 2012; 110:984–992.
40. Bays HE, Ballantyne CM, Braeckman RA, et al. Icosapent ethyl
, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs 2013; 13:37–46.
41. Nishio R, Shinke T, Otake H, et al. Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma. Atherosclerosis
42. Watanabe T, Ando K, Daidoji H, et al. A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins. J Cardiol 2017; 70:537–544.
43. Niki T, Wakatsuki T, Yamaguchi K, et al. Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound. Circ J 2016; 80:450–460.
44. Konishi T, Sunaga D, Funayama N, et al. Eicosapentaenoic acid therapy is associated with decreased coronary plaque instability assessed using optical frequency domain imaging. Clin Cardiol 2019; 42:618–628.
45. Doi M, Nosaka K, Miyoshi T, et al. Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: a randomized, controlled study. Int J Cardiol 2014; 176:577–582.
46. Bhatt DL, Steg PG, Miller M. Cardiovascular risk reduction with icosapent ethyl
. Reply. N Engl J Med 2019; 380:1678.
47▪. Orringer CE. Icosapent ethyl
: where will it fit into guideline-based medical therapy for high risk atherosclerotic cardiovascular disease
? Trends Cardiovasc Med 2019; https://doi.org/10.1016/j.tcm.2019.04.009
This article appraises the evidence for guideline-based medical therapy for ASCVD as of 2018, including recent trials supporting the use of ezetimibe and PCSK9 inhibitors in certain populations. As the REDUCE-IT trial was published after the closure of the evidence review for the 2018 guidelines, this article postulates how icosapent ethyl fits into this risk reduction landscape.
48. Randomized trial for evaluation in secondary prevention efficacy of combination therapy — statin and eicosapentaenoic acid (UMIN Clinical Trials Registry Number: UMIN000012069).
49. Budoff M, Muhlestein BJ, Le VT, et al. Effect of Vascepa (icosapent ethyl
) on progression of coronary atherosclerosis
in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: rationale and design of the EVAPORATE study. Clin Cardiol 2018; 41:13–19.
50. American Diabetes Association. 10. Cardiovascular disease
and risk management: standards of medical care in diabetes. Diabetes Care 2019; 42:S103–S123.
51▪▪. Mason PR. New insights into mechanisms of action for omega-3 fatty acids in atherothrombotic cardiovascular disease
. Curr Atheroscler Rep 2019; 21:2.
In this review, prior OM3FA cardiovascular outcomes trials are comprehensively reviewed. Special attention is made to note the differences between DHA and EPA in OM3FA preparations, and their respective biological effects on cellular function and the progression of atherosclerosis.
52. Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol 2018; 41:1281–1288.
53. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018; 206:80–93.