Residual Risk: Beyond LDL-C Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States, and its prevention and treatment continue to be an area of utmost importance.1 Elevated low-density lipoprotein cholesterol (LDL-C) is a well-established ASCVD risk factor and significant advances have been made to lower it by using established and new strategies, including statin therapy, ezetimibe, and PCSK9 inhibitors.2,3 However, while lowering LDL cholesterol (LDL-C) remains central in the prevention and treatment of ASCVD, residual risk may be present even after the optimization of LDL-C levels.4
Current therapies that primarily target LDL-C may not address other drivers of atherosclerosis, including triglycerides (TGs), which seem to be part of the causal pathway in high-risk patients.2 In certain high-risk patients, including those with pre-existing ASCVD, or that have type 2 diabetes and/or metabolic syndrome, intensive treatment with statins and newer therapies to lower LDL-C may not address the full spectrum of cardiovascular prevention.4 In these patients, the interplay between phenotypes that promote both a proinflammatory state and atherogenic dyslipidemia (including elevated TG levels), requires additional measures to optimize both primary and secondary ASCVD prevention.2,4
Elevated TG levels increase ASCVD risk, but omega-3 trials have shown mixed results about targeting HTG for reduction of adverse CVD events, with the notable exception of the REDUCE-IT trial with icosapent ethyl.5,6 The results of the REDUCE-IT trial represent an important change in how we address residual cardiovascular risk in practice in the near future, including a re-definition of what constitutes elevated levels of triglycerides.2
Lowering TGs: not a straightforward approach
Although we can debate whether triglycerides themselves or the lipid/lipoprotein company they keep are causal for ASCVD7, elevated TGs are being recognized as an important marker for ASCVD risk stratification. 3 Recent real-world studies and meta-analyses have shown that high TG levels are associated with an elevated CVD risk in high-risk statin patients with ASCVD and statin-controlled LDL-C.8,9 A recent study evaluating the association between adverse cardiovascular outcomes and HTG (200-499 mg/dL) in ASCVD patients with statin-controlled LDL-C, reported greater adverse cardiovascular events in patients with HTG compared to normal (<150 mg/dL) triglyceride levels. 8 Over the course of a follow-up of 4.2 years, patients with high TG had a 30% increased risk for myocardial infarction (MI) or coronary revascularization, and a 13% increased risk for the composite outcome of non-fatal MI, coronary revascularization, and all-cause mortality compared to normal TG patients. 8 As such, in the 2018 multi-society cholesterol guidelines, TG levels of >175mg/dL are a risk-enhancing factor to determine need for statin therapy. 3
However, there is a paucity of evidence for effective cardiovascular risk reduction with existing therapies that target elevated TGs. In all patients with hypertriglyceridemia, emphasis is placed on lifestyle modification, including weight management, increased physical activity and restriction or elimination of alcohol consumption. However, lifestyle therapy is not always sufficient to achieve adequate TG lowering. Statins are considered first line drug therapy for the management of hyperlipidemia, including for most patients with high TG, but there is substantial residual ASCVD risk among patients taking statins.8,10 Trials with currently available agents to treat hypertriglyceridemia (HTG), such as fibrates and niacin, have not been efficacious in reducing ASCVD risk either as a monotherapy or when added to statins, and has contributed to the challenges that clinicians face in targeting HTG to reduce residual ASCVD risk.4 To date, trials with omega-3 fatty acids have shown mixed results in cardiovascular prevention, and clinicians may be confused in differentiating between the different formulations and evidence about these agents for reducing ASCVD risk. 4
REDUCE-IT: The Emerging Role of Icosapent Ethyl
The omega-3 fatty acids (OM3FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower TG through reduced synthesis and release of hepatic VLDL-TG and enhanced clearance of TG from plasma.11 On a molecular level, omega-3 fatty acids have been shown to reduce endothelial dysfunction, plaque volume, and inflammation. 6 There are a variety of different prescription and generic OM3FA formulations available for the treatment of hypertriglyceridemia, including icosapent ethyl, omega-3-carboxylic acids, and omega-3-acid ethyl esters.12-14 However, many generic fish oil supplements lack the sufficient pharmacological dose of at least 2g/day of omega-3 fatty acid needed to significantly reduce serum TG levels.15 Several OM3FA concentrate prescription drugs are approved for the treatment of severe hypertriglyceridemia (TG ≥500 mg/dL).16 These formulations provide EPA and DHA in either ethyl ester or free fatty acid (carboxylic acid) forms.
Omega-3 fatty acids have been shown to reduce TG levels by 22-33% in statin-treated patients with high baseline levels of TG (25680 mg/dL) in short-term studies.17,18 Recent meta-analyses did not provide support for the role of OM3FA supplements in CVD risk, however, different formulations were used in these studies, including not completely pure OM3FA, which makes their interpretation challenging.4,19,20 To date, the one study that used a pure OM3FA agent (1.8 mg EPA) in addition to low-dose statin, JELIS, showed that EPA was associated with a 19% reduction in major coronary events.21 The ASCEND trial, which assessed the efficacy and safety of daily supplementation with OM3FA (1 g EPA + DHA) in preventing CV events (a combination of non-fatal MI, non-fatal stroke or TIA, and vascular death) in patients with diabetes and no prior cardiovascular disease, showed that OM3FA supplementation did not prevent major adverse CV events.22 However, these results of the ASCEND trial could be due to the dose of OM3FA used (1g), which has not shown positive results in previous trials, and authors suggest that higher doses (2-4 g) may yield more benefits.4,22
Recently, the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), which used higher doses of a highly purified ester of EPA, icosapent ethyl, evaluated the effects of this intervention in preventing cardiovascular events in high-risk patients with established ASCVD or diabetes plus at least an additional risk factor. 5 A total of 8179 patients, who had fasting triglyceride levels of 135-499 mg/dL and an LDL-C of 41-100 mg/dL while on background statin therapy were enrolled and randomized to receive 2g of icosapent ethyl twice daily (4g total daily dose) or placebo. 5 In this trial, patients treated with icosapent ethyl had a 25% risk reduction in the occurrence of major adverse CV events (composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization) after a median follow-up of 4.9 years, which was significant compared to placebo. 5 This included a statistically significant 20% reduction in CV death, as well as statistically significant relative risk (RR) reductions for other prespecified individual endpoints, including myocardial infarction (31% RR), stroke (28% RR), hospitalization for unstable angina (32% RR), and urgent or emergent coronary revascularization (35% RR) compared to placebo.2 Furthermore, the benefits were consistent among several prespecified subgroups, including in patients with normal TG levels (<150 mg/dL), which represented 10.3% of the study population.2 Thus, it is unlikely that the benefits observed with icosapent ethyl in the REDUCE-IT trial are merely a function of baseline TG levels, since the risk reduction in the primary and key secondary endpoints was relatively the same in those with baseline TG ≥200 mg/dL and those with what is TG values of ≥150 mg/dL, and these results are re-defining of what we perceive to be “normal” TG levels.2,23 The specific mechanisms of action that lead to these benefits with icosapent ethyl are an ongoing area of investigation.23 In this trial, icosapent ethyl was generally well tolerated; with a trend toward more bleeding-related disorders which did not reach statistical significance, and increased hospitalization rates for atrial fibrillation with icosapent ethyl compared to placebo.5 A recent sub-analysis of the REDUCE-IT trial showed that in addition to the 25% reduction in first ischemic events, icosapent ethyl was associated with a 32% reduction in second events, a 31% reduction in third events, and a 48% reduction in fourth of subsequent events, with total events being reduced by 30% compared to placebo.6
Due to the results of this study, an application for an additional indication for icosapent ethyl to reduce the risk of major CVD events was submitted to the FDA in March 2019 and is pending. Currently, this agent is approved only to treat patients with TG levels ≥500 mg/ dL to prevent acute pancreatitis.23 Although not yet FDA approved for the CV indication, recent guidelines have been modified to recommend this agent in certain patients. The American Diabetes Association (ADA) issued an update in March 2019 to its standards of care, advising that icosapent ethyl be considered to reduce CV risk in patients with diabetes and ASCVD or with other cardiac risk factors who are on a statin and have controlled LDL-C, but elevated TG levels.24
Recent results with icosapent ethyl, as demonstrated by the REDUCE-IT trial, have shown that it can significantly reduce atherosclerotic events in high-risk hypertriglyceridemic patients with clinical ASCVD or type 2 diabetes and additional markers of increased risk. As more evidence becomes available, it is expected that icosapent ethyl will play an important role in primary and secondary prevention in high-risk patients.