The clear and definitive relationship between LDL-C and ASCVD and the success of statin therapy may have directed due attention away from other important circulating lipids for risk prediction and as treatment targets. Recent findings concerning nutraceutical-mediated triglyceride-lowering have renewed the focus on lipids other than LDL-C. Evidence from RCTs, observational studies, and meta-analyses strongly suggest that consumption of oily fish and long-chain omega-3 polyunsaturated fatty acids (PUFAs) improves risk factors and biomarkers associated with cardiovascular disease [
19,
29,
30], in a manner consistent with the understanding of the biological actions of PUFAs, in particular the triglyceride-lowering effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [
31]. Because these active components can be chemically identified and standardized and appear to be closely associated with improvements in risk factors, PUFAs are an attractive target for nutraceutical development, and unusually for the field of nutraceutical research, three large, rigorous clinical trials have been published. The conflicting results of the three trials teach us important lessons about the management of cardiovascular disease in high-risk individuals and about the importance of employing the same rigour as used in the development and evaluation of nutraceuticals as we expect in the case of conventional pharmaceuticals.
In most countries, pharmaceutical preparations of “fish oil” or “PUFAs” are available for sale over-the-counter or on prescription. These preparations typically contain a variety of ingredients, often including EPA and DHA. The ASCEND trial was a placebo-controlled randomized two-by-two factorial evaluation of a once-daily dose one such preparation (460 mg EPA, 380 mg DHA—the composition recommended by the Nutrition Committee of the American Heart Association (AHA) [
32]) and aspirin 100 mg/day in 15,480 participants with diabetes—an inherently “high-risk” population. The primary endpoint was a first serious vascular event (defined as a composite myocardial infarction, stroke, transient ischemic attack, or vascular death). After an impressive mean follow-up of 7.4 years, there was no significant difference between the treatment and placebo groups with respect to the primary outcome [
33]. The VITAL study also investigated the effectiveness of a 460-mg EPA, 380-mg DHA preparation (in a two-by-two factorial placebo-controlled RCT with vitamin D
3, 2000 IU per day). The trial was conducted in a primary prevention population and used a preparation containing the AHA recommended composition [
32] (460 mg of EPA and 380 mg of DHA). The participants were 25,871 individuals, including men over the age of 50 years and women 55 years or older. The primary endpoints were a composite of major cardiovascular events (myocardial infarction, stroke, or cardiovascular death) and invasive cancer. Over a median of 5.3 years of follow-up, no significant differences were found between the placebo and treatment groups with respect to the cardiovascular composite endpoint [
34].
Following these two “negative” trials, the REDUCE-IT randomized, placebo-controlled trial surprised some commentators when it reported that over a 5-year follow-up in 8179 participants, treatment with PUFA led to a 25% relative reduction (HR 0.75 95% [CI] 0.68–0.83
p < 0.001) in first events of a composite cardiovascular outcome (including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and unstable angina). A subsequent analysis of REDUCE-IT data additionally showed that icosapent ethyl also reduced subsequent and total ischemic events [
17]. The intervention was, however, very different from that employed in ASCEND and VITAL, consisting of a substantially larger dose (4 g) of highly purified EPA (icosapent ethyl). The study is of particular interest to the consideration of a “high-risk” population, as it included statin-treated individuals with cardiovascular disease or with diabetes and other risk factors, who had elevated triglycerides. Icosapent ethyl was not free of adverse effects. Treatment was associated with an increased risk of atrial fibrillation or flutter (3.1% vs. 2.1%,
p = 0.004) and serious bleeding events (2.7% vs. 2.1%,
p = 0.06) [
18]. Nevertheless, this small increase in adverse effects is unlikely to outweigh the benefit of icosapent ethyl in reducing the risk of ASCVD in patients with elevated triglycerides. Interestingly, the STRENGTH trial, an outcomes trial of combined EPA and DHA in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol [
35], was recently halted owing to futility [
36]. Clearly the dose and composition of PUFA preparations is important in determining outcomes. Additionally, in a recent study which combined a systematic review and meta-analysis of RCTs and a Mendelian randomization, Mazidi et al. evaluated the link between omega-3 supplementation and CVD outcomes [
37]. They showed a significant reduction in the risk of coronary heart disease (CHD) death (risk ratio [RR] 0.91, 95%CI 0.85–0.97,
p = 0.010), major vascular event (RR 0.95, 95%CI 0.93–0.98,
p = 0.001), non-fatal myocardial infarction (MI) (RR 0.89, 95%CI 0.83–0.95,
p = 0.001), and all-cause mortality (RR 0.95, 95%CI 0.92–0.99,
p = 0.025) with omega-3 interventions. Based on the data from Mendelian randomization, they observed that a genetically determined higher level of serum alpha-linolenic acid (ALA) had a negative impact on the CHD risk (IVW = beta: − 4.424,
p = 1.1 × e−12) and MI (IVW = beta: − 2.081,
p = 0.009). Interestingly, such significant changes were not observed for EPA levels [
37].
Lipoprotein(a) (Lp(a)) is another relatively neglected lipoprotein which is both thrombogenic and atherogenic and which confers considerable risk of ASCVD when elevated [
38,
39]. Circulating concentrations of Lp(a) are largely genetically determined; however, dietary and nutraceutical approaches to Lp(a)-lowering including
l-carnitine and coenzyme Q10 have been evaluated and shown promise in clinical and experimental studies [
40,
41]. If nutraceutical approaches to Lp(a) are shown to be effective in RCTs, the resulting products could serve an important role in optimizing lipid-lowering therapy in individuals at high risk of ASCVD. Evidence from RCTs suggests that in some individuals, statin therapy results in a modest elevation of Lp(a) [
42,
43]. This small effect is unlikely to be of major concern, and any risk increase conferred by Lp(a) is likely to be outweighed many times over by the benefits of LDL-C-lowering. Nevertheless, if it were possible to reverse the Lp(a) elevation using nutraceuticals, this would help to optimize therapy.