Navigating omega-3s

This editorial refers to ‘Effects of omega-3 fatty acids on coronary revascularization and cardiovascular events: a meta-analysis’, by M. Dinu et al., https://doi.org/10.1093/eurjpc/zwae184. Omega-3 fatty acids (omega-3FAs), abundant in fish oil, are believed to confer a range of cardiovascular benefits, including reducing triglyceride levels and potentially lowering the risk of myocardial infarction (MI) and stroke. Despite cardiovascular disease remaining the leading cause of global mortality, the specific impact of omega-3FAs on coronary revascularization and other major cardiovascular events (MACE) continues to be a topic of ongoing debate and research.1 In the 1970s, studies indicated that the Inuit people of Greenland had low rates of coronary heart disease (CHD) while consuming a high seafood diet. This led to extensive research on the health benefits of long-chain omega-3 polyunsaturated fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).2 The EPA and DHA play pivotal roles in cardiovascular health by lowering triglycerides, reducing inflammation, and potentially preventing arrhythmias. However, their impact on outcomes like stroke and MI remains uncertain, with conflicting results from large trials in hypertriglyceridaemia patients.3 High-dose omega-3FAs can significantly lower serum triglycerides by reducing hepatic VLDL cholesterol production and enhancing lipoprotein lipase–mediated clearance of triglycerides. Depending on the baseline triglyceride concentration, administration of 2–4 g of DHA and EPA can reduce serum triglycerides by 30–50%.4 Omega-3FA consumption is linked to improved endothelial function, reduced inflammation markers, and potential benefits in glucose metabolism and body composition. Omega-3FAs affect blood pressure by reducing systemic vascular resistance and improving arterial compliance through nitric oxide production induced by EPA and DHA. Additionally, in patients with non-ischaemic cardiomyopathy and minimal symptoms on guideline-directed medication, omega-3FA treatment increases left ventricular (LV) systolic function, improves diastolic function, and functional aerobic capacity. Lastly, omega-3FAs may lower resting heart rate and induce antiarrhythmic effects.5,6 Conversely, omega-3FAs have been linked to an elevated risk of atrial fibrillation (AF). The REDUCE-IT trial reported an increase in AF incidence from 2.1% in the placebo group to 3.1% in the EPA group.3 The potential beneficial effect of omega-3FAs on clinical outcomes in patients with ischaemic heart disease has been controversial. In the GISSI-Prevenzione trial, over 11 000 patients with recent MI received 1 g of omega-3FAs with an EPA to DHA ratio of 1:2. The trial showed a significant 17% reduction in deaths from CHD. However, it showed minimal triglyceride reduction, and the reduction in CHD events was largely driven by fewer sudden cardiac deaths rather than atherothrombotic events.7 Other trials using 1 g or less of omega-3FAs did not show any clinical benefit for either primary or secondary prevention.8 The JELIS study from 2007, conducted by Yokoyama et al., investigated the effects of 1.8 g/day of EPA supplementation in over 18 000 patients without CHD on baseline low-intensity statin therapy. The study found a 19% reduction in major coronary events, with an even greater benefit in patients with elevated triglycerides. However, there was no reduction in either fatal or non-fatal MI, and the positive results were mainly due to decreased hospital admissions for unstable angina.3 In 2018, a large meta-analysis of 10 trials involving over 77 000 patients found that treatment with omega-3FAs (DHA plus EPA) did not reduce fatal or non-fatal CHD or other vascular events.8 However, the recent REDUCE-IT trial, which randomized around 8200 high-risk patients with mild to moderate hypertriglyceridaemia treated with statins to receive either 4 g/day of EPA in the form of icosapent ethyl or a placebo, showed a 25% reduction in the primary composite endpoint (time to the first MACE) and a 20% reduction in the risk of death from CHD.3 The marked benefits observed in this trial, compared with other omega-3FA trials, raise questions about whether the differences are due to the drug dose, formulation, or baseline patient dyslipidaemia. A similar trial, STRENGTH, which investigated the effects of 4 g/day of omega-3FAs, was stopped early because it was unlikely to show a benefit.9 This outcome contrasts with the positive results seen in the REDUCE-IT trial, which used 4 g/day of EPA alone. The meta-analysis by Dinu et al.,10 ‘Effects of omega-3FAs on coronary revascularization and cardiovascular events’, aimed to evaluate the impact of omega-3FA supplementation on cardiovascular outcomes. Synthesizing data from 18 randomized controlled trials involving 134 144 participants, the study sought to determine whether these fatty acids reduce the need for coronary revascularization and the incidence of MACE. Specifically, it investigated incident coronary revascularizations, MI, stroke, heart failure, unstable angina, and cardiovascular death in subjects randomized to receive EPA or EPA + DHA vs. control. The meta-analysis demonstrated that omega-3FA supplementation modestly reduced the risk of coronary revascularization (relative risk [RR] 0.90, 95% confidence interval [CI] 0.84–0.98), MI (RR 0.89, 95% CI 0.81–0.98), and cardiovascular death (RR 0.92, 95% CI 0.85–0.99) compared with controls. Notably, EPA alone exhibited greater benefits than the combination of EPA and DHA. These beneficial effects were observed even among participants who were already on statin therapy, highlighting the potential for omega-3FAs to provide additional cardiovascular protection. Compared with the previous meta-analyses, this study is distinguished by its specific focus on coronary revascularization and its comprehensive sub-analyses based on the type of omega-3FA supplementation and background statin use. The combined EPA/DHA did not show a significant statistical difference [95% CI 0.95 (0.90–1.0); P = 0.06] in reducing coronary revascularization, highlighting that the benefit is primarily due to EPA alone. These insights help clarify some of the controversies surrounding omega-3FA benefits. For instance, the separate analysis of EPA alone vs. EPA + DHA provides crucial clarity on the superior benefits of EPA in reducing cardiovascular events. The potential cost savings from reduced revascularization procedures are also noteworthy. Revascularization is not only a costly procedure but also one that significantly impacts patients’ quality of life. Therefore, the ability to reduce the incidence of these procedures through omega-3FA supplementation, particularly EPA, is highly valuable. Healthcare providers might consider recommending omega-3FA supplementation as a complementary approach to existing therapies, potentially reducing the need for invasive coronary procedures and improving patient quality of life. Furthermore, the availability of various omega-3FA supplements, both over the counter and prescribed, each differing in their composition and intended therapeutic effects, offers flexibility in clinical practice. Over-the-counter supplements typically contain varying ratios of EPA and DHA, whereas prescription formulations offer higher concentrations suited for specific medical conditions. Fish oil supplements contain natural forms of EPA and DHA, which are in their triglyceride form and should be taken with meals to enhance absorption. Preparations vary in their EPA and DHA content, with prescription options generally offering higher doses suited for treating hypertriglyceridaemia. Lovaza/Omacor (omega-3 acid ethyl esters—semi-synthetic derivative of both EPA and DHA) is aimed at reducing elevated triglyceride levels. Vascepa (icosapent ethyl—synthetic derivative of EPA that has been purified to provide concentrated doses of EPA without including DHA) is primarily indicated for severe hypertriglyceridaemia. Generic EPA is available, though it has never been studied in a large trial. The JELIS study used ‘highly purified EPA’, not eicosapent ethyl, indicating that further studies with generic EPA could be beneficial and should be encouraged. Despite its strengths, the study has limitations. It could have provided more detailed subgroup analyses based on patient demographics and comorbid conditions. Understanding how factors such as age, gender, and existing health conditions influence the effectiveness of omega-3FA supplementation would offer more tailored insights for clinical practice. The variability in study populations and methodologies, as well as differences in follow-up duration, is a limitation. Additionally, the inability to distinguish between primary and secondary prevention in some studies and the lack of separate data for percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) limits the analysis’ granularity. In conclusion, the benefits of omega-3FA supplementation for cardiovascular health have long been debated; however, the most recent meta-analysis study provides compelling evidence for its role in reducing MACE and the need for invasive procedures, particularly when administered as EPA alone. No funding was received for this editorial. No new data were generated or analysed in support of this research.

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