Cardiovascular Impact of Nutritional Supplementation With Omega-3 Fatty Acids

JACC Focus Seminar

Richard L. Weinberg, MD, PHD; Robert D. Brook, MD; Melvyn Rubenfire, MD; Kim A. Eagle, MD


J Am Coll Cardiol. 2021;77(5):593-608. 

In This Article

Omega-3 PUFAs

Mechanisms of Action

Omega-3 PUFAs alter the structure and function of cellular phospholipid membranes and have electrophysiological, vascular, and antioxidative effects. These properties offer a mechanistic framework by which omega-3 PUFAs exert cardioprotective effects (Central Illustration).[21–24]

Central Illustration.

Hypothesized Mechanisms of Omega-3 PUFAs That Decrease Cardiovascular Disease Risk
Omega-3 polyunsaturated fatty acids (PUFAs) lower triglyceride-rich lipoproteins, which may account for some but not all of their cardiovascular benefits. Omega-3 PUFAs may alter the production of inflammatory, vasodilatory, and antiaggregatory signaling molecules, thereby decreasing inflammation, combating thrombosis, and stabilizing atherosclerotic plaque. Alterations in cellular membrane composition by omega-3 PUFAs may exert an antiarrhythmic effect and resist oxidation.

EPA and DHA interact differently with cellular membranes (Figure 1).[25–27] Preclinical data describe that compared with DHA, EPA has a more stable, extended structure that promotes membrane stability, inhibits inflammation, and prevents lipid oxidation,[27] offering a hypothesis to why EPA has demonstrated CV benefits in RCTs.[23,28,29] EPA and DHA reduce the electrical excitability of cardiac myocytes and protect against sudden cardiac death.[30,31] Although the majority of RCTs have not shown a protective effect of omega-3 PUFAs on preventing atrial fibrillation,[32] a smaller RCT using omega-3 PUFA supplementation with a higher proportion of DHA showed a decrease in post-operative atrial fibrillation.[33] EPA and DHA increase systemic arterial compliance and improve endothelial function,[34–36] and may explain the association of fish oil intake with reduced blood pressure.[37]

Figure 1.

Cellular Membrane Interactions of Omega-3 Polyunsaturated Fatty Acids
Schematic representation of the hypothesized different effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the plasma membrane. The longer hydrocarbon length and additional double bond in DHA cause rapid conformational changes that increase membrane fluidity and form cholesterol domains. In contrast, EPA has a more stable structure, resulting in membrane stability and inhibition of cholesterol oxidation and inflammatory pathways. Adapted with permission from Mason et al. (27).

Omega-3 PUFAs modulate inflammation. They are involved in production of eicosanoids, prostaglandins, resolvins, protectins, and leukotrienes.[5,24,38,39] Increased cellular membrane concentrations of EPA and DHA decrease the availability of arachidonic acid as a substrate for the synthesis of proinflammatory eicosanoids.[24] EPA decreases expression of the cyclooxygenase-2 gene, a key enzyme responsible for the synthesis of proinflammatory molecules, and EPA and DHA regulate T cell function.[24,40,41]

High-dose DHA and EPA (4 g/day) typically lower triglycerides by 20% to 30%, with higher reductions in patients with more severe hypertriglyceridemia.[19] In more severe hypertriglyceridemia, DHA (but not EPA) can raise low-density lipoprotein cholesterol (Table 3).[20,42–44] The mechanisms by which omega-3 PUFAs lower triglycerides reflects, in part, increased uptake into cellular phospholipids, rather than into triacylglycerol, due to inhibition of phosphatidic acid phosphatise.[19] In addition, EPA and DHA are thought to interfere with assembly and secretion of very low-density lipoprotein and promote degradation of apolipoprotein B.[21,45–50] EPA exerts additional effects on lipoproteins and atherosclerotic plaque, which may contribute to its antiatherogenic properties.[23,51–57] The final 18-month analysis of the EVAPORATE (Effect of Vascepa on Improving Coronary Atherosclerosis in People with High Triglycerides Taking Statin Therapy) trial demonstrated significant reduction in several measures of plaque volume and composition, including a decrease in low-attenuation plaque volume by multidetector computed tomography.[58]

RCT Outcome Data

RCTs have examined the effects of omega-3 PUFAs on CV outcomes in the primary and secondary prevention settings.[17,18,59] The majority used an omega-3 PUFA dose of approximately 1 g/day. Herein, we highlight and place in context the more recent data describing the effects of omega-3 PUFAs on CV events (Table 4).

The ASCEND (A Study of Cardiovascular Events in Diabetes)[60] and VITAL (Vitamin D and Omega-3 Trial)[61] trials evaluated the effect of low-dose omega-3 PUFAs (840 mg EPA + DHA) on the primary prevention of ASCVD. In the ASCEND trial, omega-3 PUFA supplementation did not significantly reduce the primary composite outcome of serious vascular events (nonfatal myocardial infarction [MI], nonfatal stroke, transient ischemic attack, and vascular death) in a cohort of diabetic patients. In exploratory analyses, there were fewer vascular deaths (19% relative risk reduction) that achieved statistical significance. The VITAL trial was the largest and most ethnically diverse omega-3 PUFA trial, of which 5,106 (20%) participants were Black. In the VITAL trial, omega-3 PUFAs did not significantly reduce the primary composite endpoint of major ASCVD events (MI, stroke, and CVD mortality). However, there was a 28% reduction in total MI, which emerged after the first year and continued throughout the trial. There were significant reductions in other pre-specified secondary outcomes, including a 17% reduced risk for total coronary heart disease (CHD) and a 50% reduction in fatal MI (Table 4). Individuals with low baseline fish consumption (<1.5 servings/week) had decreased risk for total CV events (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.67 to 0.98). Black study participants experienced a 77% treatment-associated reduction in MI (HR: 0.23; 95% CI: 0.11 to 0.47), and derived an MI benefit irrespective of baseline fish intake.

The OMEMI (OMega-3 fatty acids in Elderly with Myocardial Infarction) trial[62] investigated whether of 930 mg EPA + 660 mg DHA per day decreased the risk of nonfatal MI, unscheduled revascularization, stroke, all-cause death, and heart failure hospitalization compared with corn oil placebo. The study population comprised older Norwegian patients (median age 74 years) who suffered an acute MI 2 to 8 weeks prior to trial enrollment. Over a 2-year follow-up, there was no difference in the primary composite endpoint. The primary safety endpoint, major bleeding events, was similar between the treatment and placebo groups. New onset atrial fibrillation occurred in 7.2% in the omega-3 PUFA group and in 4.0% in the placebo group, which approached but did not reach statistical significance (Table 4).

The STRENGTH (Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) study[63] randomized 13,078 patients to receive 4 g/day of omega-3 carboxylic acids (800 mg DHA + 2,200 mg EPA) or corn oil placebo. The patient population was at high risk for ASCVD and had hypertriglyceridemia, with 56% of the study population being secondary prevention. The trial was terminated early following the recommendation of the independent data monitoring committee, citing the low likelihood of demonstrating a clinical benefit in preventing ASCVD events. After a median follow-up of 42 months, there was no significant difference between the omega-3 PUFA group and placebo in the primary endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina: 12% in the omega-3 PUFA group versus 12.2% in the corn oil placebo group (HR: 0.99; 95% CI: 0.90 to 1.09). There was a statistically significant increased risk of atrial fibrillation in the omega-3 PUFA group compared with placebo, 2.2% versus 1.3% (HR: 1.69; 95% CI: 1.29 to 2.21).

In contrast, the REDUCE-IT trial[20] provided evidence that high-dose IPE (4 g/day EPA), protected against CV events as compared with a mineral oil placebo in high-risk patients with hypertriglyceridemia receiving maximally tolerated statin therapy. Individuals had either established ASCVD or diabetes with additional ASCVD risk factors. Patients treated with IPE had a lower rate of the primary endpoint (a composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization): 17.2% in the IPE group as compared with 22.0% in the placebo group (HR: 0.75; 95% CI: 0.68 to 0.83). In addition, there was reduction in the key composite secondary endpoint of CV death, nonfatal MI, or nonfatal stroke (Table 4). There was no significant heterogeneity in effect for the primary endpoint across triglyceride levels; however, IPE had a greater effect in those patients with triglycerides ≥200 mg/dl and high-density lipoprotein cholesterol ≤35 mg/dl. This is consistent with subgroup analyses from the open-label JELIS (Japan EPA Lipid Intervention Study), which showed a more robust reduction in ASCVD events in patients with triglycerides ≥150 mg/dl and high-density lipoprotein cholesterol <40 mg/dl.[64] Secondary analyses of the REDUCE-IT trial demonstrated that treatment with IPE decreased the risk for subsequent primary endpoint events[65] and reduced the risk for first and subsequent coronary revascularization procedures.[66] Patients in the United States demonstrated significant reductions in both the primary and secondary endpoints.[67] Although the cost of IPE is significant, it has been shown to be cost effective at a price of $4.16 per day.[68,69]

Taken as a whole, RCTs evaluating omega-3 PUFA supplementation on ASCVD outcomes have met with varying results (Table 4). Earlier trials (the DART [Diet and Reinfarction Trial], GISSI-P [Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico Prevenzione], and GISSI-HF [Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico Heart Failure] trials) reported beneficial outcomes,[70–72] while more recent trials (Alpha Omega, OMEGA [Randomized, Placebo-Controlled Trial to Test the Effect of Highly Purified Omega-3 Fatty Acids on Top of Modern Guideline-Adjusted Therapy After Myocardial Infarction], SU.FOL.OM3 [Supplémentation en Folates et Omega-3], ORIGIN [Outcome Reduction with an Initial Glargine Intervention], R&P [Risk and Prevention], AREDS2 [Age-Related Eye Disease Study 2], STRENGTH, and OMEMI trials) failed to show protection,[62,63,73–78] with the exception of the JELIS study[79] and REDUCE-IT trial.[20] The heterogeneity in outcomes may be due to methodological differences, including duration of follow-up, patient population studied, dose and formulation of omega-3 PUFAs administered, variability in use of statins, and lower-than-expected event rates (Table 4).[79] The most recent meta-analysis performed by Hu et al.[17] analyzed 13 RCTs, including the VITAL,[61] ASCEND,[60] and REDUCE-IT[20] trials. In their analysis, omega-3 PUFA supplementation had significant inverse associations with MI, CHD death, total CHD, CVD death, and total CVD (Table 5). Of note, their analysis was performed prior to the publication of the STRENGTH study and OMEMI trial, both of which did not demonstrate a protective effect of omega-3 PUFA supplementation on ASCVD outcomes.[62,63] Thus, while one should consider that in several recent RCTs omega-3 PUFAs may not offer risk reduction based on not achieving the trials' primary outcomes, the aggregated data combined with exploratory analyses of the VITAL and ASCEND trials suggest that in certain populations omega-3 PUFA supplementation may provide benefit.

The question remains as to why recent trials studying mixed omega-3 PUFAs (EPA + DHA) found no effect on ASCVD outcomes, whereas trials investigating pure EPA demonstrated a clinical benefit. Although comparisons among trials should be done prudently, one needs to consider the omega-3 PUFAs and the placebo used. The formulation of omega-3 PUFAs may be a key aspect of CV event reduction. In contrast to the VITAL, ASCEND, STRENGTH, and OMEMI trials, the REDUCE-IT trial and JELIS study used pure EPA as opposed to an EPA + DHA formulation. Given the high dose of EPA + DHA and the selection of patients with hypertriglyceridemia in the STRENGTH study, and the comparable triglyceride effects seen (19% decrease in the STRENGTH study and 18.3% decrease in the REDUCE-IT trial), if the triglyceride-lowering effect of omega-3 PUFAs was the sole driver for CV benefit, the STRENGTH study should have reduced events. Blood EPA levels were higher in the REDUCE-IT trial compared with the STRENGTH study (393% vs. 269% increase), and blood EPA levels were inversely associated with ASCVD outcomes in the REDUCE-IT trial and JELIS study but not in the STRENGTH study.[63,80,81] It remains unclear as to why these differences exist and brings to the fore the hypothesis that triglyceride-independent effects of EPA may be in part responsible for the CV benefits seen in the REDUCE-IT trial.[23,82,83] These findings also raise the question as to whether the increase in DHA levels could offset the beneficial effects of an increase in EPA; however, there is no proven biological mechanism for this explanation, and as there are no trials of DHA monotherapy on ASCVD event reduction, the effect of pure DHA remains unknown.

The choice of placebo is important in discussing the differences in the REDUCE-IT trial and STRENGTH study. The use of mineral oil as placebo was proposed to have impacted the efficacy of statin therapy and the findings seen in the REDUCE-IT trial. In the REDUCE-IT trial, the IPE group had better lipid profiles and lower levels of inflammatory markers compared with placebo. Additionally, there were increases in low-density lipoprotein cholesterol and high-sensitivity C-reactive protein in the mineral oil placebo group, an effect that was not observed in the corn oil placebo group in the STRENGTH study. An exploratory analysis by the U.S. Food and Drug Administration concluded these effects alone could not account for the positive CV outcomes seen in the REDUCE-IT trial.[84] Subsequently, comparison of a mineral oil and nonmineral oil placebo on coronary plaque progression was studied by coronary computed tomography angiography, and there were no significant differences in progression of total plaque and total noncalcified plaque volume observed.[85]