Interest in fish oil began more than 40 years ago, when it was learned that the Inuit population of Greenland had low rates of CHD, despite consuming a high saturated fat diet. It was believed that protection might be conferred by the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that were in the fish the Inuit consumed. Multiple mechanisms likely explain the beneficial effects of omega-3 fatty acids for both primary and secondary prevention of CVD, including reductions in triglyceride levels, inflammation, blood pressure, blood clotting, arrhythmias, and atherosclerotic plaque formation, and improvements in arterial and endothelial function. Fish oil supplements have few side effects, with GI symptoms being the most common (nausea, GI upset, halitosis, oily stool). There have been case reports of increased bleeding in patients taking anticoagulant or antiplatelet medications with fish oil; however, controlled studies have not found that fish oil supplement ingestion increases INR in patients taking warfarin until total EPA and DHA dose exceeds 3 g/day. Fish oil supplements are widely available over the counter and should be dosed based on their content of EPA and DHA.
1. Coronary Heart Disease
Historically, evidence from multiple large-scale observational studies and RCTs suggested that intake of fish, particularly fatty fish such as herring, anchovy, mackerel, and salmon, or ingestion of fish oil supplements containing the omega-3 fatty acids EPA and DHA, had benefit in primary and secondary prevention of CHD. One of the most impressive secondary prevention studies was the 1999 GISSI-Prevenzione study, which showed a large reduction in sudden cardiac death, total cardiovascular mortality, and overall mortality. However, more recent studies have suggested that may not be the case. The ASCEND study (with over 15,000 patients with diabetes randomized to receive either 1 g of omega-3 fatty acid or olive oil) found no significant differences between the groups in the risk of serious vascular events, including nonfatal MI, stroke, or death. In a 2019 updated meta-analysis of 127,477 participants, omega-3 supplementation was associated with significantly lower risk of MI (rate ratio [95% CI]: 0.92 [0.86-0.99]), death from CHD (rate ratio [95% CI]: 0.92 [0.86-0.98]), total CHD (rate ratio [95% CI]: 0.95- 0.99]), CVD death (rate ratio [95% CI]: 0.93 [0.88-0.99]), and total CVD (rate ratio [95% CI]: 0.97 [0.94-0.99]). These associations were even stronger with inclusion of the REDUCE-IT trial. Of note, larger doses of omega-3 supplementation were associated with greater effects, with most studies using doses between 1–2 g. The American Heart Association (AHA) does not recommend omega-3 fatty acids for primary prevention of CVD in high-risk patients or in primary prevention of stroke. The AHA states treatment is reasonable for secondary prevention of CHD and sudden cardiac death among patients with prevalent CHD.
A meta-analysis of 21 clinical trials has demonstrated the benefit of fish oil in reducing serum triglycerides with a linear dose-response relationship. Beneficial effects can be attained at doses as low as 2 g/day of omega-3 fatty acids. A dose of 4 g/day can lower triglyceride levels by 25–40%. A combination of a statin and fish oil appear to show added benefit on lipid profiles. A prescription formulation of fish oil is FDA approved for use in patients with hypertriglyceridemia. The 2019 REDUCE-IT trial examined over 8000 patients with hypertriglyceridemia on a statin who were randomly assigned to receive 2 g twice daily of a purified EPA. Patients who received this formulation had significant decreases in the risk of ischemic events at 5 years, including cardiovascular death. The 2020 STRENGTH trial of over 13,000 patients with high cardiovascular risk and hypertriglyceridemia examined a different formulation of 4 g of EPA and DHA but found no reductions in major adverse cardiovascular events.
There are clinical and epidemiologic studies that have indicated that fish oil is beneficial for patients with heart failure (HF). The GISSI-HF (Heart Failure) study was a large (n=6975) double-blind RCT investigating the effect of low-dose fish oil supplementation on patients with HF. Results showed that the treatment was well-tolerated and associated with a significant reduction of all-cause mortality and hospitalization due to cardiovascular causes. Four other RCTs have reported that fish oil supplementation in patients with HF increases LV end-diastolic volume, lowers serum BNP, reduces tumor necrosis factor, helps prevent cardiac cachexia, and improves endothelium-dependent vasodilation. A single RCT of 103 patients with nonischemic dilated cardiomyopathy similarly showed increased LV function. A UK study concluded that omega-3 fatty acid supplementation is cost-effective in patients with HF. AHA guidelines indicate that treatment with omega-3 fatty acids is reasonable for the secondary prevention of outcomes in patients with HF.
Studies of the effects of omega-3 supplementation on atrial fibrillation (chronic, post-coronary artery bypass grafting, postcardioversion) have yielded mixed results. A 2021 systematic review and meta-analysis of 81,210 patients from seven trials found that omega-3 supplementation was associated with an increased risk of atrial fibrillation. The risk appeared to be greater in trials testing doses higher than 1 g/day. The AHA does not recommend omega-3 supplementation for secondary prevention of atrial fibrillation in patients with prior atrial fibrillation or for prevention of atrial fibrillation after cardiac surgery.
Three different meta-analyses, the largest of which included 36 RCTs, and a systematic review concluded that fish oil supplementation, especially at higher doses, significantly lowers blood pressure by a small amount (systolic blood pressure by 3–6 mm Hg and diastolic blood pressure by 2–4 mm Hg). Another RCT showed fish oil ingestion augmented the blood pressure benefit achieved through weight loss.
Omega-3 supplementation has shown possible benefit in the treatment of rheumatoid arthritis. Results from small RCTs have shown significantly shorter time to remission and less risk of failure of disease-modifying antirheumatic drug therapy in individuals given omega-3 supplementation. A 2021 systematic review suggested there are beneficial effects of omega-3 fatty acids on rheumatoid arthritis disease activity, but longer, well-designed studies are needed.
The VITAL study group conducted a prospective randomized controlled study of over 25,000 participants assigned to receive 1 g of omega-3 fatty acids daily versus placebo. At a median follow-up of 5 years, supplementation did not result in a lower incidence of cancer or major cardiovascular events.
Double-blind RCTs involving pregnant women have found that omega-3 supplementation may be associated with fewer adverse outcomes, including spontaneous preterm delivery and low birth weight. In the KUDOS study, pregnant women received either 600 mg/day of DHA or a placebo beginning at 14.5 weeks' gestation and continued until delivery. Although this study found initial decreases in early preterm birth and improved visual attention in infancy, the7-year follow-up study period found no long-term benefits into childhood. In a 2019 study, supplementation with 900 mg omega-3 fatty acids from early pregnancy (less than 20 weeks of gestation) did not result in a lower incidence of early preterm delivery or a higher incidence of interventions in post-term deliveries. A 2021 meta-analysis and systematic review found that omega-3 supplementation during pregnancy did not reduce the risk of preterm birth. Although these studies seem to highlight the importance of adequate omega-3 intake in the gestational period, the benefits of supplementation are unclear. Future long-term studies are needed.
Individuals with psychosis treated with omega-3 fatty acids have been found to require less antipsychotic medication and have better overall outcomes. The NEURAPRO study of 304 patients who were deemed at high risk for psychotic disorders found no differences in psychotic conversion after 12 months of omega-3 fatty acid treatment—leading to the conclusion that omega-3 fatty acids do not offer additional benefit when other evidence-based treatments are provided.
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