Interest in fish oil began more than 40 years ago, when it was learned that the Inuit population of Greenland had low rates of coronary heart disease (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), in the fish that the Inuit consumed. Multiple mechanisms likely explain the beneficial effects of omega-3 fatty acids for both primary and secondary prevention of cardiac disease, 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 gastrointestinal symptoms being the most common (nausea, gastrointestinal upset, halitosis, oily stool). There have been case reports of increased bleeding in patients taking anticoagulant or antiplatelet medications with fish oil; however, controlled research examining the effect of fish oil supplement ingestion on the INR in patients taking warfarin has not demonstrated this risk 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 randomized controlled trials 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. Omega-3 fatty acid supplementation did not have any significant association with fatal or nonfatal CHD or vascular events in a 2018 meta-analysis. 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 myocardial infarction, stroke, or death. The American Heart Association (AHA) has recommended the following regarding treatment with omega-3 fatty acids: no treatment in primary prevention for patients with diabetes or who have high risk of cardiovascular disease or in primary prevention of stroke; treatment is reasonable for secondary prevention of CHD and sudden cardiac death among patients with prevalent CHD.
Many clinical trials have demonstrated the benefit of fish oil in reducing serum triglycerides, and a meta-analysis of 21 trials concluded the same. Most analyses also agree there is 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%. There are trials that also examine the combination of a statin and fish oil, which 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. This study found that patients who received this formulation had significant decreases in the risk of ischemic events, including cardiovascular death, at 5 years. 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. The GISSI-HF (Heart Failure) study was a very large (n = 6975) randomized, double-blind, placebo-controlled trial investigating the effect of low-dose fish oil supplementation on patients with heart failure. Results showed that the treatment was well tolerated, and there was a significant reduction of all-cause mortality and hospitalization due to cardiovascular causes in the experimental group. Four other randomized, controlled clinical trials have reported that fish oil supplementation in heart failure patients increases left ventricular end-diastolic volume, lowers serum B-type natriuretic peptide (BNP), reduces tumor necrosis factor (TNF), helps prevent cardiac cachexia, and improves endothelium-dependent vasodilation. A single randomized controlled trial of 103 patients with nonischemic dilated cardiomyopathy similarly showed increased left ventricular function. A UK study concluded that omega-3 fatty acid supplementation is cost-effective in patients with heart failure. The AHA guidelines indicate that treatment with omega-3 fatty acids is reasonable for the secondary prevention of outcomes in patients with heart failure.
Studies of the effects of omega-3 supplementation on atrial fibrillation (chronic, post-coronary artery bypass grafting [CABG], post-cardioversion) have generally yielded negative results. A 2013 meta-analysis of studies examining use of fish oil to prevent postoperative atrial fibrillation concluded strongly that there was no benefit. A 2014 study looking at high-dose fish oil in patients with a history of atrial fibrillation not receiving conventional antiarrhythmic therapy did not find reduced atrial fibrillation recurrence. A 2015 study found that preoperative administration of omega-3 fatty acids in patients who were undergoing an isolated CABG for a myocardial infarction within 3 months found a significant relative risk decrease in the incidence of atrial fibrillation postoperatively, but a 2017 trial of post-cardiothoracic surgery patients found no benefit. The AHA has indicated that treatment is not recommended for secondary prevention of atrial fibrillation in patients with prior atrial fibrillation; treatment is not indicated for prevention of atrial fibrillation after cardiac surgery.
Three different meta-analyses, the largest of which included 36 randomized trials, 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). An additional randomized trial showed fish oil ingestion augmented the blood pressure benefit achieved through weight loss.
A 2015 study assessed 140 patients in whom rheumatoid arthritis was diagnosed within the past 12 months who had not been given disease-modifying antirheumatic drugs (DMARDs). Patients were randomized 2:1 to receive high-dose fish oil (5.5 g of EPA+DHA daily) or low-dose fish oil (400 mg EPA+DHA daily) in addition to triple DMARD therapy with methotrexate, hydroxychloroquine, and sulfasalazine. Results showed significantly shorter time to remission and less failure of the DMARD therapy in the high-dose fish oil group. Another 2015 double-blind, randomized, placebo-controlled study of 60 patients with rheumatoid arthritis showed similarly significant symptomatic improvement, both as reported by patients and as assessed by physicians, as well as significantly reduced analgesic use, after 12 weeks of fish oil supplementation. While there are small low-quality trials, a 2018 meta-analysis suggested that there are beneficial effects of omega-3 fatty acids on rheumatoid arthritis disease activity.
A multicenter, double-blind, randomized controlled trial of over 500 patients with dry eye disease found no benefit at 12 months in those randomly assigned to receive 3 g of omega-3 fatty acids compared to those assigned placebo.
The VITAL study group conducted a prospective randomized controlled study of more than 25,000 participants assigned to receive 1 g of omega-3 fatty acids daily versus placebo. At a median follow-up of 5 years, the supplementation did not result in a lower incidence of major cardiovascular events or cancer.
A 2017 prospective, randomized, double-blind, placebo-controlled study with 567 patients found that the high-dose supplementation of fish oil did not result in reductions in arteriovenous fistula failure in patients with end-stage renal disease.
In a 2016 prospective randomized study of over 700 pregnant women, supplementation with 2.4 g of omega-3 fatty acid in the third trimester resulted in a reduction of persistent wheeze or asthma at 5 years in the offspring. A 2017 prospective, randomized, double-blind, placebo-controlled study with 851 pregnant patients found that omega-3 supplementation was associated with fewer adverse outcomes (spontaneous preterm delivery and low birth weight) among smokers, suggesting a protective effect. In the KUDOS study, mothers received either 600 mg/day of DHA or a placebo beginning at 14.5 weeks of gestation and capsules were provided until delivery. This study initially found significant decreases in early preterm birth and improved visual attention in infancy. However, in the 7-year follow-up study period, no consistent long-term benefits were observed 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. These studies seem to highlight the importance of adequate omega-3 intake in the gestational period, although its benefits still 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, published in 2017, examined this question further among 304 patients with ultrahigh risk for psychotic disorders. There were no differences observed in conversion to psychosis at 12 months—with the conclusion being that omega-3 fatty acids do not offer any additional benefit when other good-quality evidence-based treatments are offered.
ASCEND Study Collaborative Group; Bowman
et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379:1540.
et al; Omega-3 Treatment Trialists' Collaboration. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77 917 individuals. JAMA Cardiol. 2018;3:225.
et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11.
et al. The Kansas University DHA Outcomes Study (KUDOS) clinical trial: long-term behavioral follow-up of the effects of prenatal DHA supplementation. Am J Clin Nutr. 2019;109:1380.
Dry Eye Assessment and Management Study Research Group; Asbell
et al. n-3 Fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378:1681.
et al. Intake of ω-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: a systematic review and meta-analysis. Nutrition. 2018;45:114.
et al. A randomized trial of prenatal n-3 fatty acid supplementation and preterm delivery. N Engl J Med. 2019;381:1035.
et al; VITAL Research Group. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380:23.