Fish oil may be consumed by eating fish, extracted directly, or concentrated and put in capsule form. Active ingredients are omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]). Recently, genetically engineered yeast strains that can naturally produce substantial amounts of these oils have been engineered and are providing another source (1). Western diets typically are low in omega-3 fatty acids. (Other non-fish dietary sources of omega-3 fatty acids are walnuts and flaxseed oil.)
(See also Overview of Dietary Supplements and National Institutes of Health (NIH): Omega-3 fatty acids fact sheet for health professionals.)
Claims
Fish oil is used for prevention and treatment ofatherosclerotic cardiovascular disease, specifically by lowering triglyceride levels. Mechanisms are probably multiple but unknown. Benefits are suspected, but not yet supported, for primary prevention of atherosclerotic cardiovascular disease, lowering of cholesterol levels, slowing the progression of age-related macular degeneration and cancer, treatment of rheumatoid arthritis, dry eyes, and depression, lowering blood pressure, and prevention of cyclosporine nephrotoxicity.
Evidence
Previously, evidence indicated that EPA/DHA (EPA plus DHA in various combinations) 800 to 1500 mg/day reduces risk of myocardial infarction and death due to arrhythmia in patients who have preexisting coronary artery disease and are taking conventional drugs (2). EPA/DHA also reduces triglycerides.
The 2021 OMEMI trial (Omega-3 Fatty acids in Elderly with Myocardial Infarction) was a randomized clinical trial in which 1027 patients aged 70 to 82 years with recent (2 to 8 weeks) acute myocardial infarction were treated with 1.8 g of n-3 polyunsaturated fatty acids (PUFA) (930 mg eicosapentaenoic acid and 660 mg docosahexaenoic acid) or placebo (corn oil) daily in addition to standard of care. The primary endpoint was a composite of nonfatal acute myocardial infarction, unscheduled revascularization, stroke, all-cause death, and heart failure hospitalization after 2 years. The primary endpoint occurred in 21.4% patients on n-3 PUFA versus 20.0% on placebo (P=0.60). The authors concluded that the study did not detect a reduction in clinical events in older patients with recent acute myocardial infarction (3).
A 2016 review verified strong evidence for a dose-dependent triglyceride-lowering effect. However there was moderate-strength quality evidence for decreased risk of cardiovascular death and major adverse cardiovascular events, and low-strength quality evidence that higher doses are associated with lower risk of coronary artery disease and heart failure. There was no blood pressure–lowering effect (4).
The 2020 Cochrane review of 86 randomized controlled trials (162,796 subjects) of 12 to 88 months duration confirmed that omega-3 fatty acids decrease triglycerides and, per high-certainty evidence, have little effect on cardiovascular events and death. The review found slightly decreased cardiovascular mortality but no difference in the number of strokes or arrhythmias. The review noted that 167 participants needed treatment to prevent one coronary event, and 334 participants needed treatment to prevent one death due to coronary artery disease (5). However, the REDUCE-IT trial, which enrolled patients with established cardiovascular disease or with diabetes and other risk factors plus elevated triglyceride levels despite statin treatment, reported a significant reduction in MACE (major adverse cardiac events) using the prescription pharmacologic agent icosapent ethyl (6).
The 2019 American Heart Association science advisory has commented about the limitations of using nonprescription fish oil supplements and advises that only FDA-approved prescription products be used for hypertriglyceridemia (7).
Adverse Effects
Fishy eructation, nausea, and diarrhea may occur. Risk of bleeding increases with EPA/DHA > 3 g a day. In a large study, major bleeding rates were similar (10.7%) in the n-3 PUFA group to the patients treated with placebo (11.0%, p = 0.87) (3).
Concerns about mercury contamination are not substantiated in laboratory testing. Even so, pregnant or breastfeeding women should not take omega-3 fatty acid supplements extracted from fish and should limit consumption of certain types and amounts of fish because of the potential risk of mercury contamination.
In a large study of patients treated with icosapent ethyl, constipation, peripheral edema, and atrial fibrillation occurred more commonly than in patients treated with placebo (6).
Drug Interactions
Fish oil combined with antihypertensives may result in additive blood pressure lowering. Fish oil ingestion may increase the anticoagulant effect of warfarin, although some studies have not shown adverse bleeding events (8). Nevertheless, patients should be cautioned about the possibility of increased bleeding.
References
1. Xue Z, Sharpe PL, Hong SP, et al: Production of omega-3 eicosapentaenoic acid by metabolic engineering of Yarrowia lipolytica. Nat Biotechnol 31(8):734-740, 2013. doi: 10.1038/nbt.2622
2. MacLean CH, Mojica WA, Morton SC, et al: Effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis. Evid Rep Technol Assess (Summ) 2004;(89):1-4.
3. Kalstad AA, Myhre PL, Laake K, et al: Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 143(6):528-539, 2021. doi:10.1161/CIRCULATIONAHA.120.052209
4. Balk EM, Adams GP, Langberg V, et al: Omega-3 fatty acids and cardiovascular disease: an updated systematic review. Evid Rep Technol Assess (Full Rep) (223):1-1252, 2016. doi:10.23970/AHRQEPCERTA223
5. Abdelhamid AS, Brown TJ, Brainard JS, et al: Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease (review). Cochrane Database Syst Rev 3:CD003177, 2020. doi: 10.1002/14651858.CD003177.pub5
6. Bhatt DL, Steg PG, Miller M, et al: Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 380(1):11-22, 2019. doi: 10.1056/NEJMoa1812792
7. Skulas-Ray A, Wilson PWF, Harris WS, et al: Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation 140(12):e673-e691, 2019. doi: 10.1161/CIR.0000000000000709
8. Pryce R, Bernaitis N, Davey AK, et al: The use of fish oil with warfarin does not significantly affect either the International Normalized Ratio or incidence of adverse events in patients with atrial fibrillation and deep vein thrombosis: a retrospective study. Nutrients 8(9):578, 2016. doi:10.3390/nu8090578
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