Fish oil may be consumed by eating fish, ingesting a direct extract, or taking a concentrate form as a capsule. 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 (Fish oil may be consumed by eating fish, ingesting a direct extract, or taking a concentrate form as a capsule. 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 nonfish dietary sources of omega-3 fatty acids are walnuts and flaxseed oil.). Western diets typically are low in omega-3 fatty acids. Other nonfish dietary sources of omega-3 fatty acids are walnuts and flaxseed oil.
Claims for Fish OilClaims for Fish Oil
Fish oil is used for prevention and treatment of 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. , 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 for Fish OilEvidence for Fish Oil
The evidence supporting the use of fish oil, specifically in the form of EPA/DHA (EPA plus DHA in various combinations) to reduce cardiovascular outcomes (eg, myocardial infarction, stroke) has been mixed. However, there appears to be more consistent data that EPA/DHA can reduce serum triglycerides (The evidence supporting the use of fish oil, specifically in the form of EPA/DHA (EPA plus DHA in various combinations) to reduce cardiovascular outcomes (eg, myocardial infarction, stroke) has been mixed. However, there appears to be more consistent data that EPA/DHA can reduce serum triglycerides (2).
While there had been some previous evidence that suggested that 800 to 1500 mg/day reduced risk of myocardial infarction and death due to arrhythmia in patients who have preexisting coronary artery disease and are taking conventional drugs (3), subsequent studies have not consistently supported these findings. For example, the OMEMI trial (Omega-3 Fatty acids in Elderly with Myocardial Infarction) was a randomized 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 (4).
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. In addition, a Cochrane review of 86 randomized trials (162,796 patients) 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 1 coronary event, and 334 participants needed treatment to prevent 1 death due to coronary artery disease (2). 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 (). 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 (5).
Another subsequent meta-analysis of 15 randomized trials evaluated not only efficacy but safety of different omega-3 fatty acid supplements (including prescription products), for cardiovascular disease prevention (6). Significant findings were a 5% decrease in major cardiovascular events, a 10% decrease in myocardial infarction, and a 6% decrease in cardiovascular death. Subgroup analysis indicated cardiovascular benefit was primarily due to prescription eicosapentanoic acid (EPA) ethyl ester. There appeared to be a 25% increased risk of atrial fibrillation as well as an increased risk of stroke in patients with prior myocardial infarction. Other adverse events, such as bleeding, cancer, or gastrointestinal problems, were not found.
A large prospective cohort study including 20,338 patients with type 2 diabetes reported that fish oil supplementation and higher plasma omega-3 polyunsaturated fatty acid (n-3 PUFA) levels were associated with lower risks of macrovascular (coronary heart disease, heart failure, peripheral artery disease, and stroke) and microvascular (diabetic kidney disease, diabetic retinopathy, and diabetic neuropathy) complications (A large prospective cohort study including 20,338 patients with type 2 diabetes reported that fish oil supplementation and higher plasma omega-3 polyunsaturated fatty acid (n-3 PUFA) levels were associated with lower risks of macrovascular (coronary heart disease, heart failure, peripheral artery disease, and stroke) and microvascular (diabetic kidney disease, diabetic retinopathy, and diabetic neuropathy) complications (7).
The potential benefit of fish oil (omega 3 fatty acids) supplements for The potential benefit of fish oil (omega 3 fatty acids) supplements formetabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease), has also been evaluated. A meta-analysis of 22 randomized trials including 1366 patient found that omega-3 fatty acid supplementation decreased liver fat (as measured by ultrasound) and lipid profiles as well as body mass index (8). Further research is needed, particularly with randomized trials, to better evaluate dose-response effects for omega 3 fatty acids and additional assessment of liver fat with other methods (eg, histology, MRI, CT scan).
Adverse Effects of Fish OilAdverse Effects of Fish Oil
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) (4).
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 (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 (5).
The American College of Cardiology and other professional societies have commented on the limitations of using nonprescription fish oil supplements and advises that only FDA-approved prescription products be used for hypertriglyceridemia (The American College of Cardiology and other professional societies have commented on the limitations of using nonprescription fish oil supplements and advises that only FDA-approved prescription products be used for hypertriglyceridemia (9).
The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMEA) has issued a public statement warning about the dose-dependent increased risk of atrial fibrillation in those with cardiovascular disease or cardiovascular disease risk factors (10). A daily dose exceeding 4 grams of omega-3-acid ethyl esters was associated with an increased risk.
Drug Interactions with Fish OilDrug Interactions with Fish Oil
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 (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 (11). 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. 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
3. 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.
4. 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
5. 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
6. Yan J, Liu M, Yang D, Zhang Y, An F. Efficacy and Safety of Omega-3 Fatty Acids in the Prevention of Cardiovascular Disease: A Systematic Review and Meta-analysis. Cardiovasc Drugs Ther. 2024 Aug;38(4):799-817. doi: 10.1007/s10557-022-07379-z
7. Tian S, Guo T, Qian F, Qiu Z, Lu Q, Li R, Zhu K, Li L, Yu H, Li R, Ou Y, Pan A, Liu G. Fish Oil, Plasma n-3 PUFAs, and Risk of Macro- and Microvascular Complications among Individuals with Type 2 Diabetes. . Fish Oil, Plasma n-3 PUFAs, and Risk of Macro- and Microvascular Complications among Individuals with Type 2 Diabetes.J Clin Endocrinol Metab. 2024 Jul 12:dgae482. doi: 10.1210/clinem/dgae482
8. Lee CH, Fu Y, Yang SJ, Chi CC. Effects of Omega-3 Polyunsaturated Fatty Acid Supplementation on Non-Alcoholic Fatty Liver: A Systematic Review and Meta-Analysis. Nutrients. 2020 Sep 11;12(9):2769. doi: 10.312092769
9. Virani SS, Morris PB, Agarwala A, et al. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021;78(9):960-993. doi:10.1016/j.jacc.2021.06.011
10. Medicines and Healthcare Products Regulatory Agency. Omega-3-acid ethyl ester medicines (Omacor/Teromeg 1000 mg capsules): dose-dependent increased risk of atrial fibrillation in patients with established cardiovascular diseases or cardiovascular risk factors. Accessed February 27, 2025.
11. 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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