A quick web search would suggest countless reasons to take fish oil, a supplement that Americans have fallen in love with. In 2012, fish oil, which is composed of two omega-3 fatty acids–eicosapentaenoic acid (EPA) and docasahexaenoic acid (DHA)—was the natural product most commonly used by US adults, with nearly 20 million Americans taking the supplement.1 The potential health benefit of fish oil was first postulated in the 1970s by Danish scientists visiting an Inuit village in Greenland. The scientists discovered that the villagers, who ate a diet rich in omega-3 fatty acids, had lower levels of cholesterol and triglycerides compared to the Danish population. Early scientific studies went on to further support the idea that fish oils have a cardiovascular benefit. The popularity of fish oil was further strengthened in 2002, when the American Heart Association (AHA) issued a scientific statement concluding that “omega-3 fatty acids have been shown in epidemiological and clinical trials to reduce the incidence of cardiovascular disease,” despite mixed evidence. Fish oil sales grew sharply, with the percentage of Americans taking the supplement rising from 4.8% in 2002 to 7.8% in 2012.1 Today, fish oil companies continue to endorse an array of putative benefits from fish oil supplements, with fish oil company Nordic Naturals stating that the benefits of fish oil “go far beyond the heart” and fish oil company Dr. Tobias suggesting that it can be used to benefit patients with a whole host of diseases, including heart disease, dementia, Alzheimer’s, arthritis, symptoms of asthma, pneumonia, depression, suicide, wrinkles, acne, and psoriasis.2
Yet while fish oil is loyally embraced by many of our patients, advertised aggressively by fish oil companies, and promoted enthusiastically by the media, most of its purported health benefits have not been substantiated by scientific evidence. In fact, the only FDA-approved indication for omega-3 fatty acids is to lower triglycerides in patients with hypertriglyceridemia.3 One alleged use for fish oil has been hotly debated and explored in a variety of observational studies, animal studies, and randomized control trials: does supplementation with omega-3 fatty acids prevent cardiovascular events? Let’s review the evidence.
Much of the fanfare around this supplement has emerged from early animal experiments and small randomized controlled trials suggesting that fish oil can reduce various risk factors associated with cardiovascular disease, including systolic and diastolic blood pressure4 and resting heart rate,5 with animal studies suggesting that omega-3 fatty acids could be acting directly on cardiac electrophysiological pathways.6 One study showed that consumption of omega-3 fatty acids improved cardiac filling and myocardial efficiency in marmoset monkeys,7 and short-term experimental trials showed that consumption of omega-3 fatty acids improved left ventricular diastolic filling in healthy adults and patients with congestive heart failure.8,9 Other proposed mechanisms of the putative cardioprotective effects of omega-3 fatty acids involve improvement of endothelial function, alteration of inflammatory pathways, and decreased risk of arrhythmias.10 The real question, however, is whether modification of cardiac risk factors observed in these studies translates to a demonstrable decrease in cardiovascular events in randomized control trials.
Two early clinical trials, the GISSI-Prevenzione Trial (1999), which studied patients surviving myocardial infarction, and the JELIS Trial (2007), which studied patients with hypercholesterolemia, showed that supplementation with omega-3 fatty acids resulted in significant protection from coronary events.11,12 In 2008, the GISSI-HF trial was published, demonstrating a small mortality benefit for patients with chronic heart failure.13 However, five subsequent trials found that there was no cardioprotective benefit with omega-3 fatty acid supplementation in patients who survived myocardial infarction, had major cardiovascular risk factors, or had dysglycemia.14-18 In the past few months, three new trials have published findings on the use of omega-3 fatty acids for the prevention of cardiovascular events. The ASCEND trial, published in October 2018, studied the use of omega-3 fatty acid supplementation (1 g daily) in 15,480 patients with diabetes mellitus, with a primary composite outcome of serious vascular event or revascularization. The researchers found no differences in the primary composite outcome or in nonfatal myocardial infarction rate between the control and treatment group, in line with previous results.19
More recently, the VITAL trial, published in January 2019, studied the use of omega-3 fatty acids for the primary prevention of cardiovascular disease and cancer in 25,871 healthy participants, including 5106 black participants. The study enrolled men older than 50 and women older than 55 and followed the participants for a median of 5.3 years. In line with the findings of the ASCEND trial, supplementation with 1 g of fish oil daily did not significantly change the primary composite endpoint (major adverse cardiovascular events) in the experimental group compared to the control group. However, exploratory analysis of secondary endpoints did show a decreased rate of myocardial infarction in the omega-3 fatty acid group compared to the control group (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.59 to 0.90), especially for African Americans (HR 0.23; 95% CI 0.11 to 0.47). Another notable finding of the VITAL trial was a modest improvement in the primary composite outcome in the omega-3 fatty acid treatment arm for participants who ate less than a median of 1.5 servings of fish per week (HR 0.86; 95% CI 0.67 to 0.98). In comparison, participants who ate more than a median of 1.5 servings of fish per week (HR 1.08; 95% CI 0.88 to 1.32) did not benefit from the treatment. As the authors noted, this finding is hypothesis-generating and merits further study.20
The US Department of Agriculture recommends eating at least 8 ounces of seafood per week on a 2000-calorie diet,21 based on various studies that have suggested fish consumption is associated with decreased rates of CHD, non-fatal myocardial infarction, and stroke.22 It’s possible that participants who consume 1.5 servings of fish per week do not benefit from additional fish oil supplementation, as they already receive the cardioprotective effects from direct consumption of fish, while participants who do not regularly consume fish stand to benefit from supplementation with fish oil.
The exploratory analysis conducted by the VITAL trial needs to be interpreted with caution, as the authors did not control for multiple hypothesis testing and made no formal adjustments to confidence intervals or p-values.20 Furthermore, the benefits of fish oil found in exploratory analysis were modest. For example, the absolute risk reduction in myocardial infarction between the experimental and control group was only 0.42% for all patients and 0.47% for black patients. The absolute risk reduction in the primary outcome for participants who have lower fish intake taking fish oil compared to the placebo could not be calculated because the study did not publish the full breakdown of subjects. Still, the results of this trial suggest that supplementation of omega-3 fatty acids could have some benefit in certain circumstances. These hypotheses could be worth exploring in future randomized control trials.
Finally, another recent study, the REDUCE-IT trial, was published in January 2019, with results markedly different from its contemporaries. The trial studied the use of omega-3 fatty acid supplements (2 g twice a day) in 8179 participants with either established cardiovascular disease or with diabetes and at least one other cardiac risk factor who had been receiving statin therapy and had a fasting triglyceride level between 135 and 499 mg/dL. The primary composite outcome consisted of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The study showed a significant improvement in primary outcome in participants who took the omega-3 fatty acid supplements compared to participants who did not (HR 0.75, 95% CI 0.68-0.83). Furthermore, the fish oil group had an improvement in various prespecified secondary end points, including a composite of cardiovascular death or nonfatal myocardial infraction, fatal or nonfatal myocardial infraction, emergency or urgent revascularization, cardiovascular death, hospitalization for unstable angina, and fatal or nonfatal stroke.23
It is important to note that the REDUCE-IT trial used a far higher dose of omega-3 fatty acids, 4 g daily, compared to the ASCEND and VITAL trials, which both used 1 g daily. Another difference between ASCEND/VITAL and REDUCE-IT is that the REDUCE-IT trial used pure EPA while ASCEND and VITAL used a tablet containing a mix of DHA/EPA.20,23,24 Dosage and DHA/EPA ratio may affect the efficacy of fish oil in preventing cardiovascular disease. Finally, the ASCEND and VITAL studies looked at a diabetic and a healthy population irrespective of statin use. In contrast, the REDUCE-IT trial studied patients with known cardiovascular risk factors or established cardiovascular disease who had high triglycerides despite statin use. Thus, the positive findings of the REDUCE-IT trial further support the notion that fish oil could be useful in select groups of patients, rather than the general population.
In summary, most of the published clinical trials do not show a demonstrable reduction in cardiovascular events associated with taking fish oil, and the newly published ASCEND and VITAL trials are in line with these findings. However, fish oil could still be beneficial for select groups of patients, especially those who do not eat fish, as suggested by the VITAL study, and those with known cardiovascular disease or risk factors who have statin-resistant high triglycerides, as suggested by the REDUCE-IT trial. In fact, the AHA continues to endorse the use of fish supplements for patients with coronary heart disease, stating that “even a potential modest reduction in CHD mortality in this clinical population would justify treatment with a relatively safe therapy.”25 Regardless, more research is certainly merited to iron out the discrepancies in these aforementioned studies. Until then, if you’re not a huge fan of weekly salmon, a bit of fish oil might not hurt.
Lily Cao is a medical student at NYU School of Medicine
Reviewed by Dr. Michael Tanner, MD, associate editor, Clinical Correlations
Image courtesy of Wikimedia Commons
- Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. Trends in the use of complementary health approaches among adults: United States, 2002-2012. Natl Health Stat Report. 2015;(78):1-19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573565/.
- Whoriskey P. Fish oil pills: A $1.2 billion industry built, so far, on empty promises Washington Post. July 8, 2015. https://www.washingtonpost.com/business/economy/claims-that-fish-oil-boosts-health-linger-despite-science-saying-the-opposite/2015/07/08/db7567d2-1848-11e5-bd7f-4611a60dd8e5_story.html.
- Tajuddin N, Shaikh A, Hassan A. Prescription of omega-3 fatty acid products: considerations for patients with diabetes mellitus. Diabetes Metab Syndr Obes. 2016;9:109-118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846047/.
- Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens. 2002;20(8):1493-1499. https://www.ncbi.nlm.nih.gov/pubmed/12172309.
- Mozaffarian D, Geelen A, Brouwer IA, Geleijnse JM, Zock PL, Katan MB. Effect of fish oil on heart rate in humans: a meta-analysis of randomized controlled trials. Circulation. 2005;112(13):1945-1952. https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.105.556886?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed.
- McLennan PL. Myocardial membrane fatty acids and the antiarrhythmic actions of dietary fish oil in animal models. Lipids. 2001;36 Suppl:S111-114. https://www.ncbi.nlm.nih.gov/pubmed/11837983.
- McLennan PL, Barnden LR, Bridle TM, Abeywardena MY, Charnock JS. Dietary fat modulation of left ventricular ejection fraction in the marmoset due to enhanced filling. Cardiovasc Res. 1992;26(9):871-877. https://www.ncbi.nlm.nih.gov/pubmed/1451164.
- Ghio S, Scelsi L, Latini R, et al. Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left ventricular function in chronic heart failure: a substudy of GISSI-HF trial. Eur J Heart Fail. 2010;12(12):1345-1353. https://www.ncbi.nlm.nih.gov/pubmed/20952767.
- Grimsgaard S, Bonaa KH, Hansen JB, Myhre ES. Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemodynamics in humans. Am J Clin Nutr. 1998;68(1):52-59. https://www.ncbi.nlm.nih.gov/pubmed/9665096.
- Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58(20):2047-2067. https://www.ncbi.nlm.nih.gov/pubmed/22051327.
- Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369(9567):1090-1098. https://www.ncbi.nlm.nih.gov/pubmed/17398308.
- Hopper L, Ness A, Higgins JP, Moore T, Ebrahim S. GISSI-Prevenzione trial. Lancet. 1999;354(9189):1557. https://www.ncbi.nlm.nih.gov/pubmed/10551523.
- Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1223-1230. https://www.ncbi.nlm.nih.gov/pubmed/18757090.
- Kromhout D, Giltay EJ, Geleijnse JM. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363(21):2015-2026. https://www.ncbi.nlm.nih.gov/pubmed/20929341.
- Rauch B, Schiele R, Schneider S, et al. OMEGA, a 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. Circulation. 2010;122(21):2152-2159. https://www.ncbi.nlm.nih.gov/pubmed/21060071.
- Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg S; SU.FOL.OM3 Collaborative Group. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. BMJ. 2010;341:c6273. https://www.bmj.com/content/bmj/341/bmj.c6273.full.pdf.
- ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367(4):309-318. https://www.nejm.org/doi/full/10.1056/NEJMoa1203859.
- Risk and Prevention Study Collaborative Group. Roncaglioni MC, Tombesi M, Avanzini F, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19):1800-1808. https://www.nejm.org/doi/full/10.1056/NEJMoa1205409.
- ASCEND Study Collaborative Group. Bowman L, Mafham M, Wallendszus K, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540-1550. https://www.nejm.org/doi/full/10.1056/NEJMoa1804989.
- Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380(1):23-32. https://www.nejm.org/doi/full/10.1056/NEJMoa1811403.
- U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020 Dietary Guidelines for Americans. 8th Edition. December 2015. http://health.gov/dietaryguidelines/2015/guidelines/.
- Mozaffarian D, Appel LJ, Van Horn L. Components of a cardioprotective diet: new insights. Circulation. 2011;123(24):2870-2891. https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.110.968735.
- Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. https://www.nejm.org/doi/full/10.1056/NEJMoa1812792.
- Bowman L, Mafham M, Stevens W, et al. ASCEND: A Study of Cardiovascular Events iN Diabetes: Characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144.
- Siscovick DS, Barringer TA, Fretts AM, et al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease. Circulation. 2017;135(15):e867-e884. https://www.ahajournals.org/doi/abs/10.1161/CIR.0000000000000482