While preparing my Grand Rounds presentation on Omega-3 fatty acids and cardiovascular disease risk I reviewed in detail three recent large randomized trials which showed no benefit of fish oil supplements on cardiovascular outcomes.
These trials confirmed multiple other randomized studies in the last 20 years which have failed to show any benefit from supplementing with over-the-counter fish oil pills thus I stuck with what had I first advised in 2013:
“there is no evidence that taking over-the-counter fish oil supplements or consuming functional foods supplemented with Omega-3 fatty acids reduces your risk of cardiovascular disease”
In the past, when patients asked “are there any side effects” of taking omega-3 fatty acids (OMFAs) I would say “no, but their production wreaks havoc on the marine ecosystem and you are wasting your money and driving a multi-billion industry that should not be.”
After reviewing these recent trials in detail, however, I have realized a health hazard has been identified in the treatment arms: high dose fish oil supplements increase the risk of atrial fibrillation (AF).
This is a remarkable change from what observational studies had suggested in this area. Low blood levels of OMFAs and Vitamin D have both been associated with a higher risk of atrial fibrillation. Thus, many have advocated taking these mostly useless supplements in high doses to prevent atrial fibrillation. Of course, association does not prove causation but generates hypotheses that should be tested by the gold standard of medical science, the randomized controlled trial (RCT).
The VITAL-Rhythm RCT published last month in JAMA found no effect of supplementation with OMFAs or Vitamin D on the incidence of atrial fibrillation (or cancer or CV outcomes). The patients randomized to OMFA supplementation received low dose EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA).
The vitamin D3 dose was designed to test the effect of high-dose supplementation on cancer and CVD in a primary prevention population, and the EPA-DHA dose was recommended by the American Heart Association for cardioprotection among high-risk individuals and was above the dose recommended from dietary intake for the general population. The placebo for vitamin D3 contained soybean oil, and the placebo for EPA-DHA contained olive oil.
However, 2 large RCTS using higher-dose formulations of OMFAs in patients with established cardiovascular disease found a significantly higher risk of AF in the treatment groups.
The REDUCE-IT trial randomized high CV risk individuals to 4 g/d of highly purified EPA ethyl ester (icosapent ethyl) and showed a significantly increased , 48% higher risk of hospitalization for AF compared with placebo (3.1% vs 2.1%; P = .004) over almost 5 years of follow-up. (Of note, the benefits on CV outcomes of the icosapent ethyl used in this trial have been questioned due to the use of mineral oil in the placebo arm, something I discuss in detail in my OMFA talk.)
The STRENGTH trial, randomized patients to 4 g/d of omega-3 carboxylic acid, a mixture of EPA and DHA, vs placebo over a median of 3.2 years of follow-up and found more AF developed in the active treatment arm (2.2% vs 1.3%; HR, 1.69; 95% CI,1.29-2.21; P < .001). (Of note, there was no evidence for any benefit of OMFAs in reducing CV outcomes in this trial which utilized corn oil in the placebo arm.)
A third trial, the OMEMI trial found no benefit on reducing CV outcomes from adding 1.8 g n-3 PUFA (930 mg eicosapentaenoic acid and 660 mg docosahexaenoic acid) versus placebo (corn oil) daily to standard of care in patients aged 70 to 82 years with recent (2–8 weeks) acute myocardial infarction. A nonsignificant increased risk of incident AF was found (HR, 1.84, p=.06).
The VITAL-rhythm authors concluded
Potentially, the adverse effect on AF risk may be dose related, and the higher dosages of EPA used in these other studies might account for the significant adverse effect on AF.
I agree with the conclusions of an accompanying editorial by Dr. Greg Curffman
Considered together, the data from the 4 trials suggest, but do not prove, that there may be a dose-related risk of AF with omega-3 fatty acid intake. At a dose of 4.0 g/d, there was a highly statistically significant increase in risk (nearly a doubling). With an intermediate dose of 1.8 g/d, the increase in risk (hazard ratio, 1.84) did not achieve statistical significance, and with a standard daily dose of 840 mg/d, there was no apparent increase in risk (although the data were consistent with as much as a 24% increase in risk). Patients who choose to take omega-3 fatty acids, especially in high doses, should be informed of the risk of AF and followed up for the possible development of this common and potentially hazardous arrhythmia.
A 2019 report on the global OTC OMFA supplement industry was quite enthusiastic despite the mass of scientific evidence showing no benefits to consumers, noting 4.1 billion in global sales and anticipating 8.5 billion by 2025.
This mindless consumption (my adjective), the report noted is moving beyond pills and into “functional foods”, driven by a perception of health and performance promotion.
Omega-3 increasingly finds application in dietary supplements, functional foods & beverages, pharmaceuticals, infant formula, and pet food and feed. Dietary supplements are estimated to account for the largest market due to the fast-paced and busy lifestyles; consumers prefer consuming dietary supplements to make sure that they get their optimal share of nutrients, and omega-3 supplements are used to improve the health and performance, wherein athletes are advised adequate intake of omega-3 fatty acids for fit and healthy body.
The OMFA is a huge, powerful industry intent on promoting the consumption of their useless products. In my OMFA talk I touch on what I term the “academic-industrial” complex which has resulted from physicians/scientists who are on the payroll of the fish oil industry and in some cases own, sell and shamelessly promote their own fish oil supplements. These physicians/scientists frequently publish biased analyses of the OMFA field, searching out value where there is none.
Rather than promoting or profiting from the sale of OMFAs, physicians should be actively deprescribing fish oil supplements, allowing patients to focus on taking pills which have been proven safe and beneficial.