Does Evidence Support Benefits of Omega-3 Fatty Acids?

Thomas Kron, MD

March 30, 2022

Dietary supplements that contain omega-3 fatty acids have been widely consumed for years. Researchers have been investigating the benefits of such preparations for cardiovascular, neurological, and psychological conditions. A recently published study on omega-3 fatty acids and depression inspired neurologist Hans-Christoph Diener, MD, PhD, of the Institute for Epidemiology at the University Duisburg-Essen, Germany, to examine scientific publications concerning omega-3 fatty acids or fish-oil capsules in more detail.

Prevention of Depression

Diener tells the story of how he stumbled upon an interesting article in Journal of the American Medical Association this past December. It was about a placebo-controlled study that investigated whether omega-3 fatty acids can prevent incident depression.

As the study authors reported, treatment with omega-3 preparations in adults aged 50 years or older without clinically relevant symptoms of depression at study initiation was associated with a small but statistically significant increase in the risk for depression or clinically relevant symptoms of depression. There was no difference in mood scale value, however, over a median follow-up of 5.3 years. According to the study authors, these results did not support the administration of omega-3 preparations for the prevention of depression.

This study was, as Diener has now reported, somewhat negative, but it did arouse his interest in questions such as what biological effects omega-3 fatty acids have and what is known "about this topic with regard to neurology," he said. When reviewing the literature, he noticed that there "were association studies, ie, studies that describe that the intake of omega-3 fatty acids may possibly be associated with a lower risk of certain diseases."

Beginning With the Inuit

It all started "with observations of the Inuit [population] in Greenland and Alaska after World War II, because it was remarked upon that these people ate a lot of fish and seal meat and had a very low incidence of cardiovascular diseases." Over the years, a large number of association studies have been published, which may have encouraged the assumption that omega-3 fatty acids have positive health effects on various conditions, such as the following:

Diener believes that the problem is that these are association studies. But association does not mean that there is a causal relationship.

Disappointing Study Results

On the contrary, the results from the randomized placebo-controlled studies are truly frustrating, according to the neurologist. A meta-analysis of the use of omega-3 fatty acids in cardiovascular diseases included 86 studies with over 162,000 patients. According to Diener, it did not reveal any benefit for overall and cardiovascular mortality, nor any benefit for the reduction of myocardial infarction and stroke.

The results did indicate a trend, however, for reduced mortality in coronary heart disease. Even so, the number needed to treat for this was 334, which means that 334 people would have to take omega-3 fatty acids for years to prevent one fatal cardiac event.

Aside from this study, Diener found six studies on Alzheimer's disease and three studies on dementia with patient populations between 600 and 800. In these studies, too, a positive effect of omega-3 fatty acids could not be identified. Then he discovered another 31 placebo-controlled studies of omega-3 fatty acids for the treatment or prevention of depression and anxiety disorder. Despite including 50,000 patients, these studies also did not show any positive effect.

"I see a significant discrepancy between the promotion of omega-3 fatty acids, whether it's on television, in the 'yellow' [journalism] press, or in advertisements, and the actual scientific evidence," said Diener. "At least from a neurological perspective, there is no evidence that omega-3 fatty acids have any benefit. This is true for strokes, dementia, Alzheimer's disease, depression, and anxiety disorders."

Potential Adverse Effects

Omega-3 fatty acids also have potentially adverse effects. The VITAL Rhythm study recently provided evidence that, depending on the dose, preparations with omega-3 fatty acids may increase the risk for atrial fibrillation. As the authors write, the results do not support taking omega-3 fatty acids to prevent atrial fibrillation.

In 2019, the global market for omega-3 fatty acids reached a value of $4.1 billion. This value is expected to double by 2025, according to a comment by Gregory Curfman, MD, deputy editor of JAMA and lecturer in healthcare policy at Harvard Medical School in Boston.

As Curfman writes, this impressive amount of expenditure shows how beloved these products are and how strongly many people believe that omega-3 fatty acids are beneficial for their health. It is therefore important to know the potential risks of such preparations. One such example for this would be the risk for atrial fibrillation.

According to Curfman, in the last 2 years, four randomized clinical studies have provided data on the risk for atrial fibrillation associated with omega-3 fatty acids. In the STRENGTH study, 13,078 high-risk patients with cardiovascular diseases were randomly assigned to one of two groups. The subjects received either a high dose (4 g/day) of a combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or corn oil. After a median of 42 months, there was no significant difference between the two groups in the primary composite cardiovascular endpoint, but more frequent atrial fibrillation in the omega-3 fatty acid group, compared with the corn oil group (2.2% vs 1.3%; hazard ratio, 1.69; 95% CI, 1.29 - 2.21; P < .001).

In the REDUCE-IT study, 8179 subjects were randomly assigned to a high dose (4 g/day, as in STRENGTH) of an omega-3 fatty acid preparation consisting of a purified EPA (icosapent ethyl) or mineral oil. After a median observation period of 4.9 years, icosapent ethyl was associated with a relative reduction of the primary composite cardiovascular endpoint by 25%, compared with mineral oil. As in the STRENGTH study, this study found that the risk for atrial fibrillation associated with omega-3 fatty acids, compared with mineral oil, was significantly higher (5.3% vs 3.9%; P = .003).

In a third study (OMEMI), as Curfman reports, 1027 elderly patients who had recently had a myocardial infarction were randomly assigned to receive either a median dose of 1.8 g/day of omega-3 fatty acids (a combination of EPA and DHA) or corn oil. After two years, there was no significant difference between the two groups in primary composite cardiovascular endpoints, but 7.2% of the patients taking omega-3 fatty acids developed atrial fibrillation. In the corn oil group, this proportion was 4% (hazard ratio, 1.84; 95% CI, 0.98 - 3.45; P = .06).

The data from the four studies together indicate a potential dose-dependent risk for atrial fibrillation associated with omega-3 fatty acids, according to Curfman. At a dose of 4.0 g/day, there is a highly significant risk increase (almost double). With a median dose of 1.8 g/day, the risk increase (hazard ratio 1.84) did not reach statistical significance. At a daily standard dose of 840 mg/day, an increase in risk could not be determined.

Curfman's recommendation is that patients who take, or want to take, preparations with omega-3 fatty acids be informed of the potential development of arrhythmia at higher dosages. These patients also should undergo cardiologic monitoring, he added.

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