Benefits of Fish Oil Resurface, but Do They Hold Water?

Damian McNamara

March 12, 2020

Regular fish oil consumption is linked to a lower risk for all-cause and cardiovascular disease (CVD) mortality as well CVD events, including stroke and myocardial infarction (MI), results of a large observational study suggest. However, at least one expert is "skeptical that the results are real."

Investigators found that habitual fish oil supplementation was associated with a 13% lower risk for all-cause mortality, a 16% lower risk for CVD mortality, and a 7% lower risk for CVD events in the general population.

"Although taking fish oil supplements can cause minor side effects, such as bad breath, heartburn, nausea, and gastrointestinal discomfort, in light of the price and convenience," taking a daily nonprescription fish oil supplement is an "inexpensive, quick, and safe way for patients who want to be sure they are getting enough omega-3s," senior investigator Prof Chen Mao, Department of Epidemiology, School of Public Health, Southern Medical University, Guangdong, China, told Medscape Medical News.

The study was published online March 4 in the BMJ.

Real-World Study

As previously reported by Medscape Medical News, the recent Vitamin D and Omega-3 Trial (VITAL) study linked omega-3 fatty acid supplementation to a significantly lower risk for MI but found no association between fish oil consumption and lower risk for CVD events.

Other previous research, including a meta-analysis of 13 randomized controlled trials, support a link between omega-3 fatty acid intake, including fish oil intake, and CVD prevention.

However, the current researchers note that these studies were performed under "ideal and controlled circumstances."

To examine the potential effects of fish oil supplementation in a real-life setting, Mao and his team conducted a population-based, prospective cohort study of 427,678 adults who were enrolled in the UK Biobank study between 2006 and 2010.

The investigators compared outcomes among the 31% of study participants who reported regular dietary intake of fish oil supplements with outcomes for individuals who reported no use of fish oil supplements. They used death certificates and hospital records to track outcomes through 2018.

A total of 12,928, people died from any cause during the study period. These included 3282 CVD deaths, 1423 from MI, and 664 deaths from stroke.

There were 18,297 incident cardiovascular events, including 7754 MIs and 4009 strokes.

Fish oil intake was significantly associated with lower risk for all-cause mortality (P < .05) after adjusting for age and sex. Regular consumption also was linked to a lower incidence of cardiovascular events and related deaths, MI, and stroke (all P < .05).

Adjusted hazard ratios linked to fish oil use were 0.87 (95% confidence interval [95% CI], 0.83 – 0.90) for all-cause mortality; 0.84 (95% CI, 0.78 – 0.91) for CVD mortality; and 0.80 (95% CI, 0.70 to 0.91) for MI mortality in a multivariable analysis.

The adjusted HRs for adverse events were 0.93 (95% CI, 0.90 – 0.96) for CVD; 0.92 (95% CI, 0.88 – 0.96) for MI; and 0.90 (95% CI, 0.84 – 0.97) for stroke.

In contrast, the investigators found no significant association between fish oil use and death from stroke (HR, 0.87; 95% CI, 0.73 – 1.04; P = .14).

Sex Differences

Interestingly, the association between use of fish oil and lower all-cause mortality was stronger among men than women (HRs, 0.81 vs 0.95) and among current smokers than nonsmokers (HRs, 0.77 vs 0.90).

"Our results appear at first glance to conflict with those of the VITAL trial, which failed to show that fish oil reduced major cardiovascular events or new cancer diagnoses in men and women free from cancer and cardiovascular disease at baseline," Mao said.

However, the point estimates for a reduction in CVD events were similar for VITAL (HR, 0.92) and the current study (HR, 0.93). Furthermore, the confidence interval (0.90 – 0.96) in Mao's study suggests that omega-3 fatty acids "have a significant association with CVD events," he added

Moreover, a 2019 meta-analysis demonstrated that use of supplements was tied to lower risks for MI, total coronary heart disease, death from coronary heart disease or CVD, and total CVD, Mao said.

The findings held when researchers excluded REDUCE-IT — a trial that showed significant benefits of a prescription omega-3 fatty acid formulation for patients with high triglyceride levels, he added.

"Therefore, our findings are reasonable, indicating that habitual use of fish oils is associated with a marginal benefit for CVD events in the general population," Mao said.

Potential limitations of the study include a lack of information on the dose, formulation, and duration of fish oil consumption. In addition, because the study was observational, "it is difficult to separate the effects of a healthy lifestyle from the habitual use of fish oil supplements," the researchers note.

"It may take more definitive tests in the future to make our findings cut and dried and absolute, and both randomized and observational studies have a role to play," Mao said.

"We may conduct studies to explore what dose is needed to achieve a clinically meaningful effect," he added. He and colleagues also may evaluate omega-3 fatty acid supplementation for primary prevention in high-risk patients.

Healthy Skepticism?

Commenting on the findings for Medscape Medical News, Deepak Bhatt, MD, MPH, principal investigator of the REDUCE-IT trial, noted that "related randomized trials of these types of supplements have not demonstrated significant benefit.

"Therefore, I am skeptical that the results are real," said Bhatt, executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston, Massachusetts.

In addition, residual confounding might have affected the results, because healthy individuals who are concerned about their health tend to take supplements and vitamins and therefore appear to have better health outcomes than those who do not, he said. Further, healthy behaviors could have contributed to the observed benefits.

"Furthermore, there are data that show fish oil supplements vary from batch to batch in their exact omega-3 fatty acid content and that they contain other saturated fats as well," Bhatt added.

Also commenting for Medscape Medical News, Eric Rimm, ScD, said the results are "intriguing" and that the study adds to the literature. He noted that the study included almost half a million participants from the general population, which contrasts with cohorts from clinical trials.

The investigators found some benefits to omega-3 supplementation, added Rimm, professor of epidemiology and nutrition, director of the Program in Cardiovascular Epidemiology at the Harvard T. H. Chan School of Public Health, and professor of medicine at Harvard Medical School in Boston.

However, they did not find a difference between people who reported low levels of fish consumption and those who reported high levels, "which is generally not the case for other studies."

Although the researchers adjusted for multiple factors, "the part that concerned me is they did not look at how much red meat or fiber people were getting in their diet...so I cannot tell it's truly the omega-3 supplements" that are conferring the benefit, he added.

The study was supported by the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme, the Construction of High-level University of Guangdong, the US National Institutes of Health/National Institute on Aging, and the National Natural Science Foundation of China. Mao and Rimm have disclosed no relevant financial relationships. Bhatt was principal investigator of REDUCE-IT, and Brigham and Women's Hospital received research funding from Amarin Corp for the study.

BMJ. Published online March 4, 2020. Full text

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