Habitual use of fish oil prevents CVD, real-world data suggests


In fact, the results complement recent studies that show no general benefit from supplementation, argues JoAnn Manson.

Routinely taking fish oil supplements that are rich in omega-3 fatty acids can help prevent cardiovascular disease and its associated mortality in the long term in people who are initially heart disease-free in primary prevention.

In the UK biobank cohort, self-reported habitual use of fish oil supplements at baseline was associated with a lower risk of CVD events as well as all-cause and CVD mortality over a mean follow-up period of 8 to 9 years (adjusted HRs in the range from 0.84 to 0.93), according to researchers led by Dr. Zhi-Hao Li (Southern Medical University, Guangzhou, China).

“These results suggest that habitual use of fish oils is associated with minor benefit for CVD events in the general population, which supports their use in preventing all-cause mortality and CVD,” write Li et al. In her article published online on March 4th, 2020, before going to press in the BMJ. “Future studies are needed to investigate how the dose of fish oil supplements affects the ability to produce a clinically meaningful effect.”

At first glance, the results seem to clash with those of the VITAL Study that did not show fish oil reduced major cardiovascular events or new cancer diagnoses in men and women who were cancer and CVD-free at baseline. However, there was a decrease in the secondary endpoint of MI, and exploratory analysis suggested a lower risk of total coronary artery disease (CHD) and PCI.

Dariush Mozaffarian, MD, Dr. “If that were a coincidental finding, I would focus less on it, but that’s exactly what we would have predicted based on the mechanistic studies,” he commented on TCTMD.

Based on VITAL, “if I were to make guidelines I would say that there is some evidence that fish oil could reduce coronary artery disease in primary prevention,” said Mozaffarian. “It’s not cut and dried. It’s not absolute. We’ll need at least two more big final tries to get it cut and dried and absolute, but it’s certainly suggestive. And when you combine it with no evidence of harm and other studies like this one, observational studies, I think the entirety of the evidence is supportive. “

Evidence is mixed

Although fish oil supplements have become popular based on observational studies showing a benefit in reducing the risk of CVD, some recent randomized trials have dampened the excitement. In addition to VITAL, RISING UP showed that omega-3 fatty acid supplementation failed to reduce serious vascular events in diabetics without established cardiovascular disease.

Recent meta-analyzes of randomized trials have produced conflicting results. One released in 2018 before the results of ASCEND, VITAL and MAKE IT SMALLER The published results indicated that omega-3 fatty acid supplementation was not associated with reduced risk of CHD, stroke, coronary revascularization, and major vascular events in high-risk patients. A recent meta-analysis In contrast, the 2019 publication that included these studies showed that supplement use was associated with a lower risk of MI, total CHD, death from CHD or CVD, and all-CVD, even when REDUCE-IT – what showed significant benefits of a prescription omega -3 fatty acid formulation in patients with high triglycerides – was excluded.

We’ll need at least two more big final tries to get it cut and dried and absolute, but it’s certainly suggestive. Dariush Mozaffarian

“Although randomized controlled trials provide the best evidence of the effects of interventions, their known limitations make it difficult to extrapolate their results to large, more comprehensive populations,” write Li et al. “Therefore, additional information on the effectiveness of fish oil supplements is needed by evaluating large-scale cohort studies in practice.”

UK biobank

To do this, they looked at data from the UK Biobank, a population-based cohort of more than half a million people aged 40 to 69 from England, Scotland and Wales. The current analysis included 427,678 people (mean age 56 years; 55% women) who had neither CVD nor cancer at the start of the study and who had information on the use of dietary supplements. At the start of the study, 31.2% stated that they regularly take fish oil supplements. Patients were then followed up for a median of 8.1 years for CVD events and 9.0 years for mortality.

With multivariable fitting, habitual use of fish oil supplements was associated with a lower risk of a variety of CVD-related outcomes, with the exception of one fatal stroke.

Long-term results before and after multivariable fitting

Regular fish oil users


Adjusted HR (95% CI)

All-cause mortality



0.87 (0.83-0.90)

CVD mortality



0.84 (0.78-0.91)

Incident CVD



0.93 (0.90-0.96)

MI mortality



0.80 (0.70-0.91)




0.92 (0.88-0.96)

Stroke mortality



0.87 (0.73-1.04)




0.90 (0.84-0.97)

The relationship between fish oil use and CVD event risk appeared to be stronger in patients with predominant hypertension, while the associations with all-cause mortality risk appeared to be stronger in men and current smokers.

Discrepancy between studies

The researchers say that other studies that haven’t shown significant associations between fish oil supplementation and CVD prevention may have suffered from inadequate sample sizes and an insufficient number of outcome events.

In VITAL, for example, they calculated the post-hoc study performance for major cardiovascular events to be just 0.78. They also note that the point estimate for a reduction in CVD events was similar in VITAL (HR 0.92) and this study (HR 0.93). “The confidence interval estimate (0.90-0.96) in our study suggests that omega-3 fatty acids have a significant association with CVD events,” write Li et al. “Hence we postulate a marginal inverse association between fish oil supplementation and CVD events.”

The researchers also say the dose might come into play, noting that the dose of omega-3 fatty acids in REDUCE-IT, which met its primary endpoint, was about 4.75 times higher than in VITAL. In addition, the 2019 meta-analysis suggesting a benefit from fish oil showed that higher doses would be more effective. “This finding suggests that the conflicting results of the randomized controlled trials could be due to the sample size and dosage of fish oil supplements,” say Li et al.

They acknowledge that their own analysis has some limitations, including the lack of detailed information on the dose, formulation, and duration of use of fish oil. the potential for confusing or reverse causality; and the difficulty of separating the effects of a healthy lifestyle from those of a fish oil supplement.

Taking fish oil “very sensible”

JoAnn Manson, MD, DrPH (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), a Chair of the VITAL Steering Committee, told TCTMD, “Observational studies of supplement users and health outcomes must be considered with caution because there are many potential confounders that come into play when it comes to who is taking supplements and who is not. “Correlations in observational data therefore do not prove causality.

However, real data can complement information from randomized clinical trials, especially when the two are relatively well matched, as is the case with studies examining the effects of omega-3 fatty acid supplementation on coronary risk, Manson added.

“I think we now have a good idea of ​​the effects omega-3s have on heart health,” she said. “There seems to be a benefit in reducing the risk of coronary disease.”

There is a need for additional studies, however, and both randomized and observational studies play a role, Manson said. In particular, additional studies are needed to examine omega-3 fatty acid supplementation for primary prevention in high-risk patients with different doses and formulations. However, studies may have limited ability to examine long-term use, she added, stressing that more observational research is also needed.

Mozaffarian also highlighted the importance of observational research – with all of its inherent limitations – in studying the effects of interventions such as supplementing with fish oil on long-term disease risk.

“Experimental and observational studies each have their own strengths and limitations, and of course animal testing and other types of mechanistic studies have their own strengths and limitations,” he said. “I think there was an over-addiction and an over-emphasis on randomized controlled trials as the only standard, and we really need to use all of the evidence. So I think if you put all of the evidence together – the evidence from VITAL, the evidence from REDUCE-IT, the evidence from ASCEND, the evidence from this study – supports this. . . that low-dose fish oil supplements are likely to have some cardiovascular benefit. “

When people want to improve their health and there are signs that eating omega-3s is important, Mozaffarian said, “My first recommendation is still to eat fatty fish two or three times a week. But when for some reason people can’t eat fatty fish two or three times a week. . . or if you eat oily fish but still want to be sure that you are getting enough omega-3 fatty acids, it is very sensible to take an over-the-counter fish oil supplement every day. “


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