Unresolved Issues Regarding Proper Intake of Omega-3 Fatty Acids

In the past, it was reported that the low incidence of acute myocardial infarction among the indigenous Inuit of Greenland was related to the omega-3 fatty acids contained in the meat of seals and other foods that they habitually consume.¹ Since then, many epidemiological studies have been conducted, and in Japan, it was reported that cardiovascular mortality was lower in groups with a high fish intake.^2–4 These studies have led to the expectation that omega-3 fatty acid intake may have a preventive effect on cardiovascular events, and many intervention trials have been conducted. However, only a few of them^5–7 have shown the effect of omega-3 fatty acids in both the primary and secondary prevention of cardiovascular events. In this regard, the differences in results between the REDUCE-IT study⁷ and the STRENGTH study,⁸ which were published in recent years, are still fresh in our minds. Moreover, the results of meta-analyses suggest that the association between omega-3 fatty acid intake and cardiovascular events is not consistent.^9–11

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In this issue of the Journal, Inagaki et al¹² investigated whether the percent change in the eicosapentaenoic acid-to-arachidonic acid (EPA/AA) ratio is associated with cardiovascular event rates among acute coronary syndrome (ACS) patients receiving real-world lipid-lowering therapy other than omega-3 fatty acids. They compared the EPA/AA ratio of patients with ACS at the time of onset and 3 months later, and found that the patient group with a higher-than-median increase in EPA/AA ratio had fewer cardiovascular events, including all-cause mortality and non-fatal myocardial infarction, during the 3-year observation period.

It is interesting to note that a difference in the cumulative incidence of cardiovascular events in the 2 groups divided by the median increase in EPA/AA ratio was observed early in the observation period, and the difference gradually increased. As the patients in this study did not take omega-3 fatty acid agents and supplements, it is natural to assume that the difference in intake of omega-3 fatty acid-rich food immediately after the onset of ACS affected the EPA/AA ratio. This suggests that providing nutritional education in this respect to ACS patients during hospitalization or immediately after discharge may improve their prognosis.

Another interesting point is that patients with higher-than-median serum triglycerides (TG) levels at study entry were more likely to receive benefit from an increased EPA/AA ratio. To date, the cardioprotective effect of omega-3 fatty acids in secondary prevention patients with hypertriglyceridemia has not been determined. Therefore, it should be clarified whether patients with high serum TG levels at baseline improved their overall lifestyle, such as through weight and dietary changes, during the observation period.

In my view, the findings of the current study are interesting, but also raise critical unanswered questions (Figure). First, the mechanism by which elevated blood EPA levels reduced the cumulative incidence of cardiovascular events in the study subjects is not clear. It would be more informative if the authors had examined what was most important for preventing cardiovascular events among the multidimensional effects of EPA, such as TG lowering, low-density lipoprotein (LDL) particle size enlargement, and antiplatelet effects. Second, future research will be needed to determine whether changes in other omega-3 fatty acids, such as α-linolenic acid, docosahexaenoic acid (DHA) and docosapentaenoic acid, are associated with cardiovascular events. It is unfortunate that the current study did not mention changes in DHA levels. Third, it remains to be investigated whether the partial inhibition of omega-3 fatty acid absorption by ezetimibe has a negative effect on cardiovascular events. Finally, one would expect ingested omega-3 fatty acids to be metabolized differently depending on individual differences in intestinal microflora. Basic research on the effects of these different metabolites in atherosclerosis is another task for the future.

Figure.

Unresolved issues surrounding the preventive effect of EPA on cardiovascular events. EPA, eicosapentaenoic acid; LDL, low-density lipoprotein.

Despite the above unresolved issues, Inagaki et al¹² found that an increase in the EPA/AA ratio during the first 3 months after onset was effective in preventing recurrent cardiovascular events in ACS patients with hypertriglyceridemia. It will continue to be important to educate patients to actively consume omega-3 fatty acids and reduce excessive intake of saturated and trans fatty acids. However, I believe that the time has come to conduct further research on individual differences not only in the intake of omega-3 fatty acids, but also in their absorption from the intestine, metabolic enzymes in the body, and gut microbiota.

Disclosures

M.O. has received lecture fees from Amgen and Astellas Pharma Inc.

References

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