Effects of Omega-3 Long Chain Polyunsaturated Fatty Acid Supplementation on Cardiovascular Mortality: The Importance of the Dose of DHA

Abstract

Recent evidence on the relationship between omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation and cardiovascular health suggests that n-3 LCPUFA may no longer be efficacious. This review summarises the randomised controlled trials (RCTs) that assess the effect of n-3 LCPUFA supplementation on cardiovascular mortality. It appears that in the RCTs that showed no effect of n-3 LCPUFA on cardiovascular mortality, the dose of n-3 LCPUFA (in particular docosahexaenoic acid (DHA)) and hence the n-3 LCPUFA status, may not have been sufficiently high to demonstrate the efficacy, and/or the baseline n-3 LCPUFA status was already too high. The intention-to-treat analysis (ITT) is the gold standard for analysing RCTs and ITT is used for drug intervention trials where exposure to the drug versus no drug exposure provides two clearly distinct groups to determine the efficacy of the drug being studied. This differs in nutrition trials as often the nutrient of interest being studied is already being consumed by both groups (placebo and active) and therefore a true placebo group with absolutely no intake of the nutrient being studied is highly unlikely. Therefore, in n-3 LCPUFA supplementation trials, as there is no clear distinction between the two groups (placebo and n-3 LCPUFA), a per-protocol analysis (comparison of groups that includes only those participants that fully completed the original intervention allocation) should be conducted in addition to ITT analysis. Furthermore, blood analysis pre- and post-supplementation should be conducted to ensure that: (1) that the baseline n-3 status is not too high, in order to alleviate a potential ceiling effect; and (2) that the dose is high enough and hence the increase in omega-3 status will be high enough in order to assess the efficacy of n-3 LCPUFA supplementation.

Keywords: cardiovascular disease; dose of omega-3; long chain polyunsaturated fatty acids; omega-3; omega-3 status; randomised controlled trials.

Figure 1

Doses of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and total omega-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) from randomised controlled trials on n-3 LCPUFA supplementation and clinical cardiovascular disease (CVD) outcomes. The red line shows that a DHA dose of 500 mg or greater results in significant CVD outcomes. * Significant effects (p < 0.05); ^# only 140 per group showing a trend towards a significant effect (p = 0.063). Sign means significant and n.s. means not significant.

Figure 2

Randomised controlled trials of the effects of omega-3 supplementation that included blood sampling at baseline and post-intervention. * Significant effects (p < 0.05); ^# only 140 per group showing a trend towards a significant effect (p = 0.063); n.s: no significant effect.