Major findings

In this meta-analysis involving over 30 thousand deaths events from 11 prospective studies, both dietary and circulating n-3 LCPUFA are shown to be significantly associated with reduced risk of all-cause mortality and the associations are similar for EPA and DHA.

Other results from observational studies and clinical trials

In a recent meta-analysis of 12 prospective studies, Zhao et al.36 report a moderate reduction in all-cause mortality associated with intake of fish, a major dietary source of n-3 LCPUFA. Significantly inverse associations of dietary fish and dietary and circulating n-3 LCPUFA with risk of CHD have been consistently shown in prospective observational studies2,10. Conversely, clinical evidence regarding the health benefits of n-3 LCPUFA has been continuously inconsistent. Mozaffarian and Wu5 review the cumulative observational and clinical evidence published before 2011 regarding the effects of n-3 LCPUFA on CVD and related risk factors and conclude that there is strong evidence supporting a protective effect of n-3 LCPUFA on cardiac death. Nonetheless, more recent meta-analyses fail to show any significant protection either on CVD or on all-cause mortality. For instance, Rizos et al.11 and Chowdhury et al.10 each pooled data from 17 RCTs and report no significant effect of n-3 LCPUFA supplementation on all-cause mortality, with a summary RR of 0.96 (95% CI, 0.91–1.02) and 0.94 (95% CI: 0.86–1.03), respectively. Using a cumulative meta-analysis, Rizos et al.11 further find that a protection of n-3 LCPUFA on all-cause mortality is restricted to RCTs that are published before 2007.

The reasons for the disparate findings between observational and clinical studies are not fully understood, but several possibilities merit consideration. First, most of the RCTs, as argued by Mozaffarian and Wu5, are small in sample size and short in duration and therefore may be of a low statistical power to detect a moderate-to-weak effect associated with long-term uses. Second, participants in the trials are mostly those subjects who are at high risk for, or already suffering from CVD rather than the general populations. In such a condition, the benefits of n-3 LCPUFA may be diminished or offset by disease status or corresponding dietary modifications and medical treatments. A recent review37 summarize that post-hoc analyses of RCTs support beneficial effects of n-3 LCPUFA on CVD prevention among statins non-users and conclude that emerging uses of statins and less deficiencies of n-3 LCPUFA among participants of recent trials may explain why especially early RCTs, but not recent ones find the health benefits of n-3 LCPUFA. Given that n-3 LCPUFA and statins share several mechanisms whereby they may exert health effects (e.g., improving endothelial function, reducing inflammation and slowing atherosclerotic progresses5,38), statins may mask the action of n-3 LCPUFA in a competitive fashion.

Third, the association of n-3 LCPUFA with health outcomes may be nonlinear. A 2006 pooled analysis39 of prospective studies and randomized trials indicate that the most protections of EPA and DHA intake on CHD deaths could be achieved when the intake is up to 0.25 g/d. Furthermore, the effects on antiarrhythmia, antithrombosis and reducing heart rate and blood pressure (but not triglycerides) also appear nonlinear, with tendencies to plateau at the intakes of 0.5–0.75 g/d39. A recent report from the Cardiovascular Health Study21 demonstrate that EPA and DHA in plasma increase linearly and sharply with increasing dietary EPA and DHA lower than 0.5 g/d, whereas there are limited subsequent change in plasma concentrations despite larger increases in dietary intake. These observations suggest that diet and endogenous metabolism may jointly determine to what degree n-3 LCPUFA intake may exert their benefits to human body. If the benefits of n-3 LCPUFA indeed tend to be saturable at low-to-moderate levels, the null effects observed in the trials without taking into account diet background of participants are not surprising.

Fourth, it is possible that other nutrients (e.g., vitamins, minerals and proteins) in fish or other foods rather than n-3 LCPUFA are beneficial. It is difficult, perhaps not possible for observational studies to accurately distinguish the effects between n-3 LCPUFA and these nutrients. Finally, even if n-3 LCPUFA are one of the causal components in fish, their consumption as part of a matrix of other nutrients in foods may be essential for the benefits. We consider the fourth possibility less likely because of multiple lines of evidence from experimental research, prospective observational studies, as well as human intervention trials supporting the potential cardiovascular benefits of n-3 LCPUFA.

Strengths and limitations of the current study

Major strengths of this meta-analysis include the prospective design of original studies and the large number of events involved in the analyses. However, several limitations of this study should also be acknowledged. Since this meta-analysis is based on observational studies, potential influences of residual or unmeasured confounders on our findings cannot be fully excluded. Dietary information was mostly collected with self-reported FFQs in the original studies, which may introduce measurement error and lead some participants to be misclassified. Such misclassification would likely be nondifferential in cohort studies and to attenuate any true association. This may partly explain the observation that the associations between circulating n-3 LCPUFA and all-cause mortality were stronger than those between dietary intakes and all-cause mortality. Furthermore, the common methods we used to detect potential publication bias may be of a limited power when the number of studies is relatively small. Thus, potential impacts of publication bias on our results cannot be completely excluded.

Conclusions

In summary, this meta-analysis of prospective observational studies suggests that both dietary and circulating n-3 LCPUFA are significantly inversely associated with risk of all-cause mortality. More large prospective studies conducted among individuals with high intakes are needed to address whether there is a nonlinear association. Future well designed primary prevention trials that account for nutrition status, health conditions and medication usages of participants are also warranted to confirm our findings and those from others.