Omega-3 Fatty Acid Supplementation and All-Cause Mortality: An Updated Meta-Analysis of Randomized Controlled Trials
Background
The relationship between omega-3 fatty acid supplementation and mortality has been debated for decades, with conflicting results from individual trials. The REDUCE-IT trial reinvigorated interest by demonstrating substantial cardiovascular benefit with high-dose icosapent ethyl. However, other large trials such as VITAL and STRENGTH showed more modest or null effects. An updated meta-analysis incorporating recent large-scale trials is needed to clarify the overall evidence.
Methods
We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov through December 2025 for randomized controlled trials of omega-3 fatty acid supplementation (EPA, DHA, or combinations) with at least 500 participants and 1 year of follow-up reporting mortality outcomes. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, cardiac death, and major adverse cardiovascular events. Random-effects models were used to pool risk ratios. Subgroup analyses examined dose, formulation type (EPA-predominant vs. EPA/DHA combinations), and baseline cardiovascular risk.
Results
Thirty-eight trials involving 149,051 participants (mean follow-up, 4.2 years) were included. Omega-3 supplementation was associated with a significant reduction in all-cause mortality (RR 0.95; 95% CI, 0.92-0.98; P=0.003; NNT=167 over 4 years). Cardiovascular mortality was reduced by 8% (RR 0.92; 95% CI, 0.87-0.97; P=0.002). EPA-predominant formulations showed greater benefit for cardiovascular mortality (RR 0.83; 95% CI, 0.75-0.92) compared with EPA/DHA combinations (RR 0.96; 95% CI, 0.91-1.01; interaction P=0.01). Higher doses (above 2 g/day) were associated with greater cardiovascular benefit than lower doses. No significant effect on cancer mortality was observed (RR 0.99; 95% CI, 0.94-1.04). Atrial fibrillation risk was modestly increased with omega-3 supplementation (RR 1.12; 95% CI, 1.02-1.23), particularly with higher doses.
Conclusions
Omega-3 fatty acid supplementation reduces all-cause and cardiovascular mortality, with EPA-predominant formulations at higher doses showing the greatest benefit. The modest increase in atrial fibrillation risk warrants consideration in clinical decision-making.
Omega-3 fatty acid supplementation is associated with a modest but statistically significant reduction in all-cause mortality, driven primarily by reduced cardiovascular mortality, with the strongest evidence for EPA-predominant formulations.