Omega 3 fatty acids for prevention and treatment of cardiovascular disease.

RCTs and cohorts. RCTs: 48 randomized trials (n=36,913); follow-up 6–108 months; adults with cardiovascular disease or at high risk; mix of men and women; several trials in inflammatory diseases. Cohorts: 47 analyses from 26 cohorts (n=563,218); follow-up 4–25 years; exposures via diet or biomarkers. Many RCTs used double-blind design and adequate allocation concealment.

Fish oil- and plant-based omega-3 regimens delivered as capsules, oils, emulsions or enriched foods. Fish-based regimens delivered EPA+DHA (and sometimes DPA) daily doses ranging roughly 0.4–7 g of long-chain omega-3 fats for 6–108 months; plant-based regimens included linseed/flaxseed oil and alpha-linolenic acid (ALA)–enriched margarine; some trials used EPA+DHA in ethyl ester forms. Several studies combined dietary advice to increase oily fish with supplementation; others used enriched foods. Formulations included Omacor, MaxEPA, PurEPA, Promega, Esapent, Eskisol, EPA-ethyl ester capsules, cod liver oil, linseed oil, and omega-3–rich margarine.

Overall, dietary or supplemental omega-3 fats did not clearly reduce total mortality, cardiovascular events, or cancers in the general population or in those at risk of cardiovascular disease. Pooled RCT total mortality RR 0.87 (0.73–1.03) with significant heterogeneity; sensitivity analyses in low-bias trials yielded RR 0.98 (0.70–1.36). Combined cardiovascular events RR 0.95 (0.82–1.12). Some longer trials suggested a modest mortality reduction (RR ~0.84; 0.75–0.93) but this effect weakened when a large trial (DART 2) was removed. No robust evidence that fish- vs plant-sourced omega-3 fats differ in effectiveness. No clear cancer or stroke risk increase, though data for some outcomes were imprecise. Omega-3s consistently lower triglycerides and may modestly raise LDL; little or no effect on weight or BP. Side effects (taste, GI) increased trial drop-outs. The evidence does not justify widespread initiation of omega-3 supplementation for mortality or cardiovascular prevention, but continuing current omega-3 intake is reasonable while awaiting higher-quality long-term trials, and toxin exposure in fish oils warrants monitoring.

Significant heterogeneity and varying risk of bias across trials; one large trial (DART 2) heavily influenced results; many trials were older with methodological limitations; observational cohorts are prone to residual confounding; limited data for cancer and neurological outcomes; inconsistent reporting of toxin exposure from fish oils; findings may not apply uniformly across populations or dosing regimens.