Omega-3 Fatty Acid Supplementation and Cognitive Behavioral Therapy in Cardiovascular Risk Reduction: A Systematic Review and Exploratory Meta-Analysis

Abstract

Omega-3 fatty acids and Cognitive Behavioral Therapy (CBT) are each associated with cardiovascular benefits, but no randomized controlled trial (RCT) to date has tested their combined use. No study directly evaluated combined intervention; findings are based on separate evidence bases. We performed a meta-analysis to infer the potential combined effect of Omega-3 supplementation and CBT on cardiovascular outcomes, particularly cardiovascular mortality, using evidence from separate studies of each intervention. We searched PubMed, Scopus, Web of Science, and Cochrane through 30 Aug 2024 for RCTs and meta-analyses in adults reporting cardiovascular mortality, MI, stroke, or MACE with omega-3 supplementation and/or CBT. Fifteen studies were included (12 omega-3 RCTs; 3 meta-analyses; N=488,027). Effects were harmonized as RR/HR with 95% CIs and pooled using random-effects (DerSimonian–Laird). Heterogeneity (I²) and publication bias (funnel plot, Egger’s test) were assessed. Omega-3 supplementation showed small reductions in cardiovascular risk. The pooled effect for cardiovascular mortality across eligible RCTs was RR 0.91 (95% CI 0.84–0.97; p = 0.008). Results varied: five studies (including two large RCTs and all three meta-analyses) reported significant reductions; eight RCTs were null; one was borderline. Greater benefits appeared in high-dose/high-risk settings (e.g., REDUCE-IT with icosapent ethyl), whereas primary prevention trials (e.g., VITAL) were largely negative. Meta-analyses typically found small, positive overall effects. No included RCT evaluated formal CBT atop omega-3; thus, any combined effect is inferred, not observed. Conclusions: Pairing omega-3 with CBT is biologically and psychosocially plausible, but the expected mortality benefit is modest and indirect. Findings are exploratory and limited by heterogeneity and absence of combined-arm trials. Large, dedicated RCTs explicitly testing omega-3 + CBT are needed to confirm any additive or synergistic cardiovascular benefit.