Efficacy of folic acid supplementation in the prevention of cardiovascular disease - a systematic review and meta-analysis of randomized controlled trials

Abstract Background Cardiovascular disease (CVD) remains the leading global cause of death, with a growing interest in modifiable risk factors such as homocysteine. Elevated homocysteine contributes to atherosclerosis through endothelial dysfunction and oxidative stress. Folic acid, a key cofactor in homocysteine metabolism, has been proposed as a preventive strategy. However, recent studies have provided conflicting evidence regarding its effectiveness in preventing cardiovascular outcomes beyond stroke. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we conducted a search in multiple databases, including PubMed, Cochrane, Scopus, Web of Science, CINAHL, and EMBASE, and pre-registered on PROSPERO: CRD42024525945. Data were pooled using a random-effects model in R (version 3.4.3), with relative risks (RRs), mean differences (MD) and 95% confidence intervals (CIs) calculated. Results Our search yielded a preliminary list of 25,881 articles, with 45 studies that includes 96,962 participants meeting the inclusion criteria. These studies evaluated the effectiveness of folic acid supplementation in preventing cardiovascular disease and related events. The meta-analysis showed that folic acid supplementation reduced the risk of stroke (RR = 0.85, 95% CI: 0.76–0.96, p < 0.01) and modest reduction on overall CVD (RR = 0.95, 95% CI: 0.90–0.99, p = 0.04). No significant effects were found for mortality (RR = 0.98, 95% CI: 0.93–1.02), CHD (RR = 0.98, 95% CI: 0.91–1.06), PAD (RR = 0.94, 95% CI: 0.75–1.17), HDL (MD = 0.31, 95% CI: -0.04–0.65), or LDL (MD = -1.59, 95% CI: -8.82–5.64). Conclusions These findings reveal the capability of folic acid supplementation in reducing the risk of stroke and cardiovascular disease. However, no benefit was found for other cardiovascular endpoints. These findings support folic acid’s targeted use in primary prevention strategies, but further research is needed to refine patient selection and clarify its role in broader cardiovascular risk management. Key points 1. Stroke Risk Reduction: Folic acid supplementation significantly reduces stroke risk but has no significant effect on cardiovascular disease, coronary heart disease, or peripheral arterial disease. 2. No Effect on Lipid Profiles: Folic acid supplementation does not significantly impact high-density lipoprotein (HDL) or low-density lipoprotein (LDL) levels. 3. Study Variability and Bias: There is substantial heterogeneity and some high-risk biases across the studies included, which suggests the need for careful interpretation of the results. 4. Further Research Needed: The findings underscore the necessity for additional research to better understand how folic acid supplementation might more broadly influence cardiovascular health.