Folate and global health review series, part 3: syntheses on cardiovascular, cerebrovascular, and metabolic diseases.

Clinical Snapshot

Key Findings

• P Value: Not reported

• Effect Size: Six directional associations and five null associations at suggestive credibility level

• Primary Outcome: Cardiometabolic disease associations with folate status

• Nnt Or Sensitivity: Three dose-response relationships showing reduced risk of coronary heart disease and stroke with higher dietary folate intake

• Confidence Interval: Not specified in abstract

Clinical Application

Folate supplementation is readily available and cost-effective, but evidence insufficient for routine clinical recommendation Relevant to Australian practice given mandatory folate fortification since 2009, but current evidence insufficient to support additional supplementation recommendations beyond existing TGA-approved indications Adults in high-income countries with or at risk of cardiovascular disease, limited applicability to LMIC populations

Abstract

BACKGROUND: Cardiovascular and metabolic diseases account for an increasing share of morbidity and mortality globally. Folic acid supplementation has been linked to a lowered risk of stroke and some metabolic indicators due to its involvement in homocysteine and one-carbon metabolism and its role in the production of nitric oxide; however, the evidence on these associations is inconclusive. METHODS: We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (dietary intake, supplementation, or blood concentrations) with any cardiometabolic outcome. We performed screening, data abstraction, and risk of bias assessment in duplicate, and assessed the credibility of the evidence using predefined criteria. RESULTS: We identified 113 unique associations from 49 reviews. The included syntheses mostly had low risk of bias of and provided pooled risk estimates from intervention trials or prospective cohorts. A larger volume of evidence was available for composite cardiovascular outcomes, coronary heart disease, and stroke compared to other outcomes. No association reached a convincing or highly suggestive level of credibility. Six directional associations and five null associations met the criteria for a suggestive level of credibility. Three dose-response relationships, all at suggestive levels of credibility, supported an association between higher dietary folate intake and a reduced risk of coronary heart disease and stroke. CONCLUSION: The available evidence on the association between folate status and cardiometabolic outcomes primarily focuses on secondary prevention of cardiometabolic diseases and substantially underrepresents low- and middle-income countries. More large-scale studies are warranted to validate a relationship between folate status and cardiometabolic events or indicators. Overall, the evidence landscape around folate and cardiometabolic diseases appears to be limited both in volume and scope. REGISTRATION: PROSPERO: CRD42021265041.

References

1. 1.Yoo, S., Montazeri, A., Bennett, D., Bo, Y., Chen, P., Duthie, S., Jensen, N., Kaminga, A., Lai, J.-S., Li, X., MacFarlane, A. J., Martinez, H., McNulty, H., Momoli, F., Munger, R., Parajuli, R. P., Kent, M. P., Rubini, M., Senekal, M., Sikora, L., Stintzi, A., Theodoratou, E., Wang, H., Yaktine, A., & Little, J. (2026). Folate and global health review series, part 3: syntheses on cardiovascular, cerebrovascular, and metabolic diseases. Journal of Global Health, 16, 04160. https://doi.org/10.7189/jogh.16.04160