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

Samantha Yoo; Azita Montazeri; Derrick Bennett; Yacong Bo; Peizhan Chen; Susan Duthie; Natalie Jensen; Atipatsa Kaminga; Jun-Shi Lai; Xue Li; Amanda J MacFarlane; Homero Martinez; Helene McNulty; Franco Momoli; Ron Munger; Rajendra Prasad Parajuli; Monique Potvin Kent; Michele Rubini; Marjanne Senekal; Lindsey Sikora; Alain Stintzi; Evropi Theodoratou; Hui Wang; Ann Yaktine; Julian Little

doi:10.7189/jogh.16.04160

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

Samantha Yoo
, Azita Montazeri
, Derrick Bennett
, Yacong Bo
, Peizhan Chen
, Susan Duthie
, Natalie Jensen
, Atipatsa Kaminga
, Jun-Shi Lai
, Xue Li
, Amanda J MacFarlane
, Homero Martinez
, Helene McNulty
, Franco Momoli
, Ron Munger
, Rajendra Prasad Parajuli
, Monique Potvin Kent
, Michele Rubini
, Marjanne Senekal
, Lindsey Sikora

Alain Stintzi, Evropi Theodoratou, Hui Wang, Ann Yaktine, Julian Little

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	04160
Pages (from-to)	1-23
Number of pages	23
Journal	Journal of Global Health
Volume	16
Early online date	11 May 2026
DOIs	https://doi.org/10.7189/jogh.16.04160
Publication status	Published online - 11 May 2026

Bibliographical note

Publisher Copyright:
© 2026 The Author(s)

Data Availability Statement

The data supporting the findings of this study are available within the article and its supplementary materials.

Funding

This study was funded by Canadian Institutes for Health Research (CIHR) Grant FRN-PJT-175263. The funder had no direct or indirect involvement in the design of the review, data abstraction, synthesis, writing of the report and decision to submit the manuscript for publication.

Funders	Funder number
Canadian Institutes of Health Research	FRN-PJT-175263

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cardiovascular Diseases - prevention & control - epidemiology
Cerebrovascular Disorders - prevention & control - epidemiology
Dietary Supplements
Folic Acid - administration & dosage - therapeutic use
Global Health
Humans
Metabolic Diseases - prevention & control - epidemiology
Cerebrovascular Disorders/prevention & control
Folic Acid/administration & dosage
Cardiovascular Diseases/prevention & control
Metabolic Diseases/prevention & control

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Cite this

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., ... Little, J. (2026). Folate and global health review series, part 3: syntheses on cardiovascular, cerebrovascular, and metabolic diseases. Journal of Global Health, 16, 1-23. Article 04160. Advance online publication. https://doi.org/10.7189/jogh.16.04160

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

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.",

keywords = "Cardiovascular Diseases - prevention \& control - epidemiology, Cerebrovascular Disorders - prevention \& control - epidemiology, Dietary Supplements, Folic Acid - administration \& dosage - therapeutic use, Global Health, Humans, Metabolic Diseases - prevention \& control - epidemiology, Cerebrovascular Disorders/prevention \& control, Folic Acid/administration \& dosage, Cardiovascular Diseases/prevention \& control, Metabolic Diseases/prevention \& control",

author = "Samantha Yoo and Azita Montazeri and Derrick Bennett and Yacong Bo and Peizhan Chen and Susan Duthie and Natalie Jensen and Atipatsa Kaminga and Jun-Shi Lai and Xue Li and MacFarlane, \{Amanda J\} and Homero Martinez and Helene McNulty and Franco Momoli and Ron Munger and Parajuli, \{Rajendra Prasad\} and Kent, \{Monique Potvin\} and Michele Rubini and Marjanne Senekal and Lindsey Sikora and Alain Stintzi and Evropi Theodoratou and Hui Wang and Ann Yaktine and Julian Little",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s)",

year = "2026",

month = may,

day = "11",

doi = "10.7189/jogh.16.04160",

language = "English",

volume = "16",

pages = "1--23",

journal = "Journal of Global Health",

issn = "2047-2978",

publisher = "University of Edinburgh",

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Yoo, S, Montazeri, A, Bennett, D, Bo, Y, Chen, P, Duthie, S, Jensen, N, Kaminga, A, Lai, J-S, Li, X, MacFarlane, AJ, Martinez, H, McNulty, H, Momoli, F, Munger, R, Parajuli, RP, Kent, MP, 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, vol. 16, 04160, pp. 1-23. https://doi.org/10.7189/jogh.16.04160

TY - JOUR

T1 - Folate and global health review series, part 3: syntheses on cardiovascular, cerebrovascular, and metabolic diseases

AU - Yoo, Samantha

AU - Montazeri, Azita

AU - Bennett, Derrick

AU - Bo, Yacong

AU - Chen, Peizhan

AU - Duthie, Susan

AU - Jensen, Natalie

AU - Kaminga, Atipatsa

AU - Lai, Jun-Shi

AU - Li, Xue

AU - MacFarlane, Amanda J

AU - Martinez, Homero

AU - McNulty, Helene

AU - Momoli, Franco

AU - Munger, Ron

AU - Parajuli, Rajendra Prasad

AU - Kent, Monique Potvin

AU - Rubini, Michele

AU - Senekal, Marjanne

AU - Sikora, Lindsey

AU - Stintzi, Alain

AU - Theodoratou, Evropi

AU - Wang, Hui

AU - Yaktine, Ann

AU - Little, Julian

PY - 2026/5/11

Y1 - 2026/5/11

N2 - 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.

AB - 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.

KW - Cardiovascular Diseases - prevention & control - epidemiology

KW - Cerebrovascular Disorders - prevention & control - epidemiology

KW - Dietary Supplements

KW - Folic Acid - administration & dosage - therapeutic use

KW - Global Health

KW - Humans

KW - Metabolic Diseases - prevention & control - epidemiology

KW - Cerebrovascular Disorders/prevention & control

KW - Folic Acid/administration & dosage

KW - Cardiovascular Diseases/prevention & control

KW - Metabolic Diseases/prevention & control

UR - https://www.scopus.com/pages/publications/105038373237

U2 - 10.7189/jogh.16.04160

DO - 10.7189/jogh.16.04160

M3 - Article

C2 - 42100908

SN - 2047-2978

VL - 16

SP - 1

EP - 23

JO - Journal of Global Health

JF - Journal of Global Health

M1 - 04160

ER -

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

Abstract

Bibliographical note

Data Availability Statement

Funding

UN SDGs

Keywords

Access to Document

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Cite this