Supplementation with Folic Acid, Vitamin B12, and Vitamin B6 Associated with Reduced Risk of Stroke

by | Mar 13, 2024 | 2024, Folic Acid & Folate, Vitamin B12, Vitamin B6

Written by Taylor Woosley, Science Writer. Findings of a meta-analysis of 14 RCTs including 76,664 subjects and 2720 cases of stroke shows that supplementation of ≤0.8 mg/d folic acid combined with ≤0.4 mg/d vitamin B12 and ≤10 mg/d vitamin B6 resulted in a 39% reduced risk of stroke. 

Brain HealthStroke is the second leading cause of death globally and the third leading cause of death and disability combined1. Ischemic stroke is the most frequent type of stroke and constitutes around 80% of stroke cases2. Most ischemic stroke cases are caused by complications to atherosclerosis such as local cerebral atherothrombosis or embolization from a thrombosis within a carotid artery plaque3.

The B vitamins, including folate and vitamins B6 and B12, play vital roles in the metabolism of homocysteine, which is a major risk factor for stroke4. Vitamin B12 plays an essential role in mitochondrial energy production and cellular function, with mitochondria being a major contributor to the development of apoptotic and necrotic cell death after ischemic stroke5. Furthermore, folic acid, a water-soluble natural compound that plays an essential role in deoxyribonucleic acid and ribonucleic acid biosynthesis, has been researched for its potential to reduce the risk of stroke6.

Zhang et al. conducted a meta-analysis to analyze the efficacy of concomitant supplementation of a combination of folic acid, vitamin B12, and vitamin B6 on stroke prevention. Study inclusion consisted of following a randomized controlled trial (RCT) design, with an intervention using folic acid combined with vitamin B12 and vitamin B6 supplementation, including a control group receiving either a placebo or low dosages of B vitamins, with an intervention date ≥6 months. Additionally, the study needed to include the number of strokes in both the intervention and control group with participants being aged ≥18 years. Trials in countries with folic acid grain fortification policies were categorized as full folic acid grain fortification trials in the meta-analysis.

14 RCTs were included in the final analysis, with a combined total of 76,664 subjects and 2720 cases of stroke. Primary meta-analysis outcomes were all types of strokes. 6 trials were conducted in regions with folic acid grain fortification, 5 were conducted without folic acid grain fortification, and 3 were considered partial folic acid grain fortification. B vitamin dosages in the intervention group ranged from 0.4 to 40 mg/d of folic acid, 0.018 to 2 mg/d of vitamin B12, and 0.05 to 100 mg/d of vitamin B6. Significant findings of the study are as follows:

  • Populations in regions without grain fortification or with partial grain fortification show that combined B-vitamin supplementation significantly reduced stroke risk by 34% (RR:0.66; 95% CI: 0.50, 0.86) and 11% (RR:0.89, 95% CI:0.79, 1.00), respectively. Among populations in regions with grain fortification, the RR of stroke was 1.04 (95% CI: 0.94, 1.16).
  • A significant interaction between a combination of B-vitamin supplementation and folic acid fortification status on stroke was observed (P-interaction=0.003).
  • After combining trials without grain fortification and with partial grain fortification, a significant 35% reduction in stroke risk was observed in RCTs with folic acid ≤0.8 mg/d combined with vitamin B12 ≤0.4 mg/d and an 11% reduction in stroke risk found in RCTs with either folic acid >0.8 mg/d or/and vitamin B12 >0.4 mg/d (P-interaction=0.045).
  • Doses of folic acid ≤0.8 mg/d combined with vitamin B12 ≤0.4 mg/d and vitamin B6 ≤10 mg/d resulted in a 39% reduced risk of stroke (P-interaction=0.073).

Results of the meta-analysis of 14 RCTs shows that supplementation with a combination of folic acid, vitamin B12, and vitamin B6 significantly reduced stroke risk in populations without grain fortification or with partial grain fortification. Further research on B vitamin supplementation on stroke risk and prevention is necessary to better comprehend the findings. Study limitations include the lack of analysis on the efficacy of a combination of B vitamins on different stroke subtypes and the potential for publication bias.

Source: Zhang, Nan, ZhongYun Wu, Xinlei Bai, Yun Song, Ping Li, Xinzheng Lu, Yong Huo, and Ziyi Zhou. “Dosage exploration of combined B-vitamin supplementation in stroke prevention: a meta-analysis and systematic review.” The American Journal of Clinical Nutrition (2024).

© 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.

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Posted March 13, 2024.

Taylor Woosley studied biology at Purdue University before becoming a 2016 graduate of Columbia College Chicago with a major in Writing. She currently resides in Glen Ellyn, IL.

References:

  1. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Neurology. Oct 2021;20(10):795-820. doi:10.1016/s1474-4422(21)00252-0
  2. Liu J, Li X, Qu J. Risk factors for acute ischemic stroke in patients with type 2 diabetes mellitus. Medicine (Baltimore). Nov 24 2023;102(47):e36114. doi:10.1097/md.0000000000036114
  3. Johansson A, Drake I, Engström G, Acosta S. Modifiable and Non-Modifiable Risk Factors for Atherothrombotic Ischemic Stroke among Subjects in the Malmö Diet and Cancer Study. Nutrients. Jun 6 2021;13(6)doi:10.3390/nu13061952
  4. Yuan S, Mason AM, Carter P, Burgess S, Larsson SC. Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study. BMC Med. Apr 23 2021;19(1):97. doi:10.1186/s12916-021-01977-8
  5. Poole J, Jasbi P, Pascual AS, et al. Ischemic Stroke and Dietary Vitamin B12 Deficiency in Old-Aged Females: Impaired Motor Function, Increased Ischemic Damage Size, and Changed Metabolite Profiles in Brain and Cecum Tissue. Nutrients. Jul 19 2022;14(14)doi:10.3390/nu14142960
  6. Yang YH, Lei L, Bao YP, Zhang L. An Integrated Metabolomic Screening Platform Discovers the Potential Biomarkers of Ischemic Stroke and Reveals the Protective Effect and Mechanism of Folic Acid. Front Mol Biosci. 2022;9:783793. doi:10.3389/fmolb.2022.783793