SYSTEMATIC REVIEW article
Front. Nutr.
Sec. Nutrition and Metabolism
Effects of Folic Acid with Vitamin B12/Vitamin B6 Intervention on Serum Homocysteine Metabolism and Complications in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Provisionally accepted
- 1Macau University of Science and Technology, Taipa, Macao, SAR China
- 2Nanjing University of Chinese Medicine, Nanjing, China
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Aims: Folic acid and B vitamins play key roles in regulating serum homocysteine metabolism. Elevated homocysteine levels have been associated with insulin resistance and diabetes-related complications in patients with type 2 diabetes mellitus (T2DM). This study evaluated the effects of folic acid supplementation combined with B vitamins (B12 and B6) on homocysteine levels and complication risk in adults with T2DM. Methods: We conducted a systematic search of eight databases from inception through August 30, 2025. The primary efficacy outcome was serum homocysteine level, while safety outcomes included the overall incidence and specific types of diabetes-related complications. Meta-analyses were performed using R version 4.5.0 with the meta package (version 8.1-0), employing random-effects models. Results are presented as standardized mean differences (SMDs) with 95% confidence intervals (CIs) for continuous outcomes and risk ratios (RRs) with 95% CIs for dichotomous outcomes. Results: 29 studies met the inclusion criteria: 26 investigated folic acid plus vitamin B12, one examined folic acid plus vitamin B6, and two evaluated folic acid in combination with both vitamins B12 and B6. Supplementation with folic acid plus vitamin B12 (SMD = -2.77, 95% CI [-3.23, -2.30], P < 0.0001) significantly reduced serum homocysteine levels and decreased the incidence of total complications (RR = 0.30, 95% CI [0.24, 0.38], P < 0.0001). Similar results were also observed for specific complication subtypes. Conclusions: Supplementation with folic acid and vitamin B12 may reduce homocysteine levels and the risk of complications in patients with T2DM. The substantial heterogeneity and limited sample size of our results necessitate confirmation through additional high-quality, large-scale randomized controlled trials.
Keywords: Folic Acid, B vitamins, type 2 diabetes mellitus, Homocysteine, diabetic complications, Meta-analysis
Received: 08 Sep 2025; Accepted: 10 Nov 2025.
Copyright: © 2025 Yin, Zhao, Wang and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ziming Zhao, zhaoziming@must.edu.mo
Xu Wang, njzywangxu@126.com
Qibiao Wu, qbwu@must.edu.mo
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