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. 2016 Dec 9;8(12):798.
doi: 10.3390/nu8120798.

Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Free PMC article

Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Qianying Zhang et al. Nutrients. .
Free PMC article


The aim of this systematic review is to assess whether metformin could change the concentration of serum homocysteine (Hcy) with and without simultaneous supplementation of B-group vitamins or folic acid. A literature search was conducted in PubMed, EmBase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) reporting the concentration of serum Hcy in metformin-treated adults. Meta-analysis was applied to assess the association between metformin and the changes of Hcy concentration. Twelve publications were included in this study. In the overall analysis, metformin administration was not statistically associated with the change of Hcy when compared with the control treatment (mean difference (MD), 0.40 μmol/L; 95% confidence interval (CI), -0.07~0.87 μmol/L, p = 0.10). In the subgroup analysis, metformin was significantly associated with an increased concentration of Hcy in the absence of exogenous supplementation of folic acid or B-group vitamins (MD, 2.02 μmol/L; 95% CI, 1.37~2.67 μmol/L, p < 0.00001), but with a decreased concentration of serum Hcy in the presence of these exogenous supplementations (MD, -0.74 μmol/L; 95% CI, -1.19~-0.30 μmol/L, p = 0.001). Therefore, although the overall effect of metformin on the concentration of serum Hcy was neutral, our results suggested that metformin could increase the concentration of Hcy when exogenous B-group vitamins or folic acid supplementation was not given.

Keywords: folic acid; homocysteine; meta-analysis; metformin; systematic review; vitamin B12.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Flow diagram for study identification and inclusion.
Figure 2
Figure 2
Overall analysis on Hcy concentration and subgroup analysis on Hcy concentration of patients with or without folic acid or B-group vitamins supplementation. The changes from baseline (Mean ± SD) between the two groups were compared. SD, standard deviation; CI, confidence interval; IV, inverse variance.

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