The Impact of Metformin on Vitamin B12 Levels in Children and Adolescents: A Systematic Review and Single-Arm Meta-Analysis.

Abstract

The use of metformin among children and adolescents has risen in the past decade; however, its effect on vitamin B12 has been unclear. To address this gap, we conducted this first systematic review and single-arm meta-analysis. To investigate the effect of metformin on vitamin B12 levels. PubMed, Scopus and Web of Science were systematically searched until April 2025. The primary outcomes were the effect of metformin on vitamin B12 levels after 6 and 12 months of duration, and vitamin B12 deficiency after at least 12 months of usage. We conducted the risk-of-bias assessment using the NOS and Cochrane ROB2 tool. The mean difference (MD) and standard error (SE) were calculated and used for analysis. We assessed the heterogeneity of the studies using the chi-squared test and measured it with the I 2 statistic. A fixed effects model was applied to calculate the pooled MD in the absence of significant heterogeneity. The registration number in PROSPERO 2025 is CRD420251045023. A total of five articles were included in this systematic review and meta-analysis. The pooled rate of vitamin B12 deficiency in RCT studies after at least 12 months of use was 1.4% [95% CI: -0.012, 0.040] with mild heterogeneity (I 2 = 30.87%, p = 0.235). While in observational studies the pooled rate was 18.7% [95% CI: -0.212, 0.586] with substantial heterogeneity (I 2 = 87.93%, p = 0.004). Vitamin B12 levels decreased after 6 and 12 months of using metformin; however, it was neither statistically nor clinically significant (p > 0.05). More trials with larger sample sizes and longer durations of follow-up are needed to better understand the risk of vitamin B12 deficiency among the paediatric population. PROSPERO (CRD420251045023).