Associations between metformin use and vitamin B₁₂ levels, anemia, and neuropathy in patients with diabetes: a meta-analysis

Background: Metformin is first-line therapy for patients with diabetes. However, it may lower vitamin B₁₂ concentrations, which could have hematological or neurological implications. This meta-analyses reviewed all available studies on associations between metformin use and vitamin B₁₂ levels, anemia, and neuropathy in diabetic patients.

Methods: PubMed, Web of Knowledge, Cochrane Library, and Embase were searched to identify all relevant studies published in English prior to March 2018. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for dichotomous outcomes and pooled mean differences (MDs) and 95% CIs were calculated for continuous outcomes.

Results: Thirty-one studies were included in the meta-analyses. Compared with diabetic patients not taking metformin, patients taking metformin had a significantly higher risk of vitamin B₁₂ deficiency (RR 2.09; 95% CI 1.49, 2.93; P < 0.0001; I² = 64%) and significantly lower serum vitamin B₁₂ concentrations (MD -63.70; 95% CI -74.35, -53.05] pM; P < 0.00001; I² = 87%), which depended on dose and duration of treatment. Metformin use was also associated with significantly greater percentage decrease in serum vitamin B₁₂ concentrations from baseline in diabetic patients (MD -14.68%; 95% CI -17.98%, -11.39%; P < 0.00001; I² = 33%). Analyses revealed no significant association between metformin use and the prevalence of anemia or neuropathy.

Conclusions: Metformin use led to significantly lowered vitamin B₁₂ concentrations and significantly higher risk of vitamin B₁₂ deficiency in diabetic patients. More quality studies are needed to explore the associations between metformin use and anemia and neuropathy in these patients. Annual vitamin B₁₂ assessment in diabetic patients taking metformin is recommended.