Vitamin B12 Status in Metformin Treated Patients: Systematic Review

Objective: Randomized controlled trials and observational studies have yielded inconsistent results on the effects of metformin on vitamin B-12 reduction. We therefore performed a systematic review to analyze the effects of metformin on vitamin B-12 concentration. Methods: PubMed, Medline, Embase, and the Cochrane central registry of controlled trials were searched to identify randomized controlled trials and observational studies exploring the association between metformin and vitamin B-12 concentration in patients with type 2 diabetes mellitus or polycystic ovary syndrome. The main outcome measure was changes in serum vitamin B-12 concentration after 6-208 weeks of treatment with metformin, as compared with placebo or other anti-hyperglycemic therapy. Results: Six randomized controlled trials met the inclusion criteria. Serum vitamin B-12 concentrations were significantly lower in patients treated with metformin than in those who received placebo or rosiglitazone (mean difference [MD], -53.93 pmol/L; 95% confidence interval [CI], -81.44 to -26.42 pmol/L, P = 0.0001). Subgroup analysis identified four trials in which patients received a lower dose of metformin (<2000 mg/d) and two in which they received a higher dose (>= 2000 mg/d), with MDs in vitamin B-12 concentration after metformin treatment of -37.99 pmol/L (95% CI, -57.44 to -18.54 pmol/L, P = 0.0001) and -78.62 pmol/L (95% CI, -106.37 to -50.86 pmol/L, P<0.00001), respectively. Conclusions: The reduction of vitamin B-12 may be induced by metformin in a dose dependent manner.