Vitamin B(12) 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.