Vitamin B12 status in metformin treated patients: systematic review

PLoS One. 2014 Jun 24;9(6):e100379. doi: 10.1371/journal.pone.0100379. eCollection 2014.


Objective: Randomized controlled trials and observational studies have yielded inconsistent results on the effects of metformin on vitamin B12 reduction. We therefore performed a systematic review to analyze the effects of metformin on vitamin B12 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 B12 concentration in patients with type 2 diabetes mellitus or polycystic ovary syndrome. The main outcome measure was changes in serum vitamin B12 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 B12 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 B12 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 B12 may be induced by metformin in a dose dependent manner.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Metformin / adverse effects
  • Metformin / therapeutic use*
  • Polycystic Ovary Syndrome / blood*
  • Polycystic Ovary Syndrome / drug therapy*
  • Randomized Controlled Trials as Topic
  • Treatment Outcome
  • Vitamin B 12 / blood*


  • Hypoglycemic Agents
  • Metformin
  • Vitamin B 12

Grant support

This research was funded by grant from the National Natural Science Foundation of China, No. 30600293 (Jianwei Li) ( The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.