Association between metformin and vitamin B 12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis

Diabetes Metab. 2016 Nov;42(5):316-327. doi: 10.1016/j.diabet.2016.03.008. Epub 2016 Apr 26.


Aim: Metformin is the most widely used oral hypoglycaemic drug, but it may lower B12 status, which could have important clinical implications. We undertook a systematic review and meta-analysis of the relationship between metformin use and vitamin B12 deficiency in persons with type 2 diabetes.

Methods: Electronic database searches were undertaken (1st January 1957-1st July 2013) using the Cochrane library, Scopus, CINAHL, Grey literature databases, Pub Med Central, NICE Clinical Guidelines UK, and ongoing clinical trials. Included studies were of any study design, with data from patients with type 2 diabetes of any age or gender, taking any dose or duration of metformin. Planned primary outcomes were serum vitamin B12 levels, % prevalence or incidence of vitamin B12 deficiency and risk of vitamin B12 deficiency.

Results: Twenty-six papers were included in the review. Ten out of 17 observational studies showed statistically significantly lower levels of vitamin B12 in patients on metformin than not on metformin. Meta-analysis performed on four trials demonstrated a statistically significant overall mean B12 reducing effect of metformin of 57pmol/L [WMD (fixed)=-0.57 (95% CI: -35 to -79pmol/L)] after 6weeks to 3months of use.

Conclusion: The evidence from this review demonstrates an association between metformin usage and lower levels of vitamin B12 by 57pmol/L, which leads to frank deficiency or borderline status in some patients with type 2 diabetes. This suggests that it is prudent to monitor B12 levels in these patients who are at increased risk of deficiency.

Keywords: Diabetes mellitus; Meta-analysis; Metabolic adverse effects; Oral hypoglycaemic agents; Primary care; Vitamin deficiency.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / epidemiology
  • Female
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Metformin / adverse effects*
  • Metformin / therapeutic use
  • Middle Aged
  • Vitamin B 12 Deficiency* / chemically induced
  • Vitamin B 12 Deficiency* / complications
  • Vitamin B 12 Deficiency* / epidemiology


  • Hypoglycemic Agents
  • Metformin