title: Association between metformin and vitamin B12deficiency in patients with type 2 diabetes: A systematic review and meta-analysis.
abstract: OBJECTIVE
  Metformin is the most widely used oral hypoglycaemic drug, but it may lower B12status, which could have important clinical implications. We undertook a systematic review and meta-analysis of the relationship between metformin use and vitamin B12deficiency 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 B12levels, % prevalence or incidence of vitamin B12deficiency and risk of vitamin B12deficiency.
  
  
  RESULTS
  Twenty-six papers were included in the review. Ten out of 17 observational studies showed statistically significantly lower levels of vitamin B12in patients on metformin than not on metformin. Meta-analysis performed on four trials demonstrated a statistically significant overall mean B12reducing effect of metformin of 57pmol/L [WMD (fixed)=-0.57 (95% CI: -35 to -79pmol/L)] after 6weeks to 3months of use.
  
  
  CONCLUSIONS
  The evidence from this review demonstrates an association between metformin usage and lower levels of vitamin B12by 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 B12levels in these patients who are at increased risk of deficiency.
authors.affiliation: Department of Nutritional Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom; Ravenscroft Medical Centre, 166-168 Golders Green Road, Golders Green, NW11 8BB London, United Kingdom.
authors.forename: L E
authors.initials: LE
authors.lastname: Chapman
authors.affiliation: Department of Nutritional Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom. Electronic address: a.l.darling@surrey.ac.uk.
authors.forename: A L
authors.initials: AL
authors.lastname: Darling
authors.affiliation: Department of Nutritional Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH Guildford, United Kingdom.
authors.forename: J E
authors.initials: JE
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000453:epidemiology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D014806:Vitamin B 12 Deficiency / Q000139:chemically induced / Q000150:complications / Q000453:epidemiology
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Diabetes mellitus; Meta-analysis; Metabolic adverse effects; Oral hypoglycaemic agents; Primary care; Vitamin deficiency