title: Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial.
abstract: OBJECTIVE
  To study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin.
  
  
  METHODS
  Multicentre randomised placebo controlled trial.
  
  
  METHODS
  Outpatient clinics of three non-academic hospitals in the Netherlands.
  
  
  METHODS
  390 patients with type 2 diabetes receiving treatment with insulin.
  
  
  METHODS
  850 mg metformin or placebo three times a day for 4.3 years.
  
  
  METHODS
  Percentage change in vitamin B-12, folate, and homocysteine concentrations from baseline at 4, 17, 30, 43, and 52 months.
  
  
  RESULTS
  Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of -19% (95% confidence interval -24% to -14%; P<0.001) and in folate concentration of -5% (95% CI -10% to -0.4%; P=0.033), and an increase in homocysteine concentration of 5% (95% CI -1% to 11%; P=0.091). After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. The absolute risk of vitamin B-12 deficiency (<150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B-12 concentration (150-220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 micromol/l (95% CI 18.8 to 30.0 micromol/l), compared with a mean homocysteine level of 18.1 micromol/l (95% CI 16.7 to 19.6 micromol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 micromol/l (95% CI 14.3 to 15.5 micromol/l; P<0.001 compared with vitamin B-12 deficiency; P=0.005 compared with low vitamin B-12) for patients with a normal vitamin B-12 concentration (>220 pmol/l).
  
  
  CONCLUSIONS
  Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered. Trial registration Clinicaltrials.gov NCT00375388.
authors.affiliation: Department of Ophthalmology, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Jolien
authors.initials: J
authors.lastname: de Jager
authors.forename: Adriaan
authors.initials: A
authors.lastname: Kooy
authors.forename: Philippe
authors.initials: P
authors.lastname: Lehert
authors.forename: Michiel G
authors.initials: MG
authors.lastname: Wulffelé
authors.forename: Jan
authors.initials: J
authors.lastname: van der Kolk
authors.forename: Daniël
authors.initials: D
authors.lastname: Bets
authors.forename: Joop
authors.initials: J
authors.lastname: Verburg
authors.forename: Ab J M
authors.initials: AJ
authors.lastname: Donker
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
mesh_terms: D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D008134:Long-Term Care; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged; D012307:Risk Factors; D014805:Vitamin B 12 / Q000378:metabolism; D014806:Vitamin B 12 Deficiency / Q000139:chemically induced*
chemical_list: D007004:Hypoglycemic Agents; D006710:Homocysteine; D008687:Metformin; D005492:Folic Acid; D014805:Vitamin B 12