Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial

J Intern Med. 2003 Nov;254(5):455-63. doi: 10.1046/j.1365-2796.2003.01213.x.


Objective: Metformin is a key treatment option in type 2 diabetes. However, metformin may decrease vitamin B12 levels and increase levels of homocysteine, a cardiovascular risk factor. We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine, folate and vitamin B12 in subjects with type 2 diabetes treated with insulin.

Design: Placebo-controlled, randomized trial.

Measurements: at baseline and 16 weeks later.

Setting: This trial was conducted in the outpatient clinics of three general hospitals in The Netherlands.

Subjects: A total of 745 patients with type 2 diabetes, treated with insulin and not known with a contraindication for the use of metformin, were approached; 390 gave informed consent and entered the study. Thirty-seven subjects dropped out (12 placebo and 25 metformin users).

Intervention: Addition of metformin or placebo to insulin therapy. PRIMARY OUTCOME PARAMETERS: Serum homocysteine, folate, vitamin B12, indices of glycaemic control and body weight.

Results: Amongst those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of 4% (0.2 to 8; P=0.039) and with decreases in folate [-7% (-1.4 to -13); P=0.024] and vitamin B12 [-14% (-4.2 to -24); P<0.0001]. In addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12.

Conclusion: In patients with type 2 diabetes, 16 weeks of treatment with metformin reduces levels of folate and vitamin B12, which results in a modest increase in homocysteine. The clinical significance of these findings remains to be investigated.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Folic Acid / blood
  • Folic Acid / drug effects
  • Homocystine / blood
  • Homocystine / drug effects*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Metformin / pharmacology*
  • Middle Aged
  • Vitamin B 12 / blood


  • Hypoglycemic Agents
  • Homocystine
  • Metformin
  • Folic Acid
  • Vitamin B 12