Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment

J Intern Med. 1998 Aug;244(2):169-74. doi: 10.1046/j.1365-2796.1998.00361.x.


Objectives: Metformin treatment increases circulating homocysteine levels. We studied whether administration of folate reduces serum total homocysteine levels in patients on long-term metformin treatment.

Design: A prospective, randomized, double-blind, placebo-controlled study lasting for 12 weeks and taking place in a university hospital setting.

Subjects: Thirty patients treated with a metformin dose of at least 1000 mg day-1 for a minimum of 1 year were included. At baseline serum total homocysteine levels were within the reference range. One patient who withdrew and one who died were excluded from the statistical evaluation. Twenty-six of the remaining patients suffered from NIDDM, the other two from hyperlipidaemia.

Intervention: Patients were randomized into two groups at week 0. The folate group received 0.25 mg day-1 of folate in addition to 60 mg day-1 of Fe2+, while the placebo group received only 60 mg day-1 of Fe2+.

Main outcome measures: Fasting homocysteine, cysteine, cysteinylglycine, vitamin B12 and folate were measured at week 0, 4 and 12. Changes from week 0 to week 4 and from week 0 to week 12 were calculated.

Results: Folate administration reduced serum levels of total homocysteine in the folate group as compared with the placebo group by 13.9% (P < 0.01) and 21.7% (P < 0.001) at week 4 and 12, respectively. In the folate group versus the placebo group serum levels of vitamin B12 increased by 9.9% (P = 0.010) and 9.6% (P = 0.043) while folate levels increased by 96.9 and 89.9% at week 4 and 12, respectively.

Conclusion: The present study indicates that the homocysteine-increasing effect of metformin can be counteracted by folate administration.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / etiology*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dipeptides / blood
  • Double-Blind Method
  • Female
  • Folic Acid / therapeutic use*
  • Hematinics / therapeutic use*
  • Homocysteine / blood*
  • Homocysteine / drug effects*
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Metformin / adverse effects*
  • Metformin / therapeutic use
  • Middle Aged
  • Prospective Studies
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • Vitamin B 12 / blood


  • Dipeptides
  • Hematinics
  • Hypoglycemic Agents
  • Homocysteine
  • cysteinylglycine
  • Metformin
  • Folic Acid
  • Vitamin B 12