• folate;
  • homocysteine;
  • metformin;
  • vitamin B12

Aarsand AK, Carlsen SM (Norwegian University of Science and Technology, Trondheim, Norway.) Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment. J Intern Med 1998; 244: 169–74.


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


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


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.


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.


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.


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