Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease

Abstract

It is known that the metabolism of homocysteine (Hcy) depends on the vitamins B₆, B₁₂ and folate, and furthermore that metformin reduces serum vitamin B₁₂ levels. In order to investigate whether metformin treatment affects serum total Hcy (tHcy) levels we performed an open, prospective, randomised study in 60 non-diabetic male patients with cardiovascular disease. After a 4-week run-in period with lovastatin 40 mg day^-1, and diet and lifestyle advice, patients were randomised into two groups, both continuing the run-in treatment. One group received metformin up to 2000 mg day^-1, whereas the control group got no additional treatment.

After 12 and 40 weeks of metformin treatment, tHcy levels increased moderately but significantly by 7.2% (p<0.05) and 13.8% (p<0.05) in the metformin group relative to the control group, whereas serum vitamin B₁₂ levels decreased by 13.4% (p<0.0005) and 17.7% (p<0.0005), respectively. Serum folate levels did not change after 12 weeks, but decreased by 8.0% after 40 weeks (p=0.061) relative to the control group. Serum levels of total cysteine and methylmalonic acid (MMA) did not change.

In conclusion, metformin treatment increased tHcy levels and decreased levels of vitamin B₁₂ and folate. Since MMA levels were unchanged, it remains an open question whether the increase in tHcy levels is secondary to reduced vitamin B₁₂ levels, folate levels or a combination of both.

Key Words:

• folate
• homocysteine
• metformin
• vitamin B12