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Metformin Treatment Leads to Increased Homocysteine, Decreased Vitamin B12 and Folate in Type 2 Diabetes Patients

Metformin treatment leads to an increase in homocysteine levels in patients with type 2 diabetes who take insulin, according to a recent report from Bethesda General Hospital, Hoogeveen, Netherlands.

Homocysteine is a sulphur-containing amino acid that has recently been recognised as an independent potential risk factor for cardiovascular disease in patients with type 2 diabetes. Homocysteine requires folate and vitamin B12 to be properly metabolised, and serum vitamin B12 levels are known to decrease during metformin treatment. However, the effect of metformin on homocysteine levels was unclear based on previous studies.

To address this concern, investigators led by M.G. Wulffele performed a placebo-controlled randomised trial to examine the effects of metformin treatment on serum levels of homocysteine, vitamin B12 and folate in type 2 diabetics.

The patients (N=390) were randomised to receive either metformin (mean dose, 2163 mg/day) or placebo in addition to insulin for a period of 16 weeks. Among the patients who completed the study (n=353), 171 received metformin (mean age, 63.2 ± 9.8 years; 95 females) and 182 received placebo (mean age, 58.9 ± 11.1 years, 91 females).

The researchers found that, compared with placebo, metformin was associated with an increase in serum homocysteine levels (4% [0.2 to 8 µmol L^-1]; P=0.039), and decreases in vitamin B12 (-14% [-4.2 to -24 pmol L^-1]; P<0.0001) and folate (-7% [-1.4 to -13 nmol L^-1]; P=0.024). In addition, they used structural equation modelling to demonstrate that metformin therapy did not affect homocysteine directly. Rather, the increase in homocysteine was an indirect effect mediated by direct effects on folate and vitamin B12.

The researchers comment that, "the clinical significance of such an increase [in homocysteine] is not yet clear but may not be negligible." In support of this idea, they note a recent analysis demonstrating that a persistent increase in serum homocysteine of 3 µmol L^-1 was associated with an increased risk of coronary heart disease and stroke in nondiabetic individuals. "There is evidence that such risk increases may be greater amongst diabetic individuals," they add.

J Intern Med 2003 Nov;254:5:455-463. "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"

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