Aim: Metformin is the first-line treatment in type 2 diabetic patients. However, it may raise homocystein levels through vitamin B12 deficiency, which might adversly affects its alleged cardiovascular advantages. In this study, we investigated the association between metformin-associated vitamin B12 deficiency and the occurrence of silent myocardial ischemia and hematological abnormalities in type 2 diabetes.

Methods: This hospital-based cross-sectional study evaluated 798 asymptomatic patients with type 2 diabetes and at least one cardiovascular risk factor. Biological and clinical parameters were compared first between the 497 metformin-treated patients and the 301 metformin-free patients, and second between metformin users with and without vitamin B12 deficiency. Outcomes included vitamin B12 deficiency (15 μmol/l), anemia, macrocytosis and silent myocardial ischemia (positive stress myocardial perfusion imaging).

Results: Mean diabetes duration of the whole sample was 14.3 ± 9.5 years. Crude prevalence of vitamin B12 deficiency was 12.5% in metformin treated patients and 6.1% in metformin free patients (p<0.01). The homocystein level was not increased in metformin users, but among them it was higher in vitamin B12 deficient patients. In both univariate and multivariate analyses, metformin-associated vitamin B12 deficiency was not related to increased risks of hyperhomocysteinemia, silent myocardial ischemia, or to the combined endpoint of macrocytosis and anemia.

Conclusion: This large cross-sectional study confirms that vitamin B12 deficiency is more common among metformin users, but does not suggest a detrimental effect of metformin on silent myocardial ischemia nor on hematological abnormalities, even though such effects cannot be excluded.