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Long-Term Metformin Raises Risk for B12 Deficiency

Routine B12 monitoring is recommended.

Metformin — the most commonly prescribed oral drug for patients with type 2 diabetes — induces vitamin B12 malabsorption and therefore can raise risk for vitamin B12 deficiency. In this multicenter randomized trial, Dutch investigators assessed risk for B12 deficiency (blood level, <150 pmol/L), low vitamin B12 level (blood level, 150–220 pmol/L), and elevated blood homocysteine levels in patients with type 2 diabetes who were treated with metformin.

Overall, 390 patients received metformin (850 mg) or placebo three times daily for 4.3 years. Compared with placebo, metformin was associated with a significant 19% decrease in baseline vitamin B12 concentration. The absolute risks for vitamin B12 deficiency and low vitamin B12 level were significantly higher in the metformin group than in the placebo group: 7% and 11% higher, with numbers needed to harm of 14 and 9 per 4.3 years, respectively. Blood homocysteine levels were correspondingly and significantly elevated. Notably, the effect of metformin on lowering B12 levels increased with duration of therapy.

Comment: That metformin use is associated with lower blood B12 levels has been observed previously (JW Gen Med Feb 25 2010). However, this trial shows that metformin use raises risks for B12 deficiency, low B12 levels, and high homocysteine levels. Because B12 deficiency can result in anemia, neuropathy, and cognitive changes and because elevated blood homocysteine level is a risk factor for cardiovascular disease, the authors recommend routine monitoring of B12 levels in patients who receive metformin. Whether B12 supplementation prevents B12 deficiency in such patients is unknown.

— Paul S. Mueller, MD, MPH, FACP

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