Long-Term Metformin Treatment Linked to Vitamin B12 Deficiency

Laurie Barclay, MD

May 24, 2010

May 24, 2010 — In type 2 diabetes, long-term metformin treatment is linked to vitamin B12 deficiency, according to the results of a multicenter, randomized, placebo-controlled trial reported Online First May 20 in the BMJ.

"Metformin is considered a cornerstone in the treatment of diabetes and is the most frequently prescribed first line therapy for individuals with type 2 diabetes," write Jolien de Jager, from the Academic Medical Center in Amsterdam, the Netherlands, and colleagues. "In addition, it is one of a few antihyperglycaemic agents associated with improvements in cardiovascular morbidity and mortality, which is a major cause of death in patients with type 2 diabetes....Metformin does, however, induce vitamin B-12 malabsorption, which may increase the risk of developing vitamin B-12 deficiency — a clinically important and treatable condition."

The goal of this trial was to determine the effects of metformin on the incidence of vitamin B12 deficiency, defined as vitamin B12 levels of less than 150 pmol/L and low levels of vitamin B12 (150 - 220 pmol/L), as well as on folate and homocysteine concentrations.

At the outpatient clinics of 3 nonacademic hospitals in the Netherlands, 390 patients with type 2 diabetes being treated with insulin received 850 mg of metformin or placebo 3 times daily for 4.3 years. The primary study endpoints were percentage change from baseline in vitamin B12, folate, and homocysteine concentrations at 4, 17, 30, 43, and 52 months.

The metformin group vs the placebo group had a mean decrease in vitamin B12 concentration of −19% (95% confidence interval [CI], −24% to −14%; P < .001), a mean decrease in folate concentration of −5% (95% CI, −10% to −0.4%; P = .033), and a mean increase in homocysteine concentration of 5% (95% CI, −1% to 11%; P = .091). Metformin had no significant effect on folate concentrations, after adjustment for body mass index and smoking.

At the end of the study, the absolute risk for vitamin B12 deficiency was 7.2 percentage points higher with metformin vs placebo (95% CI, 2.3 - 12.1; P = .004), yielding a number needed to harm of 13.8 per 4.3 years (95% CI, 43.5 - 8.3). For low vitamin B12 concentrations at study end, the absolute risk was 11.2 percentage points higher with metformin vs placebo (95% CI, 4.6 - 17.9; P = .001), and number needed to harm was 8.9 per 4.3 years (95% CI, 21.7 - 5.6).

Among patients who had vitamin B12 deficiency at the end of the study, mean homocysteine level was 23.7 μmol/L (95% CI, 18.8 - 30.0 μmol/L) vs 18.1 μmol/L (95% CI, 16.7 - 19.6 μmol/L; P = .003) among patients who had low vitamin B12 concentration and 14.9 μmol/L among patients who had normal vitamin B12 concentration.

"Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations," the study authors write. "Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered."

Limitations of this study include measurement only of total vitamin B12 levels and not levels of holotranscobalamin II or methylmalonic acid, and possible underestimation of the impact of metformin treatment on the risk for clinically important vitamin B12 deficiency.

Editorial: Dietary Counseling May Help

In an accompanying editorial, Josep Vidal-Alaball and Christopher C. Butler, from the Department of Primary Care and Public Health in Heath Park, Cardiff, Wales, United Kingdom, recommend determining whether simple dietary counseling when metformin is started and at follow-up would solve the problem.

"If it does not, a trial of screening for vitamin B-12 deficiency in patients taking metformin would be needed," Drs. Vidal-Alaball and Butler write. "Patients taking metformin (not just those also treated with insulin) should be randomised to systematic serum vitamin B-12 screening or routine care, with patient oriented outcomes and costs included in the outcomes. Otherwise, we risk increasing the burden on patients and the costs of care by treating biochemical outcomes rather than outcomes that matter to patients."

Grants from Altana, Lifescan, Merck Santé, Merck Sharp & Dohme, and Novo Nordisk supported this study. The study authors and editorialists have disclosed no relevant financial relationships.

BMJ. Published online May 20, 2010. Abstract


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