People taking the diabetes drug metformin for prolonged periods increase their risk of developing vitamin B₁₂ deficiency, says a team of researchers in the Netherlands, and such deficiencies, while preventable and treatable, are likely to worsen over time if not monitored for and corrected.

Though earlier, shorter term studies had established that metformin induces vitamin B₁₂ malabsorption, little was known about the drug’s effect on serum B₁₂ levels in the long term. Vitamin B₁₂ deficiencies can cause anemia, mental changes, and neuropathy, among other serious effects; they can also result in elevated homocysteine concentrations, an independent risk factor for cardiovascular disease.

The new findings, published online May 21 in the BMJ, suggest that metformin’s deleterious effect on vitamin B₁₂ levels can continue with the duration of metformin therapy to the point of clinical deficiency (less than 150 pmol/L).

For their research, Dr. Jolien de Jager of the Academic Medical Center in Amsterdam, the Netherlands, and the Bethesda Diabetes Research Centre in Hoogeveen, the Netherlands, and colleagues, randomized 390 diabetic patients already receiving insulin therapy to either placebo or 850 mg of metformin three times daily for 4.3 years, with B₁₂, folate and homocysteine levels measured at baseline, then 4 months, then at roughly yearly intervals to 52 months (BMJ 2010;340:c2181[doi:10.1136/bmj.c2181]).

A total of 196 patients were assigned to the metformin arm (mean age 64) and 194 to the placebo arm (mean age 59). Of those, 131 patients in the metformin arm and 146 on placebo completed the study and were included in the final analysis.

The metformin group saw a mean decrease in B₁₂ concentrations of 19% from baselines, compared with subjects taking insulin and placebo. The number of metformin patients with B₁₂ deficiencies increased over the course of the study, from 3 at baseline to 19 at 52 months, compared with a much smaller increase – from 4 patients to 5 – in the placebo group.

Absolute risk of developing a B₁₂ deficiency was 7.2 percentage points higher in the metformin group; risk of developing low B₁₂ concentration (150-220 pmol/L), which the investigators said could have clinically important implications for some people, was 11.2 points higher in the metformin group.

“Our study shows that this decrease is not a transitory phenomenon, but persists and grows over time,” Dr. de Jager and colleagues wrote in their analysis.

The study was funded by grants from Altana, Lifescan, Merck Santé, Merck Sharp & Dohme, and Novo Nordisk, though none of these had a role in the study’s design. Dr. de Jager and his colleagues declared no relationships to these entities beyond funding for the study.

The researchers also saw folate concentrations of decrease of 5% from baseline in the metformin group, compared with the placebo group, and a 5% increase in homocysteine levels. However, the placebo group had a higher proportion of smokers and higher body mass index, and investigators found no statistically significant differences in folate concentration after adjusting for those factors. Nor did they find differences in folate concentration over time. Homocysteine levels were found to have increased the most in subjects whose vitamin B₁₂ levels had decreased.

One limitation of the study, Dr. de Jager and colleagues wrote in their analysis, was that because all study subjects received frequent nutrition counseling, the likelihood of vitamin deficiency may have been decreased in the study population, compared with that in the population at large. Nonetheless, they concluded, “our data provide a strong case for routine assessment of vitamin B-12 levels during long term treatment with metformin.”

In a related editorial, Dr. Josep Vidal-Alaball and Dr. Christopher C. Butler of the Department of Primary Care and Public Health in Heath Park, Cardiff (England), praised de Jager and colleagues’ study for its long duration and convincing demonstration of a difference in B₁₂ between the groups. They also wrote that it raised questions about how the clinical implications of the B₁₂ findings should be understood.

“The authors recommend that regular measurement of vitamin B-12 concentrations during long-term metformin treatment should be considered. Sadly, though, they do not report on quality of life, neurological status, or measures of fatigue,” Dr. Vidal-Alaball and Dr. Butler wrote. Although patients with B₁₂ concentrations of less than 150 pmol/L “may be at higher risk for vitamin B-12 deficiency related effects, these risks are not clearly quantified or always directly related to vitamin B-12 concentrations.” (BMJ 2010;340:c2198)

The study also raised questions about how and how often to monitor for B₁₂ deficiency, they wrote, and further, how to treat it. “It is not clear what form the intervention should take,” they wrote, as options could include dietary changes, supplements, and intramuscular injections.

Dr. Vidal-Alaball and Dr. Butler declared no competing interests.

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