Patients treated over prolonged periods with metformin, a common drug for diabetes, are at risk of developing vitamin B-12 deficiency, which is likely to get progressively worse over time, according to a new study published on bmj.com today.
Symptoms of B-12 deficiency include fatigue, mental changes, anemia and neuropathy, which can easily be misdiagnosed as being due to diabetes and its complications or to ageing.
Because vitamin B-12 deficiency is preventable, the researchers suggest that regular measurement of vitamin B-12 levels during long-term metformin treatment should be strongly considered.
Metformin is the most commonly prescribed first-line therapy for patients with type 2 diabetes. It is already known that taking metformin can lead to vitamin B-12 deficiency and could be associated with decreased folate concentrations, which might, in turn, result in an increase in homocysteine levels - a functional marker of vitamin B-12 and folate deficiency.
So researchers from the Netherlands led by Professor Coen Stehouwer set out to study the effects of metformin treatment on levels of vitamin B-12, folate, and homocysteine in 390 patients with type 2 diabetes.
They gave 850 mg of metformin to 196 of the study's participants and a placebo to the other 194 people three times daily for more than four years. Measures were taken at regular intervals of the patients' vitamin B-12 levels, folate, and homocysteine levels.
People who had taken the metformin were found to have a 19% reduction in their vitamin B-12 levels, compared with people who had taken a placebo, who had almost no change in their levels during the study.
In addition, the reduction of levels of vitamin B-12 by metformin was not temporary, but persisted and became more apparent over time.
There was also a significant rise in the number of people with deficient levels of vitamin B-12 over the period of the study if they had been taking metformin, from three patients to 19. The equivalent number for the placebo group rose from four patients to five.
Compared with people taking a placebo, people taking metformin also had a 5% increase in homocysteine, but their folate levels were the same once the researchers took body mass index and smoking figures into account. Homocysteine levels increased especially in individuals in whom vitamin B-12 levels decreased - showing that the decrease in vitamin B-12 levels were functionally meaningful.
The authors say: "Our study shows that it is reasonable to assume harm will eventually occur in some patients with metformin-induced low vitamin B12 levels."
Current guidelines indicate that metformin is a cornerstone in the treatment of type 2 diabetes, but make no recommendations on the detection and prevention of vitamin B-12 deficiency during treatment, they add. "Our data provide a strong case for routine assessment of vitamin B-12 levels during long term treatment with metformin."
Researchers from Cardiff, writing in an accompanying editorial, say: "We first need to determine whether simple dietary counseling when metformin is started and at medication reviews will solve the problem. If it does not, a trial of screening for vitamin B-12 deficiency in patients taking metformin would be needed."