Long term diabetes drug (metformin) linked to gradually worsening vitamin b-12 deficiency

Long term diabetes drug (metformin) linked to gradually worsening vitamin b-12 deficiency

Individuals with diabetes type 2 who are treated for long periods with metformin are at risk of developing gradually worsening vitamin B-12 deficiency - in other words, the vitamin deficiency grows with time, according to new research published today in the British Medical Journal (BMJ).

Vitamin B-12 deficiency symptoms include mental changes, anemia, neuropathy and fatigue, the authors write - symptoms which may be misdiagnosed as being due to diabetes, complications linked to diabetes, or ageing.

Because vitamin B-12 deficiency is preventable, the authors suggest that regular vitamin B-12 monitoring during long-term metformin treatment should be strongly considered.

Metformin is the most frequently prescribed first-line therapy for patients with diabetes type 2. It is already known that taking metformin can lead to vitamin B-12 deficiency and could be linked to lower folate concentrations, which can subsequently result in a rise in homocysteine levels - a functional marker of vitamin B-12 and folate deficiency.

So, scientists from the Netherlands led by Professor Coen Stehouwer aimed to examine the effects of metformin treatment on levels of vitamin B-12, folate, and homocysteine in 390 patients with diabetes type 2.

196 study participants were given 850mg of metformin, while 194 received a placebo (dummy drug) three times a day for over four years. Measures were taken at regular intervals of the patients' vitamin B-12 levels, folate, and homocysteine levels.

Individuals who had been given metformin were found to have a 19% reduction in their vitamin B-12 levels, compared with those in the placebo group, who had virtually no change in their levels during the study.

Moreover, the drop in levels of vitamin B-12 by metformin was not temporary, but continued, and got worse over time.

There was also a considerable increase in the number of participants 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 those in the placebo group increased from four patients to five.

Compared with individuals taking the placebo, those 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 drop in vitamin B-12 levels were functionally meaningful.

"Our study shows that it is reasonable to assume harm will eventually occur in some patients with metformin-induced low vitamin B12 levels," the authors wrote.

Existing guidelines specify that metformin is a cornerstone in the treatment of diabetes type 2, 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."

"We first need to determine whether simple dietary counselling 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," researchers from Cardiff, Wales, wrote in an accompanying editorial.

"Research: Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial"

Jolien de Jager, Adriaan Kooy, Philippe Lehert, Michiel G Wulffelé, Jan van der Kolk, Daniël Bets, Joop Verburg, Ab J M Donker, Coen D A Stehouwer


BMJ 2010;340:c2181

"Editorial: Reduced serum vitamin B-12 in patients taking metformin"

Josep Vidal-Alaball, Christopher C Butler


BMJ 2010;340:c2198

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