de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010 May 20;340:c2181.
PMID: 20488910
doi: 10.1136/bmj.c2181
http://www.bmj.com/content/340/bmj.c2181.abstract
http://www.bmj.com/content/340/bmj.c2181.long
http://www.bmj.com/content/340/bmj.c2181.full.pdf
key data
"Metformin does ... induce vitamin B12 malabsorption, which may increase the risk of developing vitamin B12 deficiency -- a clinically important and treatable condition," the researchers wrote.
390 Type 2 diabetes patients at the outpatient clinics of three nonacademic hospitals to take either metformin or a placebo pill three times per day for more than four years. The average study participant had been diagnosed with diabetes 13 years prior and had been undergoing insulin treatment for seven years. Average participant age was 61.
Among those taking metformin, vitamin B12 levels began to steadily drop relative to those who were taking a placebo pill. The biggest drop occurred in the first few months, but the decrease continued over the course of the study.
For every 8.9 patients treated with metformin, one would develop insufficient vitamin B12 levels.
The researchers found that metformin seems to inhibit the intestine's absorption of vitamin B12. Fortunately, calcium supplements appear to reverse this effect.
Metformin had no significant effect on folate concentrations, after adjustment for body mass index and smoking.
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BMJ. 2010 May 20;340:c2181. doi: 10.1136/bmj.c2181.
Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial.
de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD.
Department of Ophthalmology, Academic Medical Center, Amsterdam, Netherlands.
Comment in:
BMJ. 2010;340:c2198.
Abstract
OBJECTIVES: To study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin.
DESIGN: Multicentre randomised placebo controlled trial.
SETTING: Outpatient clinics of three non-academic hospitals in the Netherlands.
PARTICIPANTS: 390 patients with type 2 diabetes receiving treatment with insulin.
INTERVENTION: 850 mg metformin or placebo three times a day for 4.3 years.
MAIN OUTCOME MEASURES: Percentage change in vitamin B-12, folate, and homocysteine concentrations from baseline at 4, 17, 30, 43, and 52 months.
RESULTS: Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of -19% (95% confidence interval -24% to -14%; P<0.001) and in folate concentration of -5% (95% CI -10% to -0.4%; P=0.033), and an increase in homocysteine concentration of 5% (95% CI -1% to 11%; P=0.091). After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. The absolute risk of vitamin B-12 deficiency (<150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B-12 concentration (150-220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 micromol/l (95% CI 18.8 to 30.0 micromol/l), compared with a mean homocysteine level of 18.1 micromol/l (95% CI 16.7 to 19.6 micromol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 micromol/l (95% CI 14.3 to 15.5 micromol/l; P<0.001 compared with vitamin B-12 deficiency; P=0.005 compared with low vitamin B-12) for patients with a normal vitamin B-12 concentration (>220 pmol/l).
CONCLUSIONS: Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. 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. Trial registration Clinicaltrials.gov NCT00375388.
PMID: 20488910