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Metformin causes B-12 deficiency in some

Clinical Question:
Does chronic use of metformin induce cyancobalamin (vitamin B-12) deficiency?

Bottom Line:
Long-term metformin treatment will cause low vitamin B-12 levels or vitamin B-12 deficiency in approximately 1 of every 14 patients treated with the drug instead of placebo. Whether preventive supplementation of B-12 will prevent this depletion is unknown, but increased calcium intake will enhance absorption. We don't know if asymptomatic B-12 deficiency needs to be treated, but calcium supplementation and B12 treatment is inexpensive. (LOE = 2b)

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;340:c2181.  [PMID:20488910]

Study Design:
Randomized controlled trial (double-blinded)



Outpatient (primary care)

Patients in this study were recruited from outpatient clinics of 3 hospitals in the Netherlands. All were currently receiving treatment for their diabetes. The 390 patients were converted to insulin treatment from their existing treatment and then given placebo or metformin (Glucophage) 850 mg 3 times a day (allocation concealed) and treated for 4.3 years. Analysis was by intention to treat and used the last observation carried forward to account for missing data. Over the study period, 29% of patients dropped out, which is common in long studies. Approximately twice as many patients in the metformin group dropped out because of side effects (15% vs 8%). B-12 deficiency, defined as less than 200 pg/mL (< 150 pmol/L), was 7.2 percentage points higher in the metformin group, meaning that 1 additional person became B-12 deficient for every 14 patients receiving metformin instead of placebo (number needed to treat = 13.8; 95% CI, 8.3 - 43.5). Low B-12 levels, defined as 200-300 pg/mL (150 - 220 pmol/L), were 11.2 percentage points higher in the metformin group. This lowering of B-12 increased with the duration of treatment. The authors did not report on the incidence of B-12 deficiency-related symptoms or the incidence of macrocytic anemia. B-12 malabsorption can be prevented by increasing calcium intake; it is not known if oral B-12 supplementation prevents deficiency.


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