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

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.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and all authors want to declare: (1) Financial support for the submitted work from Merck Sharp & Dohme. All authors also declare: (2) No financial relationships with commercial entities that might have an interest in the submitted work; (3) No spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work; and (4) No non-financial interests that may be relevant to the submitted work.

Figures

Fig 1 HOME trial schedule

Fig 2 HOME patient profile

Fig 3 Concentrations of vitamin B-12, folate, and homocysteine with 95% confidence intervals. Solid lines represent the metformin group, dotted lines the placebo group. Number of available samples for the metformin and placebo group is indicated. Five patients were excluded from the analysis because of poor correlations between old and newly measured vitamin B-12 values (see Methods). In addition, some patients had vitamin B-12 levels below 150 pmol/l at baseline, at interim analysis, or at both stages, and were supplemented; these individuals were also excluded.

Fig 4 Homocysteine concentrations with 95% confidence intervals for patients with a normal vitamin B-12 concentration (>220 pmol/l), a low vitamin B-12 concentration (150-220 pmol/l), and vitamin B-12 deficiency (<150 pmol/l) after 4.3 years. The number of patients in each treatment group is indicated