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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 doi: (Published 20 May 2010) Cite this as: BMJ 2010;340:c2181
  1. Jolien de Jager, resident12,
  2. Adriaan Kooy, internist23,
  3. Philippe Lehert, professor of statistics4,
  4. Michiel G Wulffelé, general practitioner23,
  5. Jan van der Kolk, biochemical engineer5,
  6. Daniël Bets, program manager6,
  7. Joop Verburg, chief laboratory attendant5,
  8. Ab J M Donker, professor of internal medicine7,
  9. Coen D A Stehouwer, professor and chair8
  1. 1Department of Ophthalmology, Academic Medical Center, Amsterdam, Netherlands
  2. 2Bethesda Diabetes Research Centre, Bethesda General Hospital, Hoogeveen, Netherlands
  3. 3Department of Internal Medicine, Bethesda General Hospital, Hoogeveen, Netherlands
  4. 4Department of Statistics, Faculty of Economics, Facultés Universitaires Catholiques de Mons, Louvain Academy, Mons, Belgium
  5. 5Clinical Laboratory, Bethesda General Hospital, Hoogeveen, Netherlands
  6. 6Clinical Research and Development, Merck Netherlands, Amsterdam, Netherlands
  7. 7Department of Internal Medicine, Free University Medical Center, Amsterdam, Netherlands
  8. 8Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands
  1. Correspondence to: C D A Stehouwer cda.stehouwer{at}
  • Accepted 25 February 2010


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 at4, 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 µmol/l (95% CI 18.8 to 30.0 µmol/l), compared with a mean homocysteine level of 18.1 µmol/l (95% CI 16.7 to 19.6 µmol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 µmol/l (95% CI 14.3 to 15.5 µmol/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 NCT00375388.


  • Contributors: AK, AJMD, and CDAS are responsible for the study concept and design. JdJ, AK, MGW, and DB collected the data, and statistical analysis was conducted by PL and JdJ. JdJ, AK, PL, and CDAS undertook analysis and interpretation of the data. JdJ, AK, and CDAS drafted the manuscript, and AK, AJMD, and CDAS undertook critical revisions of the manuscript for important intellectual content. Administrative, technical or material support was provided by JvdK, DB, JV, MGW, JdJ, and AK. JdJ, AK, and PL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. JdJ, AK, and CDAS accept full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish, and as such act as guarantors for the study.

  • Funding: Hyperinsulinaemia: the Outcome of its Metabolic Effects (HOME) trial was supported by grants from Altana, Lifescan, Merck Santé, Merck Sharp & Dohme, and Novo Nordisk. The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

  • Competing interests: All authors have completed the Unified Competing Interest form at (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.

  • Ethical approval: The medical ethical committees of the three participating hospitals approved the trial protocol. The trial has been conducted in accordance with the Committee for Medicinal Products for Human Use note for guidance on good clinical practice (CPMP/ICH/135/95), dated 17 July 1996, and in accordance with the Declaration of Helsinki (revised version of Hong Kong in 1989 and Edinburgh in 2000). All patients gave written informed consent.

  • Data sharing: No additional data available.

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