Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study

Vanita R. Aroda, Sharon L. Edelstein, Ronald B. Goldberg, William C. Knowler, Santica M. Marcovina, Trevor J. Orchard, George A. Bray, David S. Schade, Marinella G. Temprosa, Neil H. White, Jill P. Crandall

Research output: Contribution to journalArticlepeer-review

313 Scopus citations


Context: Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use. Objective: To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS). Design: Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years. Setting: Twenty-seven study centers in the United States. Patients: DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively. Interventions: Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS). Main Outcome Measures: B12 deficiency, anemia, and peripheral neuropathy. Results: Low B12 (≤ 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P = .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06-1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels. Conclusions: Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.

Original languageEnglish (US)
Pages (from-to)1754-1761
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number4
StatePublished - Apr 2016

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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