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

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Abstract

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
Volume101
Issue number4
DOIs
StatePublished - Apr 1 2016

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Vitamin B 12 Deficiency
Metformin
Vitamin B 12
Medical problems
Outcome Assessment (Health Care)
Placebos
Anemia
Labels
Glucose
Glucose Intolerance

ASJC Scopus subject areas

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

Cite this

Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study. / Aroda, Vanita R.; Edelstein, Sharon L.; Goldberg, Ronald B; Knowler, William C.; Marcovina, Santica M.; Orchard, Trevor J.; Bray, George A.; Schade, David S.; Temprosa, Marinella G.; White, Neil H.; Crandall, Jill P.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 101, No. 4, 01.04.2016, p. 1754-1761.

Research output: Contribution to journalArticle

Aroda, VR, Edelstein, SL, Goldberg, RB, Knowler, WC, Marcovina, SM, Orchard, TJ, Bray, GA, Schade, DS, Temprosa, MG, White, NH & Crandall, JP 2016, 'Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study', Journal of Clinical Endocrinology and Metabolism, vol. 101, no. 4, pp. 1754-1761. https://doi.org/10.1210/jc.2015-3754
Aroda, Vanita R. ; Edelstein, Sharon L. ; Goldberg, Ronald B ; Knowler, William C. ; Marcovina, Santica M. ; Orchard, Trevor J. ; Bray, George A. ; Schade, David S. ; Temprosa, Marinella G. ; White, Neil H. ; Crandall, Jill P. / Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study. In: Journal of Clinical Endocrinology and Metabolism. 2016 ; Vol. 101, No. 4. pp. 1754-1761.
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abstract = "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.",
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AU - Aroda, Vanita R.

AU - Edelstein, Sharon L.

AU - Goldberg, Ronald B

AU - Knowler, William C.

AU - Marcovina, Santica M.

AU - Orchard, Trevor J.

AU - Bray, George A.

AU - Schade, David S.

AU - Temprosa, Marinella G.

AU - White, Neil H.

AU - Crandall, Jill P.

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N2 - 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.

AB - 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.

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