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Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study.
J Clin Endocrinol Metab 2016; 101(4):1754-61JC

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.

INTERVENTION

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.

Authors+Show Affiliations

MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.MedStar Health Research Institute (V.R.A.), Hyattsville, Maryland 20782; George Washington University (S.L.E., M.G.T.), Rockville, MD 20852; University of Miami (R.B.G.), Miami, Florida 33146; National Institute of Diabetes and Digestive and Kidney Diseases (W.C.K.), Phoenix, Arizona 85014; University of Washington (S.M.M.), Seattle, Washington 98185; University of Pittsburgh (T.J.O.), Pittsburgh, Pennsylvania 15260; Pennington Biomedical Research Institute (G.A.B.), Baton Rouge, Louisiana 70808; University of New Mexico (D.S.S.), Albuquerque, New Mexico 87131; Washington University School of Medicine (N.H.W.), St. Louis, Missouri 63110; and Albert Einstein College of Medicine (J.P.C.), Bronx, New York 10461.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26900641

Citation

Aroda, Vanita R., et al. "Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study." The Journal of Clinical Endocrinology and Metabolism, vol. 101, no. 4, 2016, pp. 1754-61.
Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101(4):1754-61.
Aroda, V. R., Edelstein, S. L., Goldberg, R. B., Knowler, W. C., Marcovina, S. M., Orchard, T. J., ... Crandall, J. P. (2016). Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. The Journal of Clinical Endocrinology and Metabolism, 101(4), pp. 1754-61. doi:10.1210/jc.2015-3754.
Aroda VR, et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101(4):1754-61. PubMed PMID: 26900641.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. 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, AU - ,, Y1 - 2016/02/22/ PY - 2016/2/23/entrez PY - 2016/2/24/pubmed PY - 2017/6/10/medline SP - 1754 EP - 61 JF - The Journal of clinical endocrinology and metabolism JO - J. Clin. Endocrinol. Metab. VL - 101 IS - 4 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. INTERVENTION: 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. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/26900641/Long_term_Metformin_Use_and_Vitamin_B12_Deficiency_in_the_Diabetes_Prevention_Program_Outcomes_Study_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2015-3754 DB - PRIME DP - Unbound Medicine ER -