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J Clin Endocrinol Metab. 2016 Apr;101(4):1754-61. doi: 10.1210/jc.2015-3754. Epub 2016 Feb 22.

Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study.

Author information

1
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.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00038727.

Comment in

PMID:
26900641
PMCID:
PMC4880159
DOI:
10.1210/jc.2015-3754
[Indexed for MEDLINE]
Free PMC Article

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