title: Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study.
abstract: Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use.
  
  
  
  To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS).
  
  
  
  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.
  
  
  
  Twenty-seven study centers in the United States.
  
  
  
  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.
  
  
  
  Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS).
  
  
  
  B12 deficiency, anemia, and peripheral neuropathy.
  
  
  
  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.
  
  
  
  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.affiliation: 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.
authors.forename: Vanita R
authors.initials: VR
authors.lastname: Aroda
authors.affiliation: 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.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Edelstein
authors.affiliation: 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.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Goldberg
authors.affiliation: 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.
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: 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.
authors.forename: Santica M
authors.initials: SM
authors.lastname: Marcovina
authors.affiliation: 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.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Orchard
authors.affiliation: 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.
authors.forename: George A
authors.initials: GA
authors.lastname: Bray
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Schade
authors.affiliation: 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.
authors.forename: Marinella G
authors.initials: MG
authors.lastname: Temprosa
authors.affiliation: 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.
authors.forename: Neil H
authors.initials: NH
authors.lastname: White
authors.affiliation: 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.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Crandall
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced*; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D005260:Female; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D014805:Vitamin B 12 / Q000097:blood; D014806:Vitamin B 12 Deficiency / Q000139:chemically induced*
chemical_list: D007004:Hypoglycemic Agents; D006710:Homocysteine; D008687:Metformin; D014805:Vitamin B 12