title: Effect of Metformin Added to Insulin on Glycemic Control Among Overweight/Obese Adolescents With Type 1 Diabetes: A Randomized Clinical Trial.
abstract: OBJECTIVE
  Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results.
  
  
  OBJECTIVE
  To assess the efficacy and safety of metformin as an adjunct to insulin in treating overweight adolescents with type 1 diabetes.
  
  
  METHODS
  Multicenter (26 pediatric endocrinology clinics), double-blind, placebo-controlled randomized clinical trial involving 140 adolescents aged 12.1 to 19.6 years (mean [SD] 15.3 [1.7] years) with mean type 1 diabetes duration 7.0 (3.3) years, mean body mass index (BMI) 94th (4) percentile, mean total daily insulin 1.1 (0.2) U/kg, and mean HbA1c 8.8% (0.7%).
  
  
  METHODS
  Randomization to receive metformin (n = 71) (≤2000 mg/d) or placebo (n = 69).
  
  
  METHODS
  Primary outcome was change in HbA1c from baseline to 26 weeks adjusted for baseline HbA1c. Secondary outcomes included change in blinded continuous glucose monitor indices, total daily insulin, BMI, waist circumference, body composition, blood pressure, and lipids.
  
  
  RESULTS
  Between October 2013 and February 2014, 140 participants were enrolled. Baseline HbA1c was 8.8% in each group. At 13-week follow-up, reduction in HbA1c was greater with metformin (-0.2%) than placebo (0.1%; mean difference, -0.3% [95% CI, -0.6% to 0.0%]; P = .02). However, this differential effect was not sustained at 26-week follow up when mean change in HbA1c from baseline was 0.2% in each group (mean difference, 0% [95% CI, -0.3% to 0.3%]; P = .92). At 26-week follow-up, total daily insulin per kg of body weight was reduced by at least 25% from baseline among 23% (16) of participants in the metformin group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% CI, 11% to 32%]; P = .003), and 24% (17) of participants in the metformin group and 7% (5) of participants in the placebo group had a reduction in BMI z score of 10% or greater from baseline to 26 weeks (mean difference, 17% [95% CI, 5% to 29%]; P = .01). Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group (mean difference, 36% [95% CI, 19% to 51%]; P < .001).
  
  
  CONCLUSIONS
  Among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control after 6 months. Of multiple secondary end points, findings favored metformin only for insulin dose and measures of adiposity; conversely, use of metformin resulted in an increased risk for gastrointestinal adverse events. These results do not support prescribing metformin to overweight adolescents with type 1 diabetes to improve glycemic control.
  
  
  BACKGROUND
  clinicaltrials.org Identifier: NCT01881828.
authors.affiliation: Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Libman
authors.affiliation: Jaeb Center for Health Research, Tampa, Florida.
authors.forename: Kellee M
authors.initials: KM
authors.lastname: Miller
authors.affiliation: Indiana University School of Medicine, Indianapolis.
authors.forename: Linda A
authors.initials: LA
authors.lastname: DiMeglio
authors.affiliation: University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Bethin
authors.affiliation: Joslin Diabetes Center, Boston, Massachusetts.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Katz
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Avni
authors.initials: A
authors.lastname: Shah
authors.affiliation: Vanderbilt University, Nashville, Tennessee.
authors.forename: Jill H
authors.initials: JH
authors.lastname: Simmons
authors.affiliation: University of Florida, Gainesville.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haller
authors.affiliation: Children's Mercy Hospital, Kansas City, Missouri.
authors.forename: Sripriya
authors.initials: S
authors.lastname: Raman
authors.affiliation: Yale University, New Haven, Connecticut.
authors.forename: William V
authors.initials: WV
authors.lastname: Tamborlane
authors.affiliation: University of Iowa, Iowa City.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Coffey
authors.affiliation: Jaeb Center for Health Research, Tampa, Florida.
authors.forename: Ashleigh M
authors.initials: AM
authors.lastname: Saenz
authors.affiliation: Jaeb Center for Health Research, Tampa, Florida.
authors.forename: Roy W
authors.initials: RW
authors.lastname: Beck
authors.affiliation: University of Colorado, Anschutz Medical Campus, Aurora.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Nadeau
mesh_terms: D000293:Adolescent; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D001835:Body Weight; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects; D009765:Obesity / Q000150:complications*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin