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Original Investigation
December 1, 2015

Effect of Metformin Added to Insulin on Glycemic Control Among Overweight/Obese Adolescents With Type 1 Diabetes: A Randomized Clinical Trial

Author Affiliations
  • 1Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
  • 2Jaeb Center for Health Research, Tampa, Florida
  • 3Indiana University School of Medicine, Indianapolis
  • 4University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York
  • 5Joslin Diabetes Center, Boston, Massachusetts
  • 6Stanford University School of Medicine, Stanford, California
  • 7Vanderbilt University, Nashville, Tennessee
  • 8University of Florida, Gainesville
  • 9Children’s Mercy Hospital, Kansas City, Missouri
  • 10Yale University, New Haven, Connecticut
  • 11University of Iowa, Iowa City
  • 12University of Colorado, Anschutz Medical Campus, Aurora
JAMA. 2015;314(21):2241-2250. doi:10.1001/jama.2015.16174

Importance  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.

Design, Setting, and Participants  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%).

Interventions  Randomization to receive metformin (n = 71) (≤2000 mg/d) or placebo (n = 69).

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.org Identifier: NCT01881828