Author
LIBMAN, INGRID - University Of Pittsburgh Medical Center | |
MILLER, KELLEE - Jaeb Center For Health Research | |
DIMEGLIO, LINDA - Indiana University School Of Medicine | |
BETHIN, KATHLEEN - University Of Buffalo | |
KATZ, MICHELLE - Joslin Diabetes Center | |
BACHA, FIDA - Children'S Nutrition Research Center (CNRC) |
Submitted to: Journal of the American Medical Association
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 11/1/2015 Publication Date: 12/1/2015 Citation: Libman, I.M., Miller, K.M., Dimeglio, L.A., Bethin, K.E., Katz, M.L., Bacha, F. 2015. Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes: A randomized clinical trial. Journal of the American Medical Association. 314(21):2241-2250. Interpretive Summary: Insulin is the main treatment for youth with type 1 diabetes (T1D). Overweight children with T1D have evidence of insulin resistance. Whether the addition of metformin (insulin sensitizer) to the treatment regimen in overweight children with T1D will help improve diabetes control is unclear. This multicenter study randomized 140 children and adolescents with T1D to metformin or placebo in addition to insulin, for 26 weeks. We did not find significant differences in glycemic control (reduction in HbA1c) between the 2 groups. However, the group that received metformin had a reduction in the total daily insulin dose and greater improvement in body mass index, compared with the placebo group. In conclusion, in overweight adolescents with T1D, the addition of metformin to insulin did not improve glycemic control after 6 months. These results do not support providing metformin to overweight adolescents with type 1 diabetes to improve glycemic control. Technical Abstract: Previous studies assessing the effect of metformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results. To assess the efficacy and safety of metformin as an adjunct to insulin in treating overweight adolescents with type 1 diabetes. 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%). Randomization to receive metformin (n'='71) (=2000 mg/d) or placebo (n'='69). 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. 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). 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. |