Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes a randomized clinical trial

Ingrid M. Libman, Kellee M. Miller, Linda DiMeglio, Kathleen E. Bethin, Michelle L. Katz, Avni Shah, Jill H. Simmons, Michael J. Haller, Sripriya Raman, William V. Tamborlane, Julie K. Coffey, Ashleigh M. Saenz, Roy W. Beck, Kristen J. Nadeau

Research output: Contribution to journalArticle

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Abstract

IMPORTANCE Previous studies assessing the effect ofmetformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results. OBJECTIVE To assess the efficacy and safety ofmetformin 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 receivemetformin (n = 71) (2000mg/d) or placebo (n = 69). MAIN OUTCOMES AND MEASURES Primary outcomewas 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 prescribingmetformin to overweight adolescents with type 1 diabetes to improve glycemic control.

Original languageEnglish (US)
Pages (from-to)2241-2250
Number of pages10
JournalJournal of the American Medical Association
Volume314
Issue number21
DOIs
StatePublished - Dec 1 2015

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Metformin
Type 1 Diabetes Mellitus
Randomized Controlled Trials
Insulin
Placebos
Body Mass Index
Endocrinology
Adiposity
Waist Circumference
Random Allocation
Body Composition
Body Weight
Outcome Assessment (Health Care)
Pediatrics
Blood Pressure
Lipids
Safety
Glucose

ASJC Scopus subject areas

  • Medicine(all)

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Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes a randomized clinical trial. / Libman, Ingrid M.; Miller, Kellee M.; DiMeglio, Linda; Bethin, Kathleen E.; Katz, Michelle L.; Shah, Avni; Simmons, Jill H.; Haller, Michael J.; Raman, Sripriya; Tamborlane, William V.; Coffey, Julie K.; Saenz, Ashleigh M.; Beck, Roy W.; Nadeau, Kristen J.

In: Journal of the American Medical Association, Vol. 314, No. 21, 01.12.2015, p. 2241-2250.

Research output: Contribution to journalArticle

Libman, IM, Miller, KM, DiMeglio, L, Bethin, KE, Katz, ML, Shah, A, Simmons, JH, Haller, MJ, Raman, S, Tamborlane, WV, Coffey, JK, Saenz, AM, Beck, RW & Nadeau, KJ 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, vol. 314, no. 21, pp. 2241-2250. https://doi.org/10.1001/jama.2015.16174
Libman, Ingrid M. ; Miller, Kellee M. ; DiMeglio, Linda ; Bethin, Kathleen E. ; Katz, Michelle L. ; Shah, Avni ; Simmons, Jill H. ; Haller, Michael J. ; Raman, Sripriya ; Tamborlane, William V. ; Coffey, Julie K. ; Saenz, Ashleigh M. ; Beck, Roy W. ; Nadeau, Kristen J. / Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes a randomized clinical trial. In: Journal of the American Medical Association. 2015 ; Vol. 314, No. 21. pp. 2241-2250.
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author = "Libman, {Ingrid M.} and Miller, {Kellee M.} and Linda DiMeglio and Bethin, {Kathleen E.} and Katz, {Michelle L.} and Avni Shah and Simmons, {Jill H.} and Haller, {Michael J.} and Sripriya Raman and Tamborlane, {William V.} and Coffey, {Julie K.} and Saenz, {Ashleigh M.} and Beck, {Roy W.} and Nadeau, {Kristen J.}",
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TY - JOUR

T1 - Effect of metformin added to insulin on glycemic control among overweight/obese adolescents with type 1 diabetes a randomized clinical trial

AU - Libman, Ingrid M.

AU - Miller, Kellee M.

AU - DiMeglio, Linda

AU - Bethin, Kathleen E.

AU - Katz, Michelle L.

AU - Shah, Avni

AU - Simmons, Jill H.

AU - Haller, Michael J.

AU - Raman, Sripriya

AU - Tamborlane, William V.

AU - Coffey, Julie K.

AU - Saenz, Ashleigh M.

AU - Beck, Roy W.

AU - Nadeau, Kristen J.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - IMPORTANCE Previous studies assessing the effect ofmetformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results. OBJECTIVE To assess the efficacy and safety ofmetformin 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 receivemetformin (n = 71) (2000mg/d) or placebo (n = 69). MAIN OUTCOMES AND MEASURES Primary outcomewas 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 prescribingmetformin to overweight adolescents with type 1 diabetes to improve glycemic control.

AB - IMPORTANCE Previous studies assessing the effect ofmetformin on glycemic control in adolescents with type 1 diabetes have produced inconclusive results. OBJECTIVE To assess the efficacy and safety ofmetformin 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 receivemetformin (n = 71) (2000mg/d) or placebo (n = 69). MAIN OUTCOMES AND MEASURES Primary outcomewas 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 prescribingmetformin to overweight adolescents with type 1 diabetes to improve glycemic control.

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