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 A 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, T1D Exchange Clinic Network Metformin RCT Study Group, Linda DiMeglio, Stephanie Woerner, Bonnie Jagielo, Jennifer Terrell, Michelle Katz, Joanne Hathway, Kerry Milaszewski, Kathleen Bethin, Michelle Ecker, Avni Shah, Kimberly Caswell, Jill Simmons, Alyssa Robertson, Kristen Nadeau, Georgeanna Klingensmith, Katherine Manseau, Steven Willi, Catherine Carchidi, Ingrid Libman, Ana Diaz, Carol Foster, Hillarie Slater, Karen Wheeler, Jamie Wood, Brian Ichihara, Michael Haller, Miriam Cintron, Kenneth Copeland, Joanne Less, Fida Bacha, Elizabeth Johnson, Ayse Cemeroglu, Lora Kleis, Robin Goland, Amy Wolk, Mark Daniels, Heather Speer, Eda Cengiz, Amy Steffen, Melinda Zgorski, Rose Gubitosi-Klug, Wendy Campbell, William Zipf, Jennifer Dyer, Dianne Sieple, Brandon Nathan, Anne Street, Janice Leschyshyn, Christine Burt Solorzano, Jennifer Puskaric, Michael Gottschalk, Marla Hashiguchi, Saleh Adi, Christine Torok, Sripriya Raman, Lois Hester, Henry Rodriguez, Danielle Henson, Ali Calikoglu, Vinnie Duncan, Helen Brown, Ingrid M Libman, Kellee M Miller, Linda A 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, T1D Exchange Clinic Network Metformin RCT Study Group, Linda DiMeglio, Stephanie Woerner, Bonnie Jagielo, Jennifer Terrell, Michelle Katz, Joanne Hathway, Kerry Milaszewski, Kathleen Bethin, Michelle Ecker, Avni Shah, Kimberly Caswell, Jill Simmons, Alyssa Robertson, Kristen Nadeau, Georgeanna Klingensmith, Katherine Manseau, Steven Willi, Catherine Carchidi, Ingrid Libman, Ana Diaz, Carol Foster, Hillarie Slater, Karen Wheeler, Jamie Wood, Brian Ichihara, Michael Haller, Miriam Cintron, Kenneth Copeland, Joanne Less, Fida Bacha, Elizabeth Johnson, Ayse Cemeroglu, Lora Kleis, Robin Goland, Amy Wolk, Mark Daniels, Heather Speer, Eda Cengiz, Amy Steffen, Melinda Zgorski, Rose Gubitosi-Klug, Wendy Campbell, William Zipf, Jennifer Dyer, Dianne Sieple, Brandon Nathan, Anne Street, Janice Leschyshyn, Christine Burt Solorzano, Jennifer Puskaric, Michael Gottschalk, Marla Hashiguchi, Saleh Adi, Christine Torok, Sripriya Raman, Lois Hester, Henry Rodriguez, Danielle Henson, Ali Calikoglu, Vinnie Duncan, Helen Brown
Abstract
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.
Source: PubMed