Abstract
ContextInsulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.ObjectiveTo compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D.HypothesisAdjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.Design, Setting, and ParticipantsA 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage.ResultsOver the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups.ConclusionsThis 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group.Trial RegistrationClinicalTrial.gov NCT01334125
Highlights
Obese/overweight youth with type 1 diabetes (T1D) often have suboptimal glycemic control [1]
This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower hemoglobin A1c (HbA1c) value in the metformin group compared to the placebo group
Compliance rate, which was initially at 90% for both arms during the run-in phase, decreased to 65% at the interval between the 6th and 9th month visit. In this nine-month randomized, double blind, placebo controlled trial, we report a 0.4% lower HbA1c value in the metformin group compared to the placebo group
Summary
Obese/overweight youth with type 1 diabetes (T1D) often have suboptimal glycemic control [1]. Though insulin resistance has been proposed as one of the causes of this poor glycemic control, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear. Randomized controlled trials with metformin in adolescents with type 2 diabetes (T2D) reported a decrease in fasting plasma glucose concentration [3]. The benefit was transient in one study [7] and no decrease was found in another [4]. The main drawback of these studies was the small sample size and lack of reporting on long term benefit and safety of adjunctive therapy in many of them [8]
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