Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial

Jack A Yanovski, Jonathan Krakoff, Christine G Salaita, Jennifer R McDuffie, Merel Kozlosky, Nancy G Sebring, James C Reynolds, Sheila M Brady, Karim A Calis, Jack A Yanovski, Jonathan Krakoff, Christine G Salaita, Jennifer R McDuffie, Merel Kozlosky, Nancy G Sebring, James C Reynolds, Sheila M Brady, Karim A Calis

Abstract

Objective: Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant.

Research design and methods: This study was a randomized double-blind placebo-controlled trial consisting of 100 severely obese (mean BMI 34.6 ± 6.6 kg/m(2)) insulin-resistant children aged 6-12 years, randomized to 1,000 mg metformin (n = 53) or placebo (n = 47) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program.

Results: Eighty-five percent completed the 6-month randomized phase. Children prescribed metformin had significantly greater decreases in BMI (difference -1.09 kg/m(2), CI -1.87 to -0.31, P = 0.006), body weight (difference -3.38 kg, CI -5.2 to -1.57, P < 0.001), BMI Z score (difference between metformin and placebo groups -0.07, CI -0.12 to -0.01, P = 0.02), and fat mass (difference -1.40 kg, CI -2.74 to -0.06, P = 0.04). Fasting plasma glucose (P = 0.007) and homeostasis model assessment (HOMA) insulin resistance index (P = 0.006) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17%. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score; those treated continuously with metformin did not significantly change BMI Z score further.

Conclusions: Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program.

Trial registration: ClinicalTrials.gov NCT00005669.

Figures

FIG. 1.
FIG. 1.
Flow of participants throughout the trial.
FIG. 2.
FIG. 2.
Changes in BMI during the study. Mean ± SEM for BMI SD score (BMI Z) and BMI during the randomized placebo-controlled phase (A and C) and the open-label phase when all participants were offered metformin (B and D). A: BMI Z score, randomized phase. B: BMI Z score, open-label phase. C: BMI, randomized phase. D: BMI, open-label phase. Intent-to-treat imputed data analyses are shown. There were significant group by time interactions (P < 0.001) during each phase for both BMI Z and BMI. *P < 0.05; **P < 0.01 for comparison of children randomized to metformin and placebo at each time point.
FIG. 3.
FIG. 3.
Reports of symptoms during the placebo-controlled phase. *P < 0.05; **P < 0.01 for comparison of children randomized to metformin and placebo at each time point. A: Nausea. B: Vomiting. C: Loose or liquid stools. D: Fatigue.

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