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Background

Pharmacological treatment options for children and adolescents with obesity are limited. Clinical trials with metformin in pediatric obesity have shown mixed results depending on dosage and age. In adults, metformin extended release (XR) has shown promising results on Body Mass Index (BMI) with fewer side effects.

Objectives

The primary objective was to investigate the effect of metformin XR together with lifestyle intervention compared with lifestyle intervention alone on BMI-standard deviation score (SDS). Secondary objectives included the effect on BMI-SDS of metformin immediate release (IR) together with lifestyle intervention compared with lifestyle intervention alone, as well as effects on glucose metabolism and cardiometabolic risk factors in the different groups. Furthermore, to determine the effect of plasma metformin concentration and age on the treatment effect, as well as the safety and tolerability of metformin in children and adolescents with obesity.

Methods

A parallel, three-armed, randomized, 6 months multi-center study with an extended-release metformin formulation (Glucophage® SR) combined with lifestyle intervention (XR+L), an immediate-release metformin formulation (Glucophage®) combined with lifestyle intervention (IR+L), or lifestyle intervention alone (LA). Children and adolescents aged 6-17 years with obesity (BMI-SDS >2.0) were included. Dosage of metformin was based on body weight. Metformin concentration was measured in plasma and urine. Lifestyle modification interventions were given to all participants at all study contacts during the treatment period. Oral glucose tolerance tests (OGTT) were conducted at the beginning and end of the intervention.

 Results

 Participants (89, of which 45 females, mean age 11.9 years, range 7-17 years, mean BMI-SDS 3.1) were randomized, and 77 participants completed the study. The treatment effect of XR+L compared with LA was -0.132 BMI-SDS (p=0.02). Mean BMI-SDS change from baseline to the end of the study was for the XR+L group -0,281 (p= 0.006), for the IR+L group -0,280 (p= 0,009), and for the LA group -0,126 (p= 0.359). A significant reduction in S-Insulin and P-Glucose was seen at several timepoints during OGTT in the IR+L group. Metformin concentration had no effect on the change in BMI-SDS. The treatment effect of XR+L or IR+L compared with LA was more pronounced in older children. Safety and tolerability profiles were comparable in all three groups.

 Conclusions

 Treatment with metformin XR + lifestyle led to a clinically significant BMI-SDS reduction in children and adolescents with obesity compared to lifestyle alone. Both extended and immediate release metformin formulations, are effective in lowering BMI-SDS, safe and generally well tolerated from the age of 7 years. Metformin is therefore suitable for treating pediatric obesity.