Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial

Abstract

Background:As adolescents with obesity and insulin resistance may be refractory to lifestyle intervention therapy alone, additional off-label metformin therapy is often used. In this study, the long-term efficacy and safety of metformin versus placebo in adolescents with obesity and insulin resistance is studied.Methods:In a randomized placebo-controlled double-blinded trial, 62 adolescents with obesity aged 10–16 years old with insulin resistance received 2000 mg of metformin or placebo daily and physical training twice weekly over 18 months. Primary end points were change in body mass index (BMI) and insulin resistance measured by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Secondary end points were safety and tolerability of metformin. Other end points were body fat percentage and HbA1c.Results:Forty-two participants completed the 18-month study (66% girls, median age 13 (12–15) years, BMI 30.0 (28.3 to 35.0) kg m−2 and HOMA-IR 4.08 (2.40 to 5.88)). Median ΔBMI was +0.2 (−2.9 to 1.3) kg m−2 (metformin) versus +1.2 (−0.3 to 2.4) kg m−2 (placebo) (P=0.015). No significant difference was observed for HOMA-IR. No serious adverse events were reported. Median change in fat percentage was −3.1 (−4.8 to 0.3) versus −0.8 (−3.2 to 1.6)% (P=0.150), in fat mass −0.2 (−5.2 to 2.1) versus +2.0 (1.2–6.4) kg (P=0.007), in fat-free mass +2.0 (−0.1 to 4.0) versus +4.5 (1.3 to 11.6) kg (P=0.047) and in ΔHbA1c +1.0 (−1.0 to 2.3) versus +3.0 (0.0 to 5.0) mmol mol−1 (P=0.020) (metformin versus placebo).Conclusions:Long-term treatment with metformin in adolescents with obesity and insulin resistance results in stabilization of BMI and improved body composition compared with placebo. Therefore, metformin may be useful as an additional therapy in combination with lifestyle intervention in adolescents with obesity and insulin resistance.

The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial

“…Although the effect of metformin might fade out over time, it remains unclear whether prolonged use (>18 months) of metformin is not effective any more (i.e., children treated with metformin return to their previous BMI-percentile), or whether it will result in persisting lower BMI-values compared to placebo. For the 18-month treatment, the current study showed that the change in BMI upon metformin in daily clinical practice was similar to results as obtained in a RCT after treatment of 18 months [8]. …”

“…This small increase in ΔBMI at 18 months was initially preceded by a substantial decrease in ΔBMI in the metformin arm at 9 months, while in the placebo arm of this RCT ΔBMI from baseline to 18 months was found to increase significantly compared to the metformin arm (i.e., ΔBMI +1.17 (−0.26–2.37) kg/m 2 ( p = 0.015)) [8]. In the current study, the course of BMI and BMI-SDS over time in the daily clinical practice group also showed an initial decrease in BMI and BMI-SDS in accordance with the RCT group.…”

“…The other group, that is, the RCT group, consisted of the patients of the metformin arm of a RCT on metformin versus placebo in obese children [8, 11]. The inclusion criteria for the patients in the RCT were age 10–16 years, obesity (defined as BMI-SDS > 2.3), insulin resistance (defined as HOMA-IR ≥ 3.4), and being of Caucasian origin.…”

“…However, the effect after >12 months of treatment was not significantly different compared to placebo [6]. As such, it seems that the maximum effect of metformin is achieved after 6–9 months of treatment, since in studies of 48 weeks and 18 months smaller effects for change in BMI were reported [7, 8]. In our RCT of 18 months, BMI decreased during the first 9 months of metformin treatment, comparable to the results in the study of 48 weeks.…”

Metformin Therapy Reduces Obesity Indices in Children and Adolescents: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

“…32,37 Out of included studies, 12 studies were performed in children 17,25,27,28,31,32,39,40,42,[44][45][46]51 and 25 studies in adolescents. [10][11][12][18][19][20][21][22][23][24]26,29,30,[33][34][35][36][37][38]41,43,[47][48][49][50] In addition, six studies were conducted in female participants, 21,26,30,31,44,47 while the others recruited participants from both genders. [10][11][12][17][18]…”