Long-term metformin treatment in adolescents with obesity and insulin resistance, results of an open label extension study

Abstract

Background/objectives: Off-label metformin is nowadays frequently used for the treatment of obesity in adolescents. However, studies on long-term metformin treatment in adolescents with obesity are scarce. Therefore, an 18 month open label extension study following an 18 months randomized placebo-controlled trial (RCT) on the efficacy, safety, and tolerability of metformin in adolescents with obesity and insulin resistance was performed.

Subjects/methods: After completion of the RCT, metformin was offered to all participants with a body mass index standard deviation score (BMI-sds) > 2.3 and Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) ≥ 3.4. Endpoints were change in BMI and HOMA-IR.

Results: Overall, 31/42 participants completed the extension study (74% girls, median age 14.8 (11.6 - 17.9), BMI 31.2 (22.3 - 45.1), HOMA-IR 3.4 (0.2 - 8.8)). At start, 22/42 (52.4%) participants were eligible for metformin of which 13 (59.0%) agreed with treatment. In participants who continued metformin, an increase was observed in BMI (+2.2 (+0.2 to +9.0)) and HOMA-IR (+13.7 (+1.6 to +48.3)). In metformin naive participants, BMI stabilized after an initial decrease (+0.5 (-2.1 to +5.1)). For HOMA-IR, a decrease was observed (-1.1 (-4.6 to +1.4)).

Conclusion: While metformin treatment in metformin naive participants seems to result in an initial decrease in BMI and HOMA-IR, there is no evidence for sustained effect after prolonged use in adolescents. Limited compliance and/or insufficient dose may explain the differences in long-term effects between adolescents and adults.

Fig. 1. Flowchart of the study population.

MM metformin during RCT and extension study, PM placebo during RCT and metformin during extension study, MP metformin during RCT and placebo during extension study, PP placebo during RCT and extension study

Fig. 2. Progression of BMI and HOMA-IR over the open label extension study, stratified by study-arm.

Median BMI (a); median HOMA-IR (b). MM metformin during RCT and extension study, PM placebo during RCT and metformin during extension study, PP placebo during RCT and extension study, MP metformin during RCT and placebo during extension study

Fig. 3. Change of HbA1c, body fat percentage, fat mass, and fat-free mass in the open label extension study.

MM metformin during RCT and extension study, PM placebo during RCT and metformin during extension study, PP placebo during RCT and extension study, MP metformin during RCT and placebo during extension study. Dotted line represents no change