Metformin in Obese Children and Adolescents (MetVoorMin)

An Efficacy, Safety and Pharmacokinetic Study on the Short-term and Long-term Use of Metformin in Obese Children and Adolescents

The purpose of this study is to determine whether metformin is effective in reducing BMI and insulin resistance in obese children and adolescents.

The prevalence of obesity in children and adolescents is increasing rapidly and is associated with significant medical and psychosocial consequences persisting into adulthood. Obesity may lead to metabolic complications, such as insulin resistance, which can progress via impaired fasted glucose and impaired glucose tolerance to type 2 diabetes mellitus (T2DM) and to the development of micro- and macro-vascular complications. Metformin, an oral anti-diabetic licensed for T2DM for adults and children from 10 years onwards, is already used off label in obese children and adolescents with insulin resistance, even though the specific effects of metformin in these obese children and adolescents have not been elucidated, particularly upon long-term use. The rationale for this study is based on the hypothesis that metformin may reduce body mass index (BMI), insulin resistance and percentage of body-fat in obese children and adolescents with insulin resistance. Further more it is anticipated that metformin may delay the progression to T2DM and thereby micro- and macro-vascular complications in obese children and adolescents with insulin resistance.

Oral administration, 500 mg daily at week 1. Every week metformin dosage increases with 500 mg, to a maximum dose of 1000 mg bid. This maximum dose will be administered till the end of the study.

Clearance where applicable expressed per body weight, age category, Tanner Stage and gender, clearance will be determined with a two-compartment pharmacokinetic model using non linear mixed effect modelling.

Volume of distribution, where applicable expressed per body weight, age category, Tanner Stage and gender, volume of distribution will be determined with a two-compartment pharmacokinetic model using non linear mixed effect modelling.

Inclusion Criteria: Age ≥ 10 and ≤ 16 years at study entry Caucasian descent Obesity defined as BMI-SDS > 2.3 Insulin resistance defined as HOMA-IR ≥ 3.4. An obtained informed consent from subjects and parents/caregivers. Exclusion Criteria: Presence of T2DM (American Diabetes Association criteria) Presence of endocrine disorders with steroid therapy Suspicion of polycystic ovarium syndrome; Height < -1.3 SD of target height; Syndrome disorders with or without mental retardation; Use of anti-hyperglycaemic drugs; Pregnancy (pregnancy test will be performed, if applicable); (History of) alcohol abuse; Impaired renal and/or hepatic function (defined as GFR < 80 ml/min. GFR=40 x length (cm) / serumcreatinin (μmol/l and ALAT >150% of normal value for age); Use of ritonavir; use of ACE inhibitors; Insufficient knowledge of the Dutch language.

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van der Aa MP, Hoving V, van de Garde EM, de Boer A, Knibbe CA, van der Vorst MM. The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial. J Obes. 2016;2016:7852648. doi: 10.1155/2016/7852648. Epub 2016 Dec 22.

van der Aa MP, Elst MA, van Mil EG, Knibbe CA, van der Vorst MM. METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study. Trials. 2014 Jun 5;15:207. doi: 10.1186/1745-6215-15-207.