An efficacy, safety and pharmacokinetic study on the short-and long-term effects of Metformin in obese children/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 glucose tolerance to type 2 diabetes mellitus (T2DM) and to the development of micro- and macro-vascular complications. Metformin may delay the progression to T2DM and thereby micro- and macro-vascular complications. In adults with T2DM, metformin has shown to reduce weight gain, hyper-insulinemia and hyperglycaemia while in adults without T2DM, metformin has shown to reduce progression from impaired glucose tolerance to T2DM. A systematic review in children and adolescents showed that metformin is moderately efficacious in the short term in reducing BMI and insulin resistance in hyper-insulinemic children and adolescents. These benefits observed in adults and the short-term benefits observed in children and adolescents have led to an increased use of metformin in obese children and adolescents with insulin resistance and even without insulin resistance. However, metformin is not licensed for this indication. Despite the fact that evidence of long-term benefit of metformin on insulin resistance and the progression to impaired glucose tolerance and T2DM are sparse, metformin is widely used off-label in obese children and adolescents with insulin resistance. In addition, the long-term effect of lifestyle intervention programs on the improvement of metabolic risk factors, like insulin resistance, remains debatably. The current project is divided in two consecutive studies: a multi-centre, double blind, placebo controlled, randomized, cross-over study (initial study) of one year duration and a multi-centre open study (follow up study) of 2 years duration. The primary aim of this project is to evaluate in a multi-centre, double blind, placebo controlled, randomized, cross-over study, the short-term efficacy and safety of metformin versus placebo in combination with lifestyle-intervention in two hundred and ten (210) obese children and adolescents with insulin resistance. Primary outcome parameters are the reduction of insulin resistance, reduction of body mass index z-score (BMI-z-score), reduction of percentage of body fat, safety and tolerability of metformin treatment. The secondary aim of this project is to develop rational dosing schemes for metformin in obese children and adolescents with insulin resistance using population pharmacokinetic (PK) and pharmacodynamic (PD) modelling. Using this modelling approach, infrequently obtained samples and observations in the clinical situation can be utilized to analyze determinants of variability in drug response. In both the population PK (drug concentrations) and PD (efficacy and safety endpoints) models the influence of age, bodyweight, BMI-z score, body fat, gender, Tanner stage and genetic constitution will be characterised resulting in individualized dosing regimens. In addition to demographic parameters, the influence of genetic variation in the SLC47A1 gene which may play an important role in the pharmacokinetics of metformin, is studied. The tertiary aim of this project is to monitor in a multi-centre open study the long-term efficacy of metformin, expressed as development of impaired glucose tolerance, T2DM and/or metabolic, micro- and macro-vascular complications in these obese children and adolescents by a two-year follow up period after the initial study period of 1 year, in which metformin is offered to all patients. In addition the long-term safety of metformin therapy will be monitored. The study will provide answers to the question whether metformin improves insulin resistance in obese children and adolescents and will result in individualized dosing regimens for children and adolescents of different age, pubertal stage, BMI z-score and genetic constitution (1 year study). The follow up period of the study (2 years) will provide data on the development of impaired glucose tolerance, T2DM and of metabolic, micro- and macro-vascular complications and safety of metformin in this obese paediatric population. The research program is highly multidisciplinary, in which specialists in Paediatrics, Clinical Pharmacology, Endocrinology, Pharmacogenetics and paramedical professionals participating.