Insulin Resistance, Obesity
Conditions
Keywords
Obesity, Children, Adolescents, Metformin, Insulin resistance
Brief summary
The purpose of this study is to determine whether metformin is effective in reducing BMI and insulin resistance in obese children and adolescents.
Detailed description
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.
Interventions
DRUGMetformin
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.
BEHAVIORALLifestyle intervention
Lifestyle intervention: 18 months physical therapy and dietary advice
Sponsors
Jeroen Bosch Ziekenhuis
St. Antonius Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
10 Years to 16 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BMI from baseline | 18 months and 36 months | Change in BMI after part 1 (double blind) and part 2 ( follow-up) |
| Change in Insulin resistance from baseline | 3; 6; 9; 12; 15; 18; 24; 30 and 36 months | calculated by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK)-parameters: clearance (ml/min) | 9 months | 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. |
| Body fat percentage | 0, 9, 18 and 36 months | — |
| Physical fitness | 0, 9, 18 and 36 months | — |
| Quality of life | 0, 9, 18 and 36 months | — |
| Long term efficacy | 36 months | Based on BMI and HOMA-IR values |
| Renal and hepatic function | 3; 6; 9; 12; 15; 18; 24; 30 and 36 months | creatinine and alat |
| Long-term tolerability | 36 months | The amount of adverse effects after 36 months |
| Microvascular complications | 36 months | Measured as micro-albuminuria |
| Macrovascular complications | 36 monthts | Measured with Pulse Wave Velocity and Augmentation Index. |
| Development of T2DM | 36 months | — |
| PK-parameters: volume of distribution (liters) | 9 months | 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. |
| Long-term safety | 36 months | Renal and hepatic function after 36 months of metformin use |
| Tolerability | 3; 6; 9; 12; 15; 18; 24; 30 and 36 months | The amount of reported adverse effects, in relation to the achieved dose level. |
Countries
Netherlands
Outcome results
None listed