Evaluation of differential effects of metformin treatment in obese children according to pubertal stage and genetic variations: study protocol for a randomized controlled trial

Abstract

BackgroundOverweight and obesity are considered to be serious public health problems. In pediatric populations, insulin resistance, dyslipidemia, and hypertension associated with obesity occur with increased frequencies. Metformin is an oral anti-hyperglycemic agent that has been demonstrated to be efficacious in the treatment of diabetic and non-diabetic obese adults. A considerable amount of pharmacogenetic research has demonstrated that genetic variation is one of the major factors affecting metformin response. Additionally, potential microbiota-mediated mechanisms of metformin effect have been recently described. However, scant work has been conducted in children, with no attention being paid to the potential effects of pubertal development. Thus, the main objective of the present study is to evaluate the effect of metformin treatment together with lifestyle recommendations in a randomized control trial (RCT) of obese children according to pubertal stage, genetic variants and signature of gut microbiota.Methods/designThis is a randomized, prospective, double-blind, placebo-controlled, multicenter trial, which is stratified by puberty and sex. Eighty pre-pubertal (40 boys and 40 girls) and 80 pubertal non-diabetic obese children (40 boys and 40 girls) are being recruited in four Spanish Clinical Hospitals. The inclusion criteria to participate in the RCT include a Body Mass Index (BMI) above the 95th percentile and age 7–14 years. The pubertal stage is determined based on the Tanner criteria. Participants are assigned to two groups in accordance with a randomization schedule and receive 1 g of metformin or placebo for six months in combination with healthy lifestyle recommendations in both groups. The primary outcomes include changes in the BMI Z score and the biomarkers associated with the early appearance of insulin resistance syndrome, inflammation, cardiovascular risk according of the presence of genetic determinants of metformin response, as well as possible modifications in microbiota.DiscussionThis study will assess the differential response of metformin treatment at six months in pre-pubertal and pubertal obese children.Trial registrationRegistered by European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1403-4) contains supplementary material, which is available to authorized users.

Metformin for Obesity in Prepubertal and Pubertal Children: A Randomized Controlled Trial

“…This randomized, double-blind, placebocontrolled trial was homogeneously conducted at 4 Spanish clinical hospitals, as previously described. 24 Children were randomly assigned to receive either metformin or placebo for 6 months. Details of the trial protocol and ethics committees have been previously published in Trials.…”

“…Details of the trial protocol and ethics committees have been previously published in Trials. 24 The Consolidated Standards of Reporting Trials statement has been considered in the report on study design and results, as well as in the abstract and flow diagram.…”

“…Children were invited to participate according to the inclusion criteria described in Table 1. 24 The data are collected in the pediatric outpatient clinics by dietitians. All participants were provided with standardized healthy lifestyle advice at the beginning of a 1-on-1 session according to recommendations for food consumption frequency following the Mediterranean diet criteria and the practice of physical activity based on the AECOSAN NAOS Strategy's NAOS Pyramid (Ministry of Health of the Spanish Government).…”

“…To assess the safety and tolerance of metformin administration, the primary evaluation criteria were the absence of adverse effects, as previously reported. 24 outcomes Measures…”

Metformin - A Panacea Pharmaceutical Agent through convergence revolution initiative

“…Metformin improves insulin sensitivity in the peripheral tissues and thereby controls excessive glucose production. Metformin has been prescribed to overcome obesity [15][16][17][18] .…”