Estudio de los efectos del tratamiento de metformina junto con recomendaciones de estilo de vida saludable en el índice de masa corporal, sensibilidad a la insulina, biomarcadores inflamatorios y de riesgo cardiovascular en niños obesos según el estado puberal

Abstract

Introduction Overweight and obesity in children are one of the most challenging health problems to address (Centers for Disease Control and Prevention (CDC) 2011). Obesity plays an important pathophysiologic role in the development of insulin resistance, dyslipidemia, and hypertension, leading to type 2 diabetes (T2D) and risk of early cardiovascular disease (CVD) (Freedman et al. 1999; Weiss et al. 2004). For pediatric patients, several investigations have confirmed that an intensive lifestyle intervention can increase weight loss and insulin sensitivity and reduce the risk of developing T2D (Diabetes Prevention Program Research Group et al. 2002). Nevertheless, a single-strategy lifestyle intervention is not always effective (Kelly et al. 2016). Additionally, efforts have been made to identify effective and safe drugs to manage pediatric obesity. Metformin is an oral antihyperglycemic agent approved by the Food Drug Administration (FDA) to treat T2D in adults and children aged >10 years and considered a first-line agent in T2D by the European Medicines Agency (EMEA). Significant weight loss induced by metformin has been demonstrated in overweight/obese adult patients with/without T2D (Golay 2008), also a decrease in cardiovascular risk profile (De Jager et al. 2005; Škrha et al. 2007; Ersoy et al. 2008; Kelly et al. 2012) and in inflammatory biomarkers as well (De Jager et al. 2005; Škrha et al. 2007; Stocker et al. 2007; Ersoy et al. 2008; Alvim de Lima et al. 2009; Chakraborty et al. 2011; Esteghamati et al. 2012; Kelly et al. 2012). Nevertheless, evidence regarding the effects of metformin in pediatric obesity is scarce. McDonagh et al. (McDonagh et al. 2014) examined the literature in obese children by a systematic review and meta-analysis. The authors concluded that the maximum reduction in body mass index (BMI) due to metformin compared to the effects of lifestyle interventions alone was in studies ranged from 6-12 months. Furthermore, metformin appears to improve the lipid profile in obese adolescents (Kay et al. 2001; Atabek & Pirgon 2008; Clarson et al. 2009). However, little is known about the effects of metformin on obesity-related complications such as cardiovascular risk and inflammation. Seven studies have evaluated the effects of metformin (1000-2000 mg/d for 3-6 months) on such conditions related to obesity in obese children and/or adolescents (Burgert et al. 2008; Clarson et al. 2009; Yanovski et al. 2011; Evia-Viscarra et al. 2012; Gómez-Díaz et al. 2012; Mauras et al. 2012; Kendall et al. 2013), obtaining some promising results. However, randomized clinical trials (RCTs) on this topic did not show a homogeneous distribution according to the pubertal stage. Puberty might exert as a potential modifier on the effect of metformin in childhood. Actually, a recent review highlights the usefulness of stratifying randomization by Tanner stage and sex to avoid large imbalances between groups in linear growth velocity and other factors associated with pubertal maturation that may affect changes in BMI (Kelly et al. 2016). Hence, we designed an RCT to determine whether metformin would have an effect on reducing the BMI z-score and improving cardiovascular and inflammatory risk biomarkers in obese children and to assess whether that effect differed depending on pubertal stage and sex. Study design The study was an intention to treat multicenter investigation, stratified by sex and pubertal status (40 prepubertal girls, 40 prepubertal boys, 40 pubertal girls, and 40 pubertal boys). Pubertal stage was determined according to Tanner criteria (Tanner & Whitehouse 1976). This randomized, double blind, placebo-controlled trial was homogeneously conducted at four Spanish Hospitals, as previously described (Pastor-Villaescusa et al. 2016). Children were randomly assigned to receive either metformin or placebo for six months. Details of the trial protocol and Ethics Committees have been previously published in Trials (Pastor-Villaescusa et al. 2016) (NºEudraCT: 2010-023061-21). The CONSORT statement (Consolidated Standards of Reporting Trials) has been considered in the report on study design and results, as well as in the abstract and flow diagram. Methodology and participants The study subjects comprised 160 patients referred from the Pediatric Endocrinology Unit of the corresponding study centers (Pastor-Villaescusa et al. 2016). The inclusion criteria to participate in the RCT included a BMI above the 95th percentile adjusted for age and sex, and age 7–14 years. The data were collected in the pediatric outpatient clinics by dieticians. Data and samples were codified according to each center and subsequently centralized at the Institute of Nutrition and Food Technology “José Mataix” (INYTA) in Granada, Spain. The participants were assigned to metformin or placebo in accordance with a randomization schedule generated by the Pharmacy Service of the Virgen de las Nieves University Hospital in Granada, with M.A.S 100 version 2.1 software (Glaxo-Welcome, Madrid, Spain) by the Support Consortium to Biomedical Research Network (CAIBER). At each center, 50% of the children were assigned to each group. All research staff was blinded to both the treatment allocation during the time of the study and the data analysis. The patients were instructed to gradually increase their dosage by taking 50 mg twice daily for ten days, followed by 500 mg twice daily until the end of the intervention. Both treatments were administered during meals. The participants attended an initial trial baseline visit, followed by two additional control visits at 2-month intervals, which comprised the assessment of blood pressure and a physical examination. To assess the safety and tolerance of metformin administration, the primary evaluation criteria were the absence of adverse effects, as previously reported (Pastor-Villaescusa et al. 2016). Conclusion The onset of childhood obesity may begin very early in life. This fact clearly has important implications for future in the development of CVD in obese children and young people. There remains a need for better pharmacological strategies to reduce cardiovascular risk in this population. In the present RCT, prepubertal children showed decreased BMI z-score and improved other parameters related to obesity after following a metformin treatment for six months, but pubertal children did not.