Evaluation of the metformin effect along with healthy lifestyle recommendations on body mass index, insulin sensitivity, inflammatory and cardiovascular risk biomarkers in obese children according to pubertal stage

Abstract

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.