Abstract
Metformin is a first-line oral antidiabetic agent that has shown additional effects in treating obesity and metabolic syndrome. Inter-individual variability in metformin response could be partially explained by the genetic component. Here, we aimed to test whether common genetic variants can predict the response to metformin intervention in obese children. The study was a multicenter and double-blind randomized controlled trial that was stratified according to sex and pubertal status in 160 children with obesity. Children were randomly assigned to receive either metformin (1g/d) or placebo for six months after meeting the defined inclusion criteria. We conducted a post hoc genotyping study in 124 individuals (59 placebo, 65 treated) comprising finally 231 genetic variants in candidate genes. We provide evidence for 28 common variants as promising pharmacogenetics regulators of metformin response in terms of a wide range of anthropometric and biochemical outcomes, including body mass index (BMI) Z-score, and glucose, lipid, and inflammatory traits. Although no association remained statistically significant after multiple-test correction, our findings support previously reported variants in metformin transporters or targets as well as identify novel and promising loci, such as the ADYC3 and the BDNF genes, with plausible biological relation to the metformin’s action mechanism. Trial Registration: Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011 (URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023061-21/ES).
Highlights
The prevalence of overweight and obese children is a serious worldwide issue and one of the major health challenges of the 21st century [1]
Our results show that the well-known variability in metformin response might have a genetic origin, in the context of weight-loss and childhood obesity
Despite the study initially being focused on the effect of metformin as an anti-obesity agent, the bulk of the findings and metformin pharmacogenetic targets were identified within the axis of glucose-related phenotypes (Figure 2)
Summary
The prevalence of overweight and obese children is a serious worldwide issue and one of the major health challenges of the 21st century [1]. Several investigations have confirmed that intensive lifestyle interventions can increase weight-loss as well as reduce the later risk of developing T2DM in children with obesity [3]. There are no approved weight-loss medications for children under 12 years of age [4]. Metformin is the first-line oral anti-hyperglycemic agent approved by the US Food Drug Administration to treat T2DM in adults and children aged >10 years. Metformin has been considered a promising compound for the amelioration of adolescent and childhood obesity; especially through the reduction of body mass index (BMI) Z-score and waist circumference (WC) [4,5,6]
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