*4.1. Influence of Intervention and BMI Changes on Metabolic Comorbidities*

The effect of BMI reduction on the improvement of metabolic status observed in the excellent responders might be expected. However, the mean decrease in HOMA index and lipid metabolism parameters observed in the 451 patients out of the total 1300 patient cohort reevaluated metabolically prior to the end of follow up, with a mean cohort decrease in BMI of −0.37 DSD, independently of the duration of follow-up, had a linear relationship with the magnitude of BMI decrease, which reinforces the idea that the change in BMI is the primary factor in metabolic health in children and adolescents with obesity. Furthermore, BMI reduction was observed in patients that became metabolically healthy during followup or that were already metabolically healthy at the onset of the study and/or at the last clinical visit; however, BMI was not reduced in patients that had persistent metabolic alterations or developed these alterations during the study.

Regardless of the criteria used for defining metabolically healthy in children with obesity [19–22], the results of this study reinforce the role of insulin resistance as the initial step for metabolic derangement in childhood obesity, even before any analytical abnormality in glucose, uric acid or lipid metabolism is detected [12,19], with metabolically healthy patients with IR showing significant differences in these metabolic parameters compared to those that are metabolically healthy without IR, even though this is not considered in the proposed consensus definition for this entity during childhood [20]. However, the consideration of insulin resistance, next to other elements such as inflammatory markers, adipokine levels or measurements of ectopic fat deposition, has been proposed in more recent revisions of this term [21,22] indicating that more precise analyses of body fat content and distribution (using DXA scan or abdominal MRI) should be considered to better describe the "metabolically healthy" phenotype in obesity. More importantly, our data indicate that during childhood, being classified as metabolically healthily obese is dynamic and mainly dependent on the evolution of the patient's BMI throughout childhood and adolescence. Additionally, the lower prevalence of metabolically healthy individuals in the Latino patients in our cohort, previously already shown to present higher insulin resistance, triglyceride levels and prevalence of liver steatosis when using our populational standards [12,41], should lead us to consider whether homogeneous standards are valid for every patient, or whether ethnic specific standards for these parameters should be advised.
