Rasmus Stenlid: Cardiovascular Risk Factors and Aspects of GLP-1 Treatment in Pediatric Obesity

Abstract

Obesity during childhood is a major health concern. We have investigated in adolescents with obesity, how pharmacological treatment with exenatide affected endogenous GLP-1 secretion, inflammation and health behaviors. Additionally, we investigated predictors of disease severity based on cardiovascular risk factors.

In the randomized controlled trial Combat-JUDO (NCT02794402) adolescents with obesity (n=44) were randomized to six months of treatment with weekly injections of the GLP-1 agonist exenatide (2mg) or placebo. Lifestyle intervention was given to both groups consisting of nutritional advice and sessions to optimize physical activity. An oral glucose tolerance test was performed, eating habits and physical activity were quantified at baseline and at end-of-trial. Proglucagon-derived peptides, measures of glucose metabolism and 92 inflammatory proteins were measured in plasma. Participants from the Beta-JUDO cohort (n=811 of which 99 were controls), aged 3-18 years, were categorized according to their BMI-SDS as obesity class I, II or III, or by their fasting insulin quartiles as quartile 1, 2, 3 or 4, with the lean participants as a control group. Prevalence of cardiometabolic risk factors was determined in each group.

Exenatide treatment lowered IL-18Rα and DPP-4, improved glycemic tolerance, did not affect endogenous GLP-1, glucagon or insulin, and improved adherence to health behavior and lifestyle treatment (HBLT). Thus, exenatide treatment improved metabolic health and adherence to HBLT. ROC analyses showed larger AUCs for fasting insulin compared to BMI-SDS for finding dyslipidemia, impaired glucose tolerance (IGT) or a combination of dyslipidemia, impaired IGT and hypertension, but not for hypertension alone. The multiple regression analysis found that fasting insulin was more strongly associated with a larger number of cardiometabolic risk factors than BMI-SDS. Thus, fasting insulin concentrations better predict individuals with elevated risk factors for future cardiovascular events than obesity class based on BMI-SDS.

We propose that, firstly, continued evaluation of pharmacological treatment options for children with obesity is essential to enhance safe and efficient treatment options for the patient group. Secondly, fasting insulin measurements should be considered for incorporation into clinical routine in children and adolescents with obesity, and that an elevated value motivates further investigation, regardless of BMI.