Background: PraderWilli Syndrome (PWS) is a genetic disorder associated with hyperphagia and hyperghrelinemia with major morbidity due to obesity. The aetiology of hyperphagia is unknown, but presumed to be multifactorial, and, as ghrelin is orexigenic, high levels may contribute to weight issues in PWS. Currently, there is no effective medical treatment for hyperphagia in PWS, but targeting appetite could be beneficial. Exenatide (Byetta (synthetic exendin-4); AstraZeneca) is a GLP1 receptor agonist which reduces appetite and weight. In rodent studies, exendin-4 decreased ghrelin levels. Thus, exenatide may be an effective treatment in PWS.
Objective and hypotheses: The objective of this pilot study was to determine the effect of a 6-month trial of exenatide on appetite, weight, and gut hormones in youth with PWS.
Method: Ten overweight or obese subjects with PWS (1325 years) were recruited for an open-label, non-randomized, 6-month longitudinal study using standard exenatide dosing. Primary outcomes were weight, BMI, truncal fat, appetite, and acylated (active) ghrelin at 0,1, 3, and 6 months and during mixed meal tolerance tests (MMTT) at 0 and 6 months. A syndrome-validated appetite questionnaire, DXAs, anthropometrics, and metabolic markers were assessed. Consistent caregivers completed questionnaires with possible scores between 11 and 55 (higher values=higher appetites). No dietary modifications were made. Data are presented as mean±S.D. and within-subject changes between visits were analysed by mixed model repeated measures.
Results: Total appetite scores significantly decreased from baseline (32.2±8.7) after 1, 3, and 6 months of treatment (27.5±8.8, 25.4±9.3, and 25.4±7.2, respectively; P=0.004). However, there were no significant changes in weight, BMI Z-score, or truncal fat. There was no significant change in fasting or ghrelin excursion during MMTT based on area under the curve data. There were no significant adverse events.
Conclusion: Exenatide was safe and effective in decreasing appetite in youth with PWS, without decreases in weight or BMI in the short term. Larger, controlled, longer-term trials are needed to confirm the safety and efficacy of exenatide, and to evaluate whether its use might induce weight loss when given in conjunction with behavioral modification.
Funding: Department of Endocrinology, Childrens Hosptial Los Angeles (CHLA) Merit Fund (8030-RR1000019-00, $30,000, 2011), NIH NCRR CTSI grant (1UL1RR031986, $10,000, 2011), and Amylin Pharmaceuticals (now AstraZeneca) (2011-E-0389, drug only, 2011).
01 - 03 Oct 2015
European Society for Paediatric Endocrinology