Treatment of hyperphagia and obesity in Prader-Willi syndrome.

Abstract

Prader-Willi syndrome (PWS) is a rare, neurodevelopmental, multisystemic syndrome caused by lack of expression of paternal genes on chromosome 15q11.2-13. PWS is characterized by muscular hypotonia, abnormal body composition, hormone deficiencies, cognitive dysfunction and behavioural issues, including hyperphagia, increasing the risk of severe obesity. A single causative gene for hyperphagia has not been identified, and regulation of hunger and satiety is complex and multifactorial, making it difficult to identify a specific neuropeptide or hormone as the most important. Cornerstone treatments are a strict, controlled diet and regular physical activity. Several clinical trials with different pharmacological agents have been performed attempting to reduce or treat hyperphagia and obesity. However, many drug programmes have been discontinued due to adverse events or not reaching endpoints. In this review, we have focused on phenomenology and management of hyperphagia, treatment with oxytocin (OT), glucagon-like-peptide-1 receptor agonists (GLP-1RA) and diazoxide choline. We conclude that controlled food access is crucial; managing expectations about food mitigates food-related behaviour; OT treatment of infants with PWS results in less severe hyperphagia at ages 3 and 4 years old; and that the effects of GLP-1RA on body weight seem modest. Studies of diazoxide choline extended-release (DCCR), the first approved treatment of hyperphagia in PWS, have shown promising results, particularly in managing severe hyperphagia, reducing fat mass and improving behavioural issues. Thus, although progress is being made in targeted pharmacological therapies to control hyperphagia, controlled food access remains crucial to prevent obesity but is not sufficient for management of food and behaviour.