SUN-682 - A Hormonal Tug-of-War: Limitations of Glucagon-Like Peptide-1 Based Therapy in Prader Willi Syndrome

Introduction: Prader-Willi Syndrome (PWS) is the most prevalent cause of syndromic obesity [1]. It is characterized by hypothalamic dysfunction, leading to impaired satiety signaling and dysregulated appetite-regulating hormones. Growth hormone deficiency contributes to reduced lean body mass, a lower basal metabolic rate, and decreased energy expenditure. Behavioral disturbances, such as food-seeking behaviors and poor impulse control, are frequently observed due to concurrent dysfunction of the prefrontal cortex and limbic system.

Case Presentation: A 29-year-old man with PWS and type 2 diabetes was evaluated for progressive weight gain despite behavioral interventions and prolonged GLP-1 receptor agonist (GLP-1 RA) therapy. He previously received dulaglutide and semaglutide up to 2 mg weekly over 1.5 years, with ~40-lb weight gain. He had discontinued childhood growth hormone therapy and continued behavioral strategies for hyperphagia. Labs showed A1c 6.5%, hyperinsulinemia, elevated C-peptide, normal IGF-1, and hypogonadotropic hypogonadism (testosterone 82 ng/dL). Tirzepatide and testosterone were initiated; however, despite dose escalation of tirzepatide to 12.5 mg weekly, he continued to gain weight with worsening food-seeking behaviors and A1c increased to 7.0%. Diazoxide choline 150 mg daily was initiated with planned uptitration; follow-up is pending.

Discussion: Although GLP-1 RAs are effective in managing general obesity, their efficacy in PWS is inconsistent. Case series and observational studies have demonstrated variable outcomes  [2,3]. It may be attributed to impaired hypothalamic satiety regulation, which limits the efficacy of peripheral agents like GLP-1 RAs  [4]. A systematic review concluded that while GLP-1 RAs may help improve glycemic control, their impact on weight in patients with PWS is unpredictable [5]. Our patient exhibited paradoxical weight gain despite high dose GLP-1 agonists which underscore the need for a personalized approach with an agent which would target the pathways involved in hyperphagia that the GLP-1 RAs don’t act on. Newly FDA approved drug, diazoxide choline has shown to have promising results in PWS. In the DESTINY PWS trial, this drug significantly improved hyperphagia in patients with severe baseline symptoms and showed benefits in body composition and behavioral outcomes (6). It activates ATP-sensitive potassium (K-ATP) channels, suppressing pancreatic insulin secretion, reducing adipose fat mass, and downregulating neuropeptide Y–mediated hyperphagia.

Conclusion: While GLP-1 RAs are widely used in managing obesity, their effectiveness alone in PWS is limited due to underlying hypothalamic dysfunction and altered satiety signaling. In combination with diazoxide choline, multiple pathways are targeted which would enhance appetite control and improve overall body composition.

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