Shared Hyperphagia phenotypes and variable response to semaglutide in adults with neurodevelopmental obesity

Abstract

Adults with neurodevelopmental disorders (NDD) are at high risk of developing obesity, yet systematic evaluations of their eating behavior profiles remain scarce. In this study, participants were adults with overweight or obesity associated with a genetically confirmed NDD with intellectual disability (ID). We characterized multidimensional eating behavior phenotypes across three groups: Prader-Willi syndrome (PWS) and Bardet-Biedl syndrome (BBS), the two most frequent syndromic forms of obesity, and other neurodevelopmental genetic conditions associated with obesity (“other NDD”). We then evaluated the glucagon-like peptide-1 receptor agonist (GLP1-RA) semaglutide-associated changes in real-world conditions. We assessed eating behavior in 149 adults with NDD (PWS, n = 90; BBS, n = 13; other NDD, n = 46) using the Dykens Hyperphagia Questionnaire (HQ), the Children’s Eating Behavior Questionnaire (CEBQ), and the Parental–Developmental Disorders Quality of Life questionnaire (Par-DD-QoL). In a subgroup with longitudinal follow-up (PWS, n = 8; other NDD, n = 12), changes in body weight and eating behavior were evaluated after 12 months of semaglutide treatment (2.4 mg/week). Given the limited sample size, these subgroup analyses were considered hypothesis-generating and were not adjusted for multiple comparisons. Groups exhibited marked hyperphagic traits, with earlier onset of food interest in PWS and BBS (mean 6.6 and 2.7 years, respectively) compared with other NDD group (10.5 years). Distinct profiles emerged: PWS was characterized by lower food fussiness and desire to drink, whereas BBS tended to show higher satiety responsiveness. Nearly half of caregivers (46.4%) reported moderate-to-severe impairment in QoL. Neuroleptic use and type 2 diabetes were associated with higher hyperphagia scores, whereas having undergone pediatric-to-adult transition was associated with lower scores. After 12 months of semaglutide, no significant changes in BMI or eating behavior were observed in PWS (-0.9 (3.5) kg/m 2 ; p = 0.507; -1.1% weight loss). In contrast, the other NDD group showed significant BMI reduction (-4.3 (2.1) kg/m 2 ; p < 0.001; -8.7% weight loss), decreased food responsiveness (-1.0 (0.8); p < 0.05), and improved satiety responsiveness (+ 0.6 (0.9); p < 0.05). Hyperphagia extends beyond classical hypothalamic obesity syndromes such as PWS and BBS to a broader range of NDD. Semaglutide was associated with limited behavioral and weight effects in PWS, but with weight-loss and appetite-regulation benefits in other NDD-related obesity. Early behavioral monitoring, individualized interventions, and caregiver support are crucial to improve long-term outcomes in syndromic obesity.