Children’s Nutrition Research Center Staff Publications
Language
English
Publication Date
1-1-2024
Journal
Obesity Research & Clinical Practice
DOI
10.1016/j.orcp.2024.07.001
PMID
38987029
PMCID
PMC11427144
PubMedCentral® Posted Date
7-10-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Background: Smith Magenis Syndrome (SMS) is a rare genetic disorder caused by RAI1 haploinsufficiency. Obesity in people with SMS is believed partially due to dysfunction of the proximal melanocortin 4 receptor (MC4R) pathway. We therefore studied effects of treatment with the MC4R agonist setmelanotide on obesity and hunger, as well as metabolic, cardiac and safety, in individuals with SMS.
Methods: People with SMS received once-daily setmelanotide injections, with the dose titrated bi-weekly to a maximum of 3 mg over ∼1 month; and a full-dose treatment duration of 3mo. The primary outcome was percent change in body weight. Secondary outcomes included hunger, waist circumference, body composition, and safety.
Results: 12 individuals, ages 11-39 y, enrolled and 10 completed the full-dose treatment phase. Mean percent change in body weight at end-treatment was - 0.28 % [(95 % CI, -2.1 % to 1.5 %; n = 12; P = 0.66]. Participants experienced a significant decrease in total cholesterol associated with a significant decrease in HDL-cholesterol and a trend for lower LDL-cholesterol. Self-reported hunger was reduced at end-treatment (p = 0.011). All participants reported adverse events (AEs), most commonly injection-site reactions and skin hyperpigmentation. No AEs led to withdrawal or death.
Conclusions: In this trial, setmelanotide did not significantly reduce body weight in participants with SMS. Participants reported significant differences in hunger, but such self-reports are difficult to interpret without a placebo-treated group. The changes in lipid profiles require further investigation. Results of this study do not suggest that dysfunction of the proximal MC4R pathway is the main etiology for obesity in people with SMS.
Keywords
Humans, Receptor, Melanocortin, Type 4, alpha-MSH, Male, Adult, Female, Adolescent, Obesity, Young Adult, Child, Treatment Outcome, Hunger, Waist Circumference, Weight Loss, Body Composition, Body Weight, Obesity, pharmacotherapy, setmelanotide, melanocortin agonist, Smith-Magenis Syndrome, hyperphagia
Published Open-Access
yes
Recommended Citation
Lazareva, Julia; Sisley, Stephanie R; Brady, Sheila M; et al., "Investigation of Setmelanotide, an MC4R Agonist, for Obesity in Individuals With Smith-Magenis Syndrome" (2024). Children’s Nutrition Research Center Staff Publications. 264.
https://digitalcommons.library.tmc.edu/staff_pub/264
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Dietetics and Clinical Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Nutrition Commons