J Clin Endocrinol Metab. 2026 Oct 19:dgag345. doi: 10.1210/clinem/dgag345. Online ahead of print.
ABSTRACT
INTRODUCTION: Patients with severe obesity due to proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiencies resulting in impaired melanocortin-4 receptor (MC4R) signaling may be at risk for obesity-related comorbidities. Here, we report metabolic parameters and metabolic syndrome severity in patients before and after treatment with the MC4R agonist setmelanotide.
METHODS: Patients from phase 3 studies of setmelanotide for POMC (NCT02896192) or LEPR (NCT03287960) deficiencies with complete metabolic parameter data were included in this analysis. Metabolic parameters and metabolic severity Z scores based on body mass index (MetS-Z-BMI scores) were reported at baseline and following ∼1 year of setmelanotide treatment in these patients; subgroup analyses were conducted by sex, age, genotype, and response to treatment.
RESULTS: Metabolic parameters were evaluated in 18 of 21 patients enrolled in phase 3 trials. Group means for most parameters were within the normal range at baseline, excluding weight-related measures, fasting glucose, and triglycerides. The overall baseline mean (standard deviation [SD]) MetS-Z-BMI score was 1.49 (1.33). Most patients saw improvement in ≥1 metabolic parameter at week 52. The overall mean (SD) change in MetS-Z-BMI score after ∼1 year of treatment was -1.05 (0.88). Among subgroup analyses, MetS-Z-BMI score reductions were significantly greater in achievers of weight-based thresholds compared with nonachievers (P = .0187) and in patients with deficiencies in POMC compared with LEPR (P = .0278).
CONCLUSION: Setmelanotide was associated with a reduction in specific metabolic parameters and metabolic syndrome severity (MetS-Z-BMI scores) in patients with POMC or LEPR deficiencies.
PMID:42895739 | DOI:10.1210/clinem/dgag345