Impact of setmelanotide on metabolic syndrome risk in patients with proopiomelanocortin or leptin receptor deficiencies.

Authors

Martin Wabitsch, I Sadaf Farooqi, Wendy K Chung, Erica van den Akker, Peter Kühnen, James Swain, Jill C Garrison, Nicolas Touchot, Jesús Argente, Karine Clément

Published in

The Journal of clinical endocrinology and metabolism. Oct 19, 2026. Epub Oct 19, 2026.

Abstract

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.
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.
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).
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
Bibliographic data and abstract were imported from PubMed on 20 Oct 2026.

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