Impact of setmelanotide on metabolic syndrome risk in patients with POMC and LEPR deficiency

Martin Wabitsch; Wendy Chung; Peter Kuhnen; James Swain; Jill Garrison; Nicolas Touchot; Jesus Argente; Karine Clement

doi:10.1530/endoabs.99.EP57

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Endocrine Abstracts (2024) 99 EP57 | DOI: 10.1530/endoabs.99.EP57

ECE2024 Eposter Presentations Diabetes, Obesity, Metabolism and Nutrition (383 abstracts)

Impact of setmelanotide on metabolic syndrome risk in patients with POMC and LEPR deficiency

Martin Wabitsch ¹ , Wendy Chung ² , Peter Kühnen ³ , James Swain ⁴ , Jill Garrison ⁵ , Nicolas Touchot ⁵ , Jesús Argente ⁶ & Karine Clément ⁷

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¹Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany; ²Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States; ³Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, Institute for Experimental Pediatric Endocrinology, Berlin, Germany; ⁴Honor Health Research Institute, Scottsdale, United States; ⁵Rhythm Pharmaceuticals, Inc., Boston, United States; ⁶Department of Pediatrics and Pediatric Endocrinology, Universidad Autónoma de Madrid, University Hospital Niño Jesús, CIBER ‘Fisiopatología de la obesidad y nutrición’ (CIBEROBN), Instituto de Salud Carlos III; IMDEA Food Institute, Madrid, Spain; ⁷Assistance Publique Hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital; Sorbonne University, Inserm, Nutrition and Obesity, Systemic Approaches (NutriOmique) Research Group, Paris, France

Background: Proopiomelanocortin (POMC; including biallelic variants in PCSK1) and leptin receptor (LEPR) deficiency are associated with hyperphagia and early-onset, severe obesity. Treatment with the melanocortin-4 receptor agonist setmelanotide for 1 year results in significant and sustained improvements in weight (POMC, −25.6%; LEPR, −12.5%), hunger, and quality of life. We used the metabolic syndrome Z score based on body mass index (MetS-Z-BMI) to assess the effect of setmelanotide treatment on long-term risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Each 1.0-point increase in MetS-Z-BMI increases the odds of future CVD and T2DM by 9.8 and 2.7, respectively, when assessed in children and by 2.4 and 2.8, respectively, when assessed in adults.

Methods: Parameters from Phase 3 trials of patients with POMC (NCT02896192) or LEPR (NCT03287960) deficiency were used to calculate MetS-Z-BMI score change after 1 year of setmelanotide. Long-term clinical responders to setmelanotide were defined as achieving ≥10% weight loss (if ≥18 years old) or ≥0.3-point BMI Z score reduction (if <18 years old) after 1 year.

Results: Eighteen patients (56% female, 11-36 years old) were evaluated. A decrease in mean (SD) MetS-Z-BMI was observed in clinical responders after 1 year of setmelanotide (n=14; −1.31 [0.84]). Nonresponders (n=4) achieved minimal decrease in MetS-Z-BMI (−0.17 [0.23]; difference between groups, −1.13, P=0.0187). Responders with POMC (n=9) and LEPR deficiency (n=5) had changes in MetS-Z-BMI of −1.63 (0.84) and −0.72 (0.48), respectively. MetS-Z-BMI change was similar in female and male responders.

Conclusions: Clinical response to setmelanotide led to decreases in MetS-Z-BMI in patients with POMC and LEPR deficiency associated with reduced risk of developing CVD and T2DM in other populations. These data suggest that early initiation of setmelanotide may reduce future risk of T2DM and CVD.