{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:43:37Z","timestamp":1792424617969,"version":"4.5.0"},"reference-count":44,"publisher":"The Endocrine Society","license":[{"start":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:00:00Z","timestamp":1792368000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Rhythm Pharmaceuticals, Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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 \u223c1 year of setmelanotide treatment in these patients; subgroup analyses were conducted by sex, age, genotype, and response to treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 \u22651 metabolic parameter at week 52. The overall mean (SD) change in MetS-Z-BMI score after \u223c1 year of treatment was \u22121.05 (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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag345","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:30:02Z","timestamp":1792423802000},"source":"Crossref","is-referenced-by-count":0,"title":["Impact of setmelanotide on metabolic syndrome risk in patients with proopiomelanocortin or leptin receptor deficiencies"],"prefix":"10.1210","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8693-2647","authenticated-orcid":false,"given":"Martin","family":"Wabitsch","sequence":"first","affiliation":[{"name":"Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm , 89075 Ulm ,","place":["Germany"]},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site , 89075 Ulm ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7609-3504","authenticated-orcid":false,"given":"I Sadaf","family":"Farooqi","sequence":"additional","affiliation":[{"name":"Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]},{"name":"NIHR Cambridge Biomedical Research Centre , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy K","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children's Hospital, Harvard Medical School , Boston, MA 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"van den Akker","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Pediatrics, Sophia Children's Hospital and Obesity Center CGG, Erasmus University Medical Center , 3015 GD Rotterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0211-176X","authenticated-orcid":false,"given":"Peter","family":"K\u00fchnen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology and Diabetology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin und Humboldt-Universit\u00e4t zu Berlin , 10117 Berlin ,","place":["Germany"]},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site , 13353 Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Swain","sequence":"additional","affiliation":[{"name":"Honor Health Research Institute , Scottsdale, AZ 85258 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill C","family":"Garrison","sequence":"additional","affiliation":[{"name":"Rhythm Pharmaceuticals, Inc. , Boston, MA 02116 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Touchot","sequence":"additional","affiliation":[{"name":"Rhythm Pharmaceuticals, Inc. , Boston, MA 02116 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5826-0276","authenticated-orcid":false,"given":"Jes\u00fas","family":"Argente","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Pediatric Endocrinology, Universidad Aut\u00f3noma de Madrid, University Hospital Ni\u00f1o Jes\u00fas , 28009 Madrid ,","place":["Spain"]},{"name":"CIBER \u201cFisiopatolog\u00eda de la obesidad y nutrici\u00f3n\u201d (CIBEROBN), Instituto de Salud Carlos III , 28029 Madrid ,","place":["Spain"]},{"name":"IMDEA Food Institute , 28049 Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4619-6785","authenticated-orcid":false,"given":"Karine","family":"Cl\u00e9ment","sequence":"additional","affiliation":[{"name":"Assistance Publique H\u00f4pitaux de Paris, Nutrition Department, Piti\u00e9-Salp\u00eatri\u00e8re Hospital , 75013 Paris ,","place":["France"]},{"name":"Inserm, Nutrition and Obesities, Systemic Approaches, NutriOmique Research Group, Sorbonne Universit\u00e9 , 75005 Paris 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