Impact of setmelanotide on metabolic syndrome risk in patients with bardet-biedl syndrome

Haqq Andrea M.; Christine Poitou-Bernert; Wendy Chung; Anoop Iqbal; Elizabeth Forsythe; Sonali Malhotra; Nicolas Touchot; Karine Clement; Jesus Argente

doi:10.1530/endoabs.99.EP25

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Endocrine Abstracts (2024) 99 EP25 | DOI: 10.1530/endoabs.99.EP25

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

Impact of setmelanotide on metabolic syndrome risk in patients with bardet-biedl syndrome

Andrea M. Haqq ¹ , Christine Poitou-Bernert ² , Wendy Chung ³ , Anoop Iqbal ⁴ , Elizabeth Forsythe ⁵ , Sonali Malhotra ⁶ , Nicolas Touchot ⁷ , Karine Clément ² & Jesús Argente ⁸

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¹Division of Pediatric Endocrinology, University of Alberta, Edmonton, AB, Canada, Edmonton, Canada; ²Nutrition Department, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital; Sorbonne University, Inserm, Nutrition and Obesity, Systemic Approaches (NutriOmique) Research Group, Paris, France; ³Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, United States; ⁴Department of Clinical Research, Marshfield Clinic Research Institute, Marshfield, United States; ⁵Clinical Genetics Department, Guys and St. Thomas’ Hospitals, London, and National Bardet-Biedl Syndrome Clinics, Great Ormond Street Hospital, London, United Kingdom; ⁶Rhythm Pharmaceuticals, Inc.; Massachusetts General Hospital; Harvard Medical School, Boston, United States; ⁷Rhythm Pharmaceuticals, Inc., Boston, United States; ⁸Department 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

Background: Patients with Bardet-Biedl syndrome (BBS), a rare syndrome associated with obesity and hyperphagia, commonly manifest traits of metabolic syndrome, including abdominal obesity, impaired fasting glucose, low high-density lipoprotein cholesterol, hypertriglyceridemia, and hypertension. Setmelanotide treatment results in significant improvement in weight, hunger, and quality of life in these patients and may improve measures associated with metabolic syndrome development. We evaluated the metabolic syndrome Z score based on body mass index (MetS-Z-BMI), a measure of long-term risk for developing 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: Data from a Phase 3 trial of patients with BBS (NCT03746522) were used to calculate MetS-Z-BMI score after 1 year of setmelanotide. Patients who achieved a meaningful response of ≥10% weight loss (if ≥18 years old) or ≥0.3-point BMI Z score reduction (if <18 years old) were compared with patients who did not meet those thresholds.

Results: Of 32 patients with BBS enrolled, 22 were evaluable (59% female, 10-44 years old). Setmelanotide was associated with reduced mean (SD) MetS-Z-BMI score after 52 weeks in patients with a meaningful weight response (n=16; −0.54 [0.56]). Patients not meeting weight thresholds (n=6) had an increase in MetS-Z-BMI (+0.17 ([0.50]; between-group difference, −0.71, P=0.129). MetS-Z-BMI change was generally comparable between females and males.

Conclusions: In addition to reduced hyperphagia and improved quality of life with setmelanotide, meaningful reductions in weight-related outcomes are associated with decreases in MetS-Z-BMI score in patients with BBS. These data suggest that early treatment initiation may lead to reduction in future risk of T2DM and CVD development.