EP649 - ECE_2874 - Setmelanotide treatment in severe hypothalamic obesity: report of two cases

Abstract

Hypothalamic obesity is a rare, severe, and treatment-resistant condition caused by genetic or acquired hypothalamic damage. It is characterized by hyperphagia, impaired satiety, rapid weight gain, and high cardiometabolic risk. Conventional lifestyle and pharmacological treatments are largely ineffective, and bariatric surgery shows limited benefit due to impaired central satiety signaling. Setmelanotide, a selective melanocortin-4 receptor (MC4R) agonist, may bypass disrupted hypothalamic pathways and represent a targeted therapeutic option. We report two patients with severe hypothalamic obesity treated with setmelanotide. The first patient is a 22-year-old male who developed hypothalamic dysfunction after surgical resection of a craniopharyngioma, with complete loss of satiety and rapid weight gain of approximately 50 kg within four months. At baseline, body mass index (BMI) was 42.1 kg/m². Weight gain persisted despite optimized pituitary hormone replacement, dietary intervention, and off-label semaglutide. Setmelanotide was initiated and titrated to the maximum recommended dose. The second patient is a 19-year-old female with hypothalamic obesity associated with a possible hypothalamic amartoma. She gained 30 kg within a year, reaching a BMI of 50.2 kg/m². She was recently initiated on setmelanotide. In the first patient, treatment resulted in a weight loss of 16.5 kg over seven months, with BMI decreasing from 42.1 to 37.5 kg/m². In the second patient, body weight decreased by 10.5 kg after 1.5 months of therapy, with BMI reducing from 50.2 to 46.7 kg/m². Setmelanotide was generally well tolerated. The first patient experienced skin hyperpigmentation, transient nausea, and episodes of prolonged erections, none requiring discontinuation. Despite reduced thirst perception in the context of central diabetes insipidus, serum sodium remained stable under desmopressin therapy. No significant adverse effects were observed in the second patient. These cases support the potential efficacy and acceptable safety of setmelanotide in severe hypothalamic obesity of acquired or idiopathic origin. Early targeted therapy may help limit progressive weight gain when conventional treatments fail. Further prospective studies are warranted.