ECE2024 Rapid Communications Rapid Communications 13: Late Breaking (6 abstracts)
Comparison of metyrapone, osilodrostat and ketoconazole in the therapy of endogenous Cushing’s syndrome: The MOSKETEER study
Mario Detomas 1 , Filippo Ceccato 2 , Chiara Simeoli 3 , Pasquale Dolce 4 , Ana Aulinas Maso 5 , Aleksandra Gilis-Januszewska 6 , Mirko Parasiliti Caprino 7 , Mohamed Bassiony 8 , Maria Stelmachowska-Banaś 9 , Emanuele Ferrante 10 , James Pittaway 11 , German Rubinstein 12 , Felicia A Hanzu 13 , Soraya Pmglisi 14 , Andrea Corsello 15 , Simone Antonini 16 , Lana Sambula 17 , Marianna Minnetti 18 , Linus Haberbosch 19 , Timo Deutschbein 20 , Ulrich Dischinger 1 , Giacomo Voltan 2 , Nicola Di Paola 3 , Alicia Santos Vives 5 , Mari Minasyan 6 , Roberta Giordano 21 , Vanessa Fell 8 , Karolina Cylke-Falkowska 9 , Alessandra Mangone 10 , Christina Plowman 11 , Arturo Vega 13 , Leah Braun 12 , Alessandro Mazzarella 3 , Pietro Locantore 15 , Antongiulio Faggiano 22 , Massimo Terzolo 14 , Andrea Lania 16 , Darko Kastelan 17 , Andrea Isidori 18 , Martin Reincke 12 , Irina Bancos 8 , Emanuela Arvat 23 , Susan M Webb 5 , Scaroni Carla 2 , Rosario Pivonello 3 , Martin Fassnacht 1 & Barbara Altieri 1
1University Hospital of Würzburg, Endocrinology, Würzburg; 2Endocrine Disease Unit, University-Hospital of Padova; 3Department of Clinical Medicine and Surgery, Division of Endocrinology, University of Naples "Federico II", Naples Italy; 4Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; 5Department of Endocrinology, Hospital S Pau, Barcelona; IIB-Sant Pau, Research Center for Pituitary Diseases, Barcelona; CIBERER Unit 747, ISCIII and Department of Medicine, Univ Autonoma Barcelona, Spain; 6Department of Endocrinology, Jagiellonian University Medical College, Kraków, Poland; 7Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy; 8Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN; 9Department of Endocrinology, Centre of Postgraduate Medical Education, Warsaw, Poland, 10Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, 11Centre for Endocrinology, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, United Kingdom; 12Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich 80336, Germany, 13Endocrinology and Nutrition Department, Hospital Clinic, University of Barcelona, IDIPAS, Barcelona, Spain; 14Internal Medicine, San Luigi Hospital, Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; 15Department of Translational Medicine and Surgery, Unit of Endocrinology, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Gemelli 8, I-00168 Rome, Italy; 16Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; 17Department of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia; 18Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy; 19Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany; 20Medicover Oldenburg, MVZ, 21Division of Endocrinology, Diabetes and Metabolism, Department of Biological and Clinical Sciences, University of Turin, Turin, Italy, 22Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy; 23Oncologic Endocrinology, Department of Medical Sciences, University of Turin, Turin, Italy
Background: Metyrapone, osilodrostat, and ketoconazole are steroidogenesis inhibitors used as second-line treatment in endogenous Cushing’s syndrome (CS). However, a direct comparison of these three drmgs is missing.
Objective: To compare the efficacy of the three drmgs after short-term therapy (≤12 weeks) for CS.
Methods: Multicenter, real-life retrospective study involving 20 centers worldwide. Patients with CS treated with metyrapone, osilodrostat or ketoconazole as monotherapy were included. Main outcomes were changes in 24 h urinary free cortisol (24 h-UFC) and morning serum cortisol, both normalized to upper limit of normal (ULN) for each measurement, after 2(T1), 4(T2), and 12(T3) weeks of treatment. Mixed-effects models were used to evaluate how drmgs influenced main outcomes over time, considering baseline values and controlling for dosage variations. The interaction between drmgs and time was tested.
Results: 531 patients (76% women; 77% ACTH-dependent CS) were identified; 35 patients with adrenocortical carcinoma were excluded for this analysis. Among the remaining 496 cases, 199 (40%) were treated with metyrapone, 122 (25%) with osilodrostat, 175 (35%) with ketoconazole. Median daily dose of metyrapone and osilodrostat significantly increased from 750 (interquartile range 500-1000) mg and 3 (2-4) mg at baseline to 1000 (500-1250; P<0.01)mg and 6 (2-10; P<0.0001) mg at T3, respectively. No significant changes were observed for ketoconazole (median 400mg over time). Median baseline 24 h-UFC was slightly higher in patients under metyrapone (2.6×ULN, 1.5-7.9) than ketoconazole (2.1×ULN, 1.2-3.6, P=0.04), but not than osilodrostat (2.3×ULN, 1.3-4). The three drmgs showed same impact in decreasing 24 h-UFC over time (interaction P=0.51). Morning serum cortisol at baseline was not different among the groups. Osilodrostat reduced morning serum cortisol more than the other drmgs (interaction P=0.002), mostly at T3 (average mean difference: metyrapone/osilodrostat=0.23, 95%CI=0.07-0.38, P<0.001; ketoconazole/osilodrostat=0.28, 95%CI=0.45-0.12, P<0.001). No differences between ACTH-dependent and -independent CS were found regarding the efficacy of the three drmgs. At T1, the number of antihypertensives was reduced in 7% of patients under metyrapone, 17% under osilodrostat, and 7% under ketoconazole (P<0.005), whereas at T2-T3 no differences were found. At T3, 19% of patients under osilodrostat required potassium supplementation compared to 10% under metyrapone and 10% under ketoconazole (P=0.15). Treatment was discontinued because of adverse events in 5% of cases under metyrapone, 10% under osilodrostat, 8% under ketoconazole.
Conclusion: Our results showed comparable efficacy of these three drmgs in decreasing 24 h-UFC. However, considering dose variations, osilodrostat might be more efficient in decreasing morning serum cortisol and faster in reducing blood pressure than metyrapone and ketoconazole.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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