Adverse Event Profile Differences Between Metyrapone and Osilodrostat: A Pharmacovigilance Study of the FDA Adverse Event Reporting System

Abstract

Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase, yet their safety profile has not been comprehensively analyzed. The objective of this study is to compare the adverse events (AEs) associated with osilodrostat and metyrapone based on the Food and Drug Administration Adverse Event Reporting System (FAERS). AEs were classified according to the System Organ Class (SOC) in the Medical Dictionary for Regulatory Activities (MedDRA) version 26.1. Adverse event (AE) signals of osilodrostat and metyrapone were determined by calculating reporting odds ratios (ROR). A total of 1380 and 449 AE reports were retrieved from osilodrostat and metyrapone, respectively, involving 26 and 27 SOC categories. Unexpected AEs such as asthenia, decrease of blood potassium, myalgia, increase of blood pressure, abdominal distension, increase of blood testosterone, nephrolithiasis, and hunger were associated with osilodrostat. while metyrapone was linked with respiratory failure, deep vein thrombosis, interstitial lung disease, liver function test abnormal, and respiratory distress. Among osilodrostat-treated patients, those aged between 18 to 65 years old were more likely to develop adrenal insufficiency, fatigue, tachycardia, than those older than 65. Male patients treated with metyrapone have the significantly higher incidence of the increased blood corticotrophin, muscular weakness and acute respiratory distress syndrome compared to females. During treatment with osilodrostat and metyrapone, clinicians need to monitor the effects of AEs varied by gender and age and to pay more attention to new AE signals.

Keywords

osilodrostat - metyrapone - adverse events - disproportionality analysis

Publication History

Received: 18 July 2025

Accepted after revision: 18 August 2025

Accepted Manuscript online:
18 August 2025

Article published online:
18 September 2025

• References

• 1 Lacroix A, Feelders RA, Stratakis CA. et al. Cushing’s syndrome. Lancet 2015; 386: 913-927
• 2 Eisenhofer G, Constantinescu G. Commentary on cryptogenic Cushing syndrome due to a white lie. Clin Chem 2020; 66: 661-662
• 3 Hakami OA, Ahmed S, Karavitaki N. Epidemiology and mortality of Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab 2021; 35: 101521
• 4 Valassi E. Clinical presentation and etiology of Cushing’s syndrome: data from ERCUSYN. J Neuroendocrinol 2022; 34: e13114
• 5 Wengander S, Trimpou P, Papakokkinou E. et al. The incidence of endogenous Cushing’s syndrome in the modern era. Clin Endocrinol (Oxf) 2019; 91: 263-270
• 6 Nieman LK, Biller BMK, Findling JW. et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 2807-2831
• 7 Braun LT, Rubinstein G, Zopp S. et al. Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment. Endocrine 2020; 70: 218-231
• 8 Detomas M, Altieri B, Deutschbein T. et al. Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushing’s syndrome: results from a single center cohort study. Front Endocrinol (Lausanne) 2022; 13: 903545
• 9 Pivonello R, Simeoli C, Di Paola N. et al. Cushing’s disease: adrenal steroidogenesis inhibitors. Pituitary 2022; 25: 726-732
• 10 Perosevic M, Tritos NA. Clinical utility of osilodrostat in Cushing’s disease: review of currently available literature. Drug Des Devel Ther 2023; 17: 1303-1312
• 11 Broersen LHA, Jha M, Biermasz NR. et al. Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis. Pituitary 2018; 21: 631-641
• 12 Bertagna X, Pivonello R, Fleseriu M. et al. LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab 2014; 99: 1375-1383
• 13 Fleseriu M, Pivonello R, Young J. et al. Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, phase II study in Cushing’s disease. Pituitary 2016; 19: 138-148
• 14 Pivonello R, Fleseriu M, Newell-Price J. et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 2020; 8: 748-761
• 15 Hu H, Fu Z, Liu J. et al. Pulmonary haemorrhage and haemoptysis associated with bevacizumab-related treatment regimens: a retrospective, pharmacovigilance study using the FAERS database. Front Pharmacol 2024; 15: 1339505
• 16 Liu D, Mao W, Hu B. et al. A real-world pharmacovigilance study of polatuzumab vedotin based on the FDA adverse event reporting system (FAERS). Front Pharmacol 2024; 15: 1405023
• 17 Shu Y, Ding Y, Liu Y. et al. Post-marketing safety concerns with secukinumab: a disproportionality analysis of the FDA adverse event reporting system. Front Pharmacol 2022; 13: 862508
• 18 Kerr S, Greenland S, Jeffrey K. et al. Understanding and reporting odds ratios as rate-ratio estimates in case-control studies. J Glob Health 2023; 13: 4101
• 19 Daniel E, Aylwin S, Mustafa O. et al. Effectiveness of metyrapone in treating Cushing’s syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metab 2015; 100: 4146-4154
• 20 Ceccato F, Zilio M, Barbot M. et al. Metyrapone treatment in Cushing’s syndrome: a real-life study. Endocrine 2018; 62: 701-711
• 21 Shimatsu A, Biller BM, Fleseriu M. et al. Osilodrostat treatment in patients with Cushing’s disease of Asian or non-Asian origin: a pooled analysis of two phase III randomized trials (LINC 3 and LINC 4). Endocr J 2024; 71: 1103-1123
• 22 Gadelha M, Snyder PJ, Witek P. et al. Long-term efficacy and safety of osilodrostat in patients with Cushing’s disease: results from the LINC 4 study extension. Front Endocrinol (Lausanne) 2023; 14: 1236465
• 23 Lightman SL, Birnie MT, Conway-Campbell BL. Dynamics of ACTH and cortisol secretion and implications for disease. Endocr Rev 2020; 41: bnaa002
• 24 Kidawara Y, Kakutani-Hatayama M, Fukuoka H. et al. Prolonged hypokalemia following metyrapone treatment for primary bilateral macronodular adrenal cortical disease. JCEM Case Rep 2024; 2: luae015
• 25 Boughton C, Taylor D, Ghataore L. et al. Mineralocorticoid hypertension and hypokalaemia induced by posaconazole. Endocrinol Diabetes Metab Case Rep 2018; 17-0157
• 26 Azziz R, Amiri M, Bril F. et al. Approach to the patient: hirsutism. J Clin Endocrinol Metab 2025; 9: dgaf226