Chronotherapy With Once-Daily Osilodrostat Improves Cortisol Rhythm, Quality of Life, and Sleep in Cushing's Syndrome

Journal article

Context: Medical therapy for Cushing syndrome (CS) typically aims to reduce daily cortisol output without addressing circadian rhythm restoration. No licensed drugs target this goal. Objective: We investigated the efficacy and safety of timed, once-daily osilodrostat administration in improving circadian cortisol profiles in CS. Methods: A prospective, multicenter study evaluated patients with well-controlled CS on a stable twice-daily osilodrostat therapy before and 60 to 90 days after transitioning to a single equivalent daily dose at 19:00 ± 1 hour. Circadian steroid analysis was performed on saliva, serum, and urine using ultra-high performance liquid chromatography–tandem mass spectrometry. Additional assessments included cardio-metabolic markers, quality of life, sleep function, and safety outcomes. Results: Sixteen patients (4 males; 7 pituitary, mean age 53.3 ± 11.8 years) were enrolled. At baseline, CS was well-controlled with a mean osilodrostat dose of 4.2 ± 1.3 mg. After transitioning, salivary cortisol exposure decreased significantly during the afternoon to early morning period (AUC16:00-08:00: −6.1 [−0.15 to −12.1] ng/mL/h, P = .029). Quality of life and sleep improved (CushingQoL: +4.2, P = .029; Pittsburgh Sleep Quality Index: −1.7, P = .049). Serum steroid precursors, including 11-deoxycorticosterone (−3.1 ng/mL/h, P = .008) and 11-deoxycortisol (−17.8 ng/mL/h, P = .005), decreased. Eight patients advancing dosing to 16:00 ± 1 hour showed comparable reductions, with phase shifts in acrophase and nadir. No patients developed adrenal insufficiency, liver toxicity, electrocardiogram abnormalities, or loss of disease control. Conclusion: Once-daily osilodrostat effectively and safely treats patients with biochemically controlled CS, improving circadian cortisol profiles, quality of life, and sleep. Findings support further exploration of chronotherapy-based approaches in CS management.

Authors: Ferrari, D; Bonaventura, I; Simeoli, C; Tomaselli, A; Vincenzi, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: The Journal of Clinical Endocrinology & Metabolism
• Volume: 110
• Issue: 12
• Pages: 3525-3537
• Publication date: 2025-04-02
• DOI: 10.1210/clinem/dgaf206
• EISSN: 1945-7197
• ISSN: 0021972X, 0021-972X
• Language: English
• Keywords: Cushing's Disease; cortisol circadian rhythm; saliva; chrono-pharmacology; hypercortisolism; medical therapy; salivary cortisol; Cushing's syndrome; cortisone