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

INTRODUCTION: Medical therapy for Cushing's syndrome (CS) typically aims to reduce daily cortisol output without addressing circadian rhythm restoration. No licensed drugs target this 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 60-90 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 UHPLC-MS/MS. 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; PSQI: -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, ECG abnormalities, or loss of disease control. CONCLUSIONS: 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.