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

IF 5.1 2区医学 Q1 ENDOCRINOLOGY & METABOLISM Journal of Clinical Endocrinology & Metabolism Pub Date : 2025-11-18 DOI:10.1210/clinem/dgaf206

Davide Ferrari, Ilaria Bonaventura, Chiara Simeoli, Alessandra Tomaselli, Ludovica Vincenzi, Dario De Alcubierre, Francesca Sciarra, Flavio Rizzo, Lorenzo Cerroni, Nicola Di Paola, Marianna Minnetti, Emilia Sbardella, Mary Anna Venneri, Riccardo Pofi, Rosario Pivonello, Daniele Gianfrilli, Valeria Hasenmajer, Andrea M Isidori

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Abstract

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.

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每日一次奥西罗司他的慢性疗法可改善库欣综合征患者的皮质醇节律、生活质量和睡眠。

简介：库欣综合征（CS）的药物治疗通常旨在减少皮质醇的日排出量，而不涉及昼夜节律的恢复。目前还没有针对这一目标的特许药物。我们研究了定时、每日一次服用奥司洛前列素对改善库欣综合征患者昼夜节律皮质醇分布的有效性和安全性：一项前瞻性多中心研究评估了接受稳定的每日两次奥司洛前列腺素治疗并控制良好的CS患者，在过渡到每日19:00±1小时单次等量给药之前和之后的60-90天。使用 UHPLC-MS/MS 对唾液、血清和尿液进行了昼夜节律类固醇分析。其他评估包括心血管代谢指标、生活质量、睡眠功能和安全结果：16 名患者（4 名男性；7 名垂体患者，平均年龄（53.3 ± 11.8）岁）入组。基线时，CS得到良好控制，平均奥司洛前列素剂量为4.2±1.3毫克。过渡后，唾液皮质醇暴露量在下午至清晨期间显著下降[AUC16:00-08:00: -6.1 (-0.15 to -12.1) ng/mL/h，p = .029]。生活和睡眠质量得到改善（CushingQoL：+4.2，p = .029；PSQI：-1.7，p = .049）。血清类固醇前体减少，包括 11-脱氧皮质酮（-3.1 ng/mL/h，p = .008）和 11-脱氧皮质醇（-17.8 ng/mL/h，p = .005）。八名患者将给药时间提前至 16:00 ± 1 小时，结果显示降幅相当，前相位和后相位发生了阶段性变化。没有患者出现肾上腺功能不全、肝脏毒性、心电图异常或病情失控：结论：每日一次的奥司洛前列素能有效、安全地治疗生化控制型 CS 患者，改善昼夜皮质醇分布、生活质量和睡眠。研究结果支持进一步探索基于时间疗法的 CS 治疗方法。

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来源期刊

Journal of Clinical Endocrinology & Metabolism 医学-内分泌学与代谢

CiteScore

11.40

自引率

5.20%

发文量

673

审稿时长

1 months

期刊介绍： The Journal of Clinical Endocrinology & Metabolism is the world"s leading peer-reviewed journal for endocrine clinical research and cutting edge clinical practice reviews. Each issue provides the latest in-depth coverage of new developments enhancing our understanding, diagnosis and treatment of endocrine and metabolic disorders. Regular features of special interest to endocrine consultants include clinical trials, clinical reviews, clinical practice guidelines, case seminars, and controversies in clinical endocrinology, as well as original reports of the most important advances in patient-oriented endocrine and metabolic research. According to the latest Thomson Reuters Journal Citation Report, JCE&M articles were cited 64,185 times in 2008.