目的:库欣病与皮质醇过量暴露导致的高发病率和生活质量(QoL)受损有关。当前的研究通过控制平均尿游离皮质醇(mUFC)的程度,探索了在osilodrostat(有效的口服11β-羟化酶抑制剂)治疗期间皮质醇增多症的临床体征和其他具体表现的改善。
方法:LINC3(NCT02180217)是一种前瞻性,开放标签,为期48周的osilodrostat研究(起始剂量:2mgbid;最大剂量:30mgbid),招募了137名患有库欣病和mUFC>正常上限(ULN)1.5倍的成年人。mUFC(正常范围11~138nmol/24h),心脏代谢参数(血压,体重,腰围,身体质量指数,总胆固醇,空腹血糖,糖化血红蛋白),皮质醇增多症的身体表现(面部红肿,条纹,脂肪分布,瘀伤,多毛症[女性],肌肉萎缩)和QoL进行了评估。如果≤ULN,则将mUFC定义为受控,如果>ULN但从基线降低≥50%,则部分控制,如果>ULN且从基线降低<50%,则不受控。在整个研究中允许合并用药。
结果:分别在第24周和第48周,93例(67.9%)和91例(66.4%)患者的mUFC得到控制,部分控制在20(14.6%)和13(9.5%),24例(17.5%)和33例(24.1%)不受控制。总的来说,mUFC控制或部分控制的患者在第24周的心脏代谢相对于基线的平均改善大于未控制的患者;在第48周,无论mUFC控制如何,均出现改善.一般来说,无论mUFC控制如何,身体表现和QoL均从基线逐渐改善。
结论:与库欣病相关的皮质醇增多症的临床体征和其他特定表现的改善与mUFC降低同时发生。试用注册NCT02180217(2014年7月首次发布)。
OBJECTIVE: Cushing\'s disease is associated with substantial morbidity and impaired quality of life (QoL) resulting from excess cortisol exposure. The current study explored improvements in clinical signs and additional specific manifestations of hypercortisolism during
osilodrostat (potent oral 11β-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC).
METHODS: LINC 3 (NCT02180217) was a prospective, open-label, 48-week study of
osilodrostat (starting dose: 2 mg bid; maximum: 30 mg bid) that enrolled 137 adults with Cushing\'s disease and mUFC > 1.5 times the upper limit of normal (ULN). mUFC (normal range 11‒138 nmol/24 h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if ≤ ULN, partially controlled if > ULN but ≥ 50% reduction from baseline, and uncontrolled if > ULN and < 50% reduction from baseline. Concomitant medications were permitted throughout the study.
RESULTS: At weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control.
CONCLUSIONS: Improvements in clinical signs and additional specific manifestations of hypercortisolism associated with Cushing\'s disease occurred alongside decreases in mUFC. Trial registration NCT02180217 (first posted July 2014).