Department of Molecular and Clinical Endocrinology and Oncology, Section of Endocrinology, University of Naples Federico II, Naples, Italy.
N Engl J Med. 2012 Mar 8;366(10):914-24. doi: 10.1056/NEJMoa1105743.
Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5.
In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12.
Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients.
The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.).
库欣病与高发病率和死亡率相关。作为一种潜在的治疗方法，帕瑞肽具有独特而广泛的生长抑素受体结合谱，对生长抑素受体亚型 5 具有高亲和力。
在这项双盲、3 期研究中，我们将 162 例尿游离皮质醇水平至少为正常范围上限 1.5 倍的库欣病成人患者随机分为两组，分别接受皮下注射帕瑞肽 600μg（82 例）或 900μg（80 例），每日 2 次。尿游离皮质醇水平不超过正常范围上限 2 倍且不超过 3 个月时的基线水平的患者继续接受随机分配的剂量；其余所有患者加用帕瑞肽 300μg，每日 2 次。主要终点是 6 个月时尿游离皮质醇水平达到或低于正常范围上限且未增加剂量。开放性治疗持续至 12 个月。
帕瑞肽 600μg 组 82 例患者中有 12 例和帕瑞肽 900μg 组 80 例患者中有 21 例达到主要终点。两组患者的尿游离皮质醇水平在第 2 个月时下降约 50%，此后一直保持稳定。与基线水平不超过正常范围上限 5 倍的患者相比，基线水平较高的患者实现正常尿游离皮质醇水平的频率更高。血清和唾液皮质醇以及血浆促肾上腺皮质激素水平降低，库欣病的临床体征和症状减轻。162 例患者中有 118 例出现与高血糖相关的不良事件；其他不良事件与其他生长抑素类似物相关的不良事件相似。尽管皮质醇水平下降，但治疗开始后不久血糖和糖化血红蛋白水平升高，然后稳定；162 例患者中有 74 例开始使用降血糖药物治疗。
接受帕瑞肽治疗的库欣病患者皮质醇水平显著下降，支持其作为促肾上腺皮质激素分泌垂体腺瘤的靶向治疗方法的潜在用途。（由诺华制药公司资助；ClinicalTrials.gov 编号，NCT00434148。）
