Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.
Department of Endocrinology, Medical University-Sofia, Sofia, Bulgaria.
Front Endocrinol (Lausanne). 2021 Apr 7;12:595894. doi: 10.3389/fendo.2021.595894. eCollection 2021.
Cushing's syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS.
SONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases.
Normalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; = 0.0006 null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal.
Treatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM.
(ClinicalTrials.gov), NCT01838551.
库欣综合征（CS）与多种合并症相关，包括糖尿病（DM）。左酮康唑，一种口服酮康唑立体异构体，正在临床试验中用于治疗 CS。
SONICS 是一项在确诊 CS 且平均 24 小时尿游离皮质醇（mUFC）≥1.5×ULN 的成人中进行的前瞻性、开放标签、3 期研究，包括剂量滴定、6 个月维持期和 6 个月扩展期。这项亚分析评估了左酮康唑在进入维持期的 DM 患者（n=28）或无 DM 患者（n=49）中的疗效。在剂量滴定和维持期期间，评估了整体人群（n=94）的安全性。
在维持期结束时（EoM），mUFC 正常化，且在维持期不增加剂量（SONICS 主要终点），在 DM 患者中观察到 46%（95%CI，28 至 66%；=0.0006，≤20%的无效假设），在无 DM 患者中观察到 33%（95%CI，20 至 48%；=0.0209）。在 EoM，DM 患者的平均 HbA1c 从基线时的 6.9%降至 6.2%，无 DM 患者从 5.5 降至 5.3%。DM 患者的空腹血糖均值从 6.85mmol/L（123.4mg/dl）降至 5.82mmol/L（104.9mg/dl），无 DM 患者从 5.11mmol/L（92.1mg/dl）降至 4.66mmol/L（84.0mg/dl）。DM 患者更常见的不良反应包括恶心（58.3%）、呕吐（19.4%）和尿路感染（16.7%）；均未导致研究药物停药。
左酮康唑治疗导致 mUFC 持续正常化和血糖控制改善，DM 患者的改善更为显著。
（ClinicalTrials.gov），NCT01838551。
