Aims/hypothesis

In the Study Of diabetic Nephropathy with AtRasentan (SONAR), the endothelin receptor antagonist (ERA) atrasentan slowed progression of chronic kidney disease (CKD) in individuals with type 2 diabetes. Pre-clinical research suggests sex-based differences in the endothelin system might influence the efficacy and safety of atrasentan. We therefore assessed the effects of atrasentan in men and women participating in SONAR.

Methods

SONAR was a double-blind, placebo-controlled trial that compared atrasentan 0.75 mg/day with placebo in individuals with type 2 diabetes and CKD (eGFR 25–75 ml/min per 1.73 m², urine albumin/creatinine ratio [UACR] 300–5000 mg/g). The primary endpoint was defined as the time from randomisation to the first occurrence of a doubling in serum creatinine or kidney failure (eGFR <15 ml/min per 1.73 m², chronic dialysis, kidney transplantation or death from kidney failure). Hospitalisation for heart failure was the secondary endpoint. We performed Cox proportional hazards regression analyses to compare the treatment effect of atrasentan between male and female participants on the risk of the composite kidney outcome as well as hospitalisation for heart failure. Additionally, differences between male and female participants in atrasentan plasma exposure and eGFR change were assessed using, respectively, a t test and linear mixed effect model.

Results

Among 3668 randomised participants, 946 (25.8%) were female. Atrasentan significantly reduced the risk of the composite kidney outcome in female participants (HR 0.46 [95% CI 0.28, 0.76]) but not in male participants (HR 0.83 [95% CI 0.65, 1.05]; p value for interaction 0.032). Atrasentan compared with placebo reduced eGFR decline to a greater extent in female than in male participants (treatment effect difference between male vs female participants −0.99 ml/min per 1.73 m², p value for interaction=0.020). The RR for hospitalisation for heart failure with atrasentan vs placebo was 1.14 (95% CI 0.74, 1.76) in male participants and 1.88 (95% CI 0.98, 3.63) in female participants (p value for interaction=0.217). Female participants also had significantly higher atrasentan plasma exposure than male participants (geometric mean AUC 54.5 vs 42.6 ng/ml×h; p<0.001).

Conclusions/interpretation

Atrasentan showed greater kidney protection in female than in male participants but also induced more heart failure events in the female participants. These data suggest that sex-specific dosing regimens may be considered to optimise ERA treatment.

Trial registration

ClinicalTrials.gov NCT01858532

Graphical Abstract

中文翻译：

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2 型糖尿病和慢性肾病患者对内皮素受体拮抗剂 atrasentan 反应的性别差异：SONAR 试验的事后分析

 目标/假设

在使用 AtRasentan （SONAR） 的糖尿病肾病研究中，内皮素受体拮抗剂 （ERA） atrasentan 减缓了 2 型糖尿病患者慢性肾病 （CKD） 的进展。临床前研究表明，内皮素系统中基于性别的差异可能会影响 atrasentan 的疗效和安全性。因此，我们评估了 atrasentan 对参与 SONAR 的男性和女性的影响。

 方法

SONAR 是一项双盲、安慰剂对照试验，在 2 型糖尿病和 CKD 患者中比较了阿曲生坦 0.75 mg/天与安慰剂（eGFR 25-75 ml/min/1.73 m²，尿白蛋白/肌酐比值 [UACR] 300-5000 mg/g）。主要终点定义为从随机分组到血清肌酐或肾功能衰竭首次出现加倍的时间（eGFR <15 ml/min / 1.73 m²，慢性透析，肾移植或肾功能衰竭死亡）。因心力衰竭住院是次要终点。我们进行了Cox比例风险回归分析，以比较男性和女性受试者atrasentan的治疗效果对复合肾脏结局风险以及心力衰竭住院风险的影响。此外，分别使用 t 检验和线性混合效应模型评估男性和女性参与者在 atrasentan 血浆暴露和 eGFR 变化方面的差异。

 结果

在 3668 名随机参与者中，946 名 （25.8%） 为女性。Atrasentan 显著降低了女性参与者复合肾脏结局的风险 （HR 0.46 [95% CI 0.28， 0.76]），但男性参与者没有 （HR 0.83 [95% CI 0.65， 1.05];交互作用的 p 值 0.032）。与安慰剂相比，Atrasentan 对女性参与者 eGFR 下降的程度比男性参与者更大（男性与女性参与者之间的治疗效果差异 -0.99 ml/min 每 1.73 m²，交互作用的 p 值 = 0.020）。男性参与者与安慰剂相比，阿曲生坦因心力衰竭住院的 RR 为 1.14 （95% CI 0.74， 1.76），女性参与者为 1.88 （95% CI 0.98， 3.63） （交互作用的 p 值 = 0.217）。女性参与者的 atrasentan 血浆暴露量也显著高于男性参与者（几何平均 AUC 54.5 vs 42.6 ng/ml×h;p<0.001）。

结论/解释

Atrasentan 在女性参与者中显示出比男性参与者更大的肾脏保护作用，但在女性参与者中也诱导了更多的心力衰竭事件。这些数据表明，可以考虑使用性别特异性给药方案来优化 ERA 治疗。

 试用注册

ClinicalTrials.gov NCT01858532

 图形摘要