zin. Background Endothelin receptor antagonists (ERAs) reduce albuminuria but are limited by fluid retention risk, particularly in patients with CKD. Combining ERAs with sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have diuretic effects, offers a promising strategy to mitigate fluid retention. In this post hoc analysis of the Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD) trial, we assessed fluid dynamics in patients with CKD treated with the ERA zibotentan alone and in combination with the SGLT2 inhibitor dapagliflozin. Methods In the ZENITH-CKD trial, 508 patients with CKD (eGFR ≥20 ml/min per 1.73 m2 and a urinary albumin-creatinine ratio of 150–5000 mg/g) were randomized to treatment with placebo, dapagliflozin 10 mg plus placebo, zibotentan (0.25, 1.5, or 5 mg) plus dapagliflozin 10 mg, and zibotentan 5 mg plus placebo. We evaluated correlations between changes in fluid retention markers and bioimpedance-measured extracellular fluid in response to zibotentan treatment. We used Cox proportional hazards regression to assess the association between zibotentan/dapagliflozin treatment, baseline characteristics, and fluid retention and the relationship between zibotentan plasma exposure and fluid retention. Results After 3 weeks of treatment with zibotentan 0.25, 1.5, or 5 mg plus dapagliflozin 10 mg, changes in body weight (β=0.36 [95% confidence interval (CI), 0.26 to 0.45]) per kg, B-type natriuretic peptide (β=0.38 [95% CI, 0.22 to 0.54]) per doubling, and hemoglobin (β=−0.29 [95% CI, −0.48 to −0.10]) per g/dl were independently associated with changes in extracellular fluid. Higher doses of zibotentan were associated with significantly higher risk of fluid retention compared with dapagliflozin alone (zibotentan 5 mg hazard ratio (HR) 8.50 [95% CI, 3.40 to 21.30]). The HR attenuated when zibotentan was combined with dapagliflozin (zibotentan/dapagliflozin 5/10 mg HR 3.09 [95% CI, 1.08 to 8.80], zibotentan/dapagliflozin 1.5/10 mg 2.70 [95% CI, 1.44 to 5.07], and zibotentan/dapagliflozin 0.25/10 mg HR 1.21 [95% CI, 0.50 to 2.91]). The risk of fluid retention was higher with higher zibotentan exposure and lower eGFR. Conclusions High doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin. Clinical Trial registry name and registration number: ZENITH-CKD Trial, NCT04724837....

中文翻译：

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Zibotentan 单独使用以及与达格列净联合使用对 CKD 患者体液潴留的影响


津。背景 内皮素受体拮抗剂 (ERA) 可减少蛋白尿，但受到体液潴留风险的限制，特别是在 CKD 患者中。将 ERA 与具有利尿作用的钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂相结合，为减轻液体潴留提供了一种有前途的策略。在 Zibotentan 和 Dapagliflozin 治疗 CKD (ZENITH-CKD) 试验的事后分析中，我们评估了单独使用 ERA zibotentan 以及与 SGLT2 抑制剂 dapagliflozin 联合治疗的 CKD 患者的体液动力学。方法 在 ZENITH-CKD 试验中，508 名 CKD 患者（eGFR ≥20 ml/min/1.73 m2，尿白蛋白肌酐比为 150-5000 mg/g）被随机分配到安慰剂组、达格列净 10 mg 加安慰剂组、 zibotentan（0.25、1.5 或 5 mg）加达格列净 10 mg，以及 zibotentan 5 mg 加安慰剂。我们评估了 zibotentan 治疗后液体潴留标记物的变化与生物阻抗测量的细胞外液之间的相关性。我们使用 Cox 比例风险回归来评估 zibotentan/达格列净治疗、基线特征和液体潴留之间的关联以及 zibotentan 血浆暴露和液体潴留之间的关系。结果 使用 zibotentan 0.25、1.5 或 5 mg 加达格列净 10 mg 治疗 3 周后，每公斤 B 型钠尿肽的体重变化（β=0.36 [95% 置信区间 (CI)，0.26 至 0.45]）每次倍增（β=0.38 [95% CI，0.22 至 0.54]）和每 g/dl 血红蛋白（β=-0.29 [95% CI，-0.48 至 -0.10]）与细胞外液的变化独立相关。 与单独使用达格列净相比，更高剂量的 zibotentan 与显着更高的液体潴留风险相关（zibotentan 5 mg 风险比 (HR) 8.50 [95% CI，3.40 至 21.30]）。当 zibotentan 与达格列净联合使用时，HR 减弱（zibotentan/达格列净 5/10 mg HR 3.09 [95% CI，1.08 至 8.80]，zibotentan/达格列净 1.5/10 mg 2.70 [95% CI，1.44 至 5.07]，以及 zibotentan/达格列净 0.25/10 mg HR 1.21 [95% CI，0.50 至 2.91]）。 zibotentan 暴露量越高和 eGFR 越低，液体潴留的风险就越高。结论 高剂量的 zibotentan 与较高的液体潴留风险相关，较低剂量和添加达格列净可减弱这种风险。临床试验注册名称和注册号：ZENITH-CKD Trial，NCT04724837....