Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Steno Diabetes Center Copenhagen, Herlev, Denmark.
J Am Soc Nephrol. 2024 Oct 1;35(10):1381-1390. doi: 10.1681/ASN.0000000000000436. Epub 2024 Jul 12.
Increasing doses of the endothelin receptor antagonist zibotentan and lower eGFR were associated with a higher risk of fluid retention. The higher risk of fluid retention could be attenuated by the combination of zibotentan with the sodium-glucose cotransporter 2 inhibitor dapagliflozin.
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 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.
In the ZENITH-CKD trial, 508 patients with CKD (eGFR ≥20 ml/min per 1.73 m 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.
After 3 weeks of treatment with zibotentan 0.25, 1.5, or 5 mg plus dapagliflozin 10 mg, changes in body weight (=0.36 [95% confidence interval (CI), 0.26 to 0.45]) per kg, B-type natriuretic peptide (=0.38 [95% CI, 0.22 to 0.54]) per doubling, and hemoglobin (=−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.
High doses of zibotentan were associated with a higher risk of fluid retention, which was attenuated with lower doses and the addition of dapagliflozin.
: ZENITH-CKD Trial, NCT04724837.
内皮素受体拮抗剂（ERAs）可降低白蛋白尿，但存在液体潴留风险，尤其是在 CKD 患者中。将 ERAs 与具有利尿作用的钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂联合使用，提供了一种减轻液体潴留的有希望的策略。在这项 Zibotentan 和 Dapagliflozin 用于治疗 CKD（ZENITH-CKD）试验的分析中，我们评估了接受 ERA 齐博坦单独治疗和与 SGLT2 抑制剂达格列净联合治疗的 CKD 患者的液体动力学。
在 ZENITH-CKD 试验中，508 名 CKD 患者（eGFR≥20 ml/min/1.73 m，尿白蛋白-肌酐比为 150-5000 mg/g）被随机分配接受安慰剂、达格列净 10 mg 加安慰剂、齐博坦（0.25、1.5 或 5 mg）加达格列净 10 mg 和齐博坦 5 mg 加安慰剂治疗。我们评估了液体潴留标志物变化与生物电阻抗测量的细胞外液对齐博坦治疗的反应之间的相关性。我们使用 Cox 比例风险回归来评估齐博坦/达格列净治疗、基线特征和液体潴留之间的关联，以及齐博坦血浆暴露与液体潴留之间的关系。
在接受齐博坦 0.25、1.5 或 5 mg 加达格列净 10 mg 治疗 3 周后，体重变化（每公斤 0.36 [95%置信区间 0.26 至 0.45]）、B 型利钠肽（每加倍 0.38 [95%置信区间 0.22 至 0.54]）和血红蛋白（每克/dl 降低 0.29 [95%置信区间 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，齐博坦的较高剂量与液体潴留的风险显著增加相关（齐博坦 5 mg 风险比（HR）8.50 [95%置信区间 3.40 至 21.30]）。当齐博坦与达格列净联合使用时，HR 减弱（齐博坦/达格列净 5/10 mg HR 3.09 [95%置信区间 1.08 至 8.80]，齐博坦/达格列净 1.5/10 mg HR 2.70 [95%置信区间 1.44 至 5.07]，齐博坦/达格列净 0.25/10 mg HR 1.21 [95%置信区间 0.50 至 2.91]）。较高的齐博坦暴露量和较低的 eGFR 与液体潴留风险增加相关。
高剂量的齐博坦与液体潴留风险增加相关，与较低剂量和添加达格列净联合使用可减轻这种风险。
ZENITH-CKD 试验，NCT04724837。
