Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Division of Nephrology, University of Utah Health, Salt Lake City, UT, USA.
Cardiovasc Diabetol. 2023 Sep 16;22(1):251. doi: 10.1186/s12933-023-01964-8.
Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD.
We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25-75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300-5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model.
In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9).
More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR.
RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.
胰岛素抵抗（IR）是 2 型糖尿病的病理生理标志，与慢性肾脏病（CKD）有关。实验研究表明，内皮素-1 会增加 IR。我们评估了 IR 与心肾结局的关系，以及选择性内皮素受体拮抗剂 atrasentan 对 2 型糖尿病和 CKD 患者 IR 的影响。
我们使用了 RADAR 和 SONAR 试验的数据，这些试验招募了 2 型糖尿病和 CKD 患者（eGFR 25-75 mL/min/1.73 m²，尿白蛋白与肌酐比值为 300-5000 mg/g）。使用稳态模型评估（HOMA-IR）计算 IR。使用多变量 Cox 比例风险回归评估 HOMA-IR 与预先指定的心肾结局之间的关系，并使用线性混合效应模型评估 atrasentan 对 HOMA-IR 的影响。
在 SONAR 试验中，HOMA-IR 每增加一个对数单位，复合心肾结局的风险就会增加[风险比 1.32（95%CI 1.09,1.60；p=0.004）]、肾脏结局[风险比 1.30（95%CI 1.00,1.68；p 值=0.048）]和肾脏或全因死亡率结局[风险比 1.25（95%CI 1.01,1.55；p 值=0.037）]。在 RADAR 试验（N=123）的 12 周治疗后，与安慰剂相比，atrasentan 0.75 mg/天和 1.25 mg/天分别降低了 19.1（95%CI -17.4,44.3）和 26.7%（95%CI -6.4,49.5）的 HOMA-IR。在 SONAR 试验（N=1914）中，与安慰剂相比，atrasentan 0.75 mg/天降低了 9.6%（95%CI 0.6,17.9）的 HOMA-IR。
更严重的 IR 与心肾结局风险增加相关。内皮素受体拮抗剂 atrasentan 降低了 IR。
RADAR 试验（使用 atrasentan 降低患有肾病的糖尿病患者的残余白蛋白尿）：NCT01356849。SONAR 试验（使用 atrasentan 研究糖尿病肾病）：NCT01858532。
