Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial
Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial
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DOI：
10.1016/s0140-6736(19)30772-x
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发表时间：
2019-05-11
期刊：
影响因子：
168.9
通讯作者：
de Zeeuw, Dick
中科院分区：
文献类型：
--
作者：
Heerspink, Hiddo J. L.;Parving, Hans-Henrik;de Zeeuw, Dick
背景：使用低剂量选择性内皮素a受体拮抗剂阿特拉森短期治疗2型糖尿病患者可减少蛋白尿而不引起明显的钠潴留。我们报道阿特拉森坦治疗对主要肾脏预后的长期影响。我们在41个国家的689个地点进行了这项双盲、随机、安慰剂对照试验。我们招募了年龄在18-85岁的2型糖尿病患者，估计肾小球滤过率（eGFR）为25-75 mL/min / 1.73 m(2)体表面积，尿白蛋白/肌酐比（UACR）为300-5000 mg/g，接受了最大限度的标记或耐受肾素-血管紧张素系统抑制至少4周。在随机分组前的富集期，参与者每天口服0.75 mg阿特拉森。UACR下降至少30%且在富集期无大量液体潴留的患者（应答者）被纳入双盲治疗期。应答者被随机分配接受每日0.75 mg口服阿特拉森坦或安慰剂。所有的患者和研究者都被掩盖到治疗分配。主要终点是所有应答者意向治疗人群中血清肌酐（持续>= 30天）翻倍或终末期肾病（eGFR < 15 mL/min / 1.73 m(2)，持续>= 90天，慢性透析>= 90天，肾移植或肾功能衰竭死亡）的综合结果。对所有接受至少一剂指定研究治疗的患者进行安全性评估。该研究已在ClinicalTrials注册。网址：NCT01858532。2013年5月17日至2017年7月13日期间，共筛查了11087例患者；5117进入富集期，4711完成富集期。其中，2648名患者有反应，并被随机分配到阿特拉森组（n=1325）或安慰剂组（n=1323）。中位随访时间为2.2年（IQR 1.4-2.9）。阿特拉森坦组1325例患者中有79例（6.0%）和安慰剂组1323例患者中有105例（7.9%）发生原发性复合肾终点事件（风险比[HR] 0.65 [95% CI 0.49-0.88]; p=0.0047）。体液潴留和贫血不良事件，以前归因于内皮素受体拮抗剂，在阿特拉森坦组比安慰剂组更频繁。阿特拉森坦组1325例患者中有47例（3.5%）因心力衰竭住院，安慰剂组1323例患者中有34例（2.6%）因心力衰竭住院（HR 1.33 [95% CI 0.85-2.07]; p=0.208）。阿特拉森坦组58例（4.4%）死亡，安慰剂组52例（3.9%）死亡（HR 1.09 [95% CI 0.75-1.59]; p=0.65）。阿特拉森降低了糖尿病和慢性肾脏疾病患者肾脏事件的风险，这些患者被选中以优化疗效和安全性。这些数据支持选择性内皮素受体拮抗剂在保护终末期肾病高风险2型糖尿病患者肾功能方面的潜在作用。Elsevier Ltd.版权所有版权所有。
Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR < 15 mL/min per 1.73 m(2) sustained for >= 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.