Background

The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization.

Objectives

The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict HF risk.

Methods

Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (>3 kg body weight increase or BNP increase to >300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations.

Results

Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P = 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.08-1.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78).

Conclusions

In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment. (Study Of Diabetic Nephropathy With Atrasentan [SONAR]; NCT01858532)

中文翻译：

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对内皮素受体拮抗剂阿曲生坦的反应中 BNP 增加与心力衰竭事件有关

背景

在 SONAR（阿曲生坦糖尿病肾病研究）试验中，内皮素受体拮抗剂阿曲生坦降低了 2 型糖尿病和慢性肾病 (CKD) 患者肾衰竭的风险，尽管心力衰竭 (HF) 的发生率在数值上较高住院。

目标

本研究的目的是评估 Atrasentan 治疗期间 B 型利钠肽 (BNP) 和体重的早期变化是否可以预测 HF 风险。

方法

患有 2 型糖尿病和 CKD 的参与者进入开放标签富集阶段，以评估对阿曲生坦 0.75 mg/天的反应。没有大量体液潴留（体重增加 > 3 kg 或 BNP 增加至 > 300 pg/mL）的参与者被随机分配到阿特拉生坦 0.75 mg/天或安慰剂组。Cox 比例风险回归用于评估 atrasentan 与安慰剂对 HF 住院的预设安全性结果的影响。

结果

在 3,668 名患者中，阿曲生坦组 73 名（4.0%）参与者和安慰剂组 51 名参与者（2.8%）发生心衰（HR：1.39；95% CI：0.97-1.99；P = 0.072）。在一项多变量分析中，心衰风险与较高的基线 BNP（HR：2.32；95% CI：1.81-2.97）和反应富集期间 BNP 增加百分比（HR：1.46；95% CI：1.08-1.98）相关。体重变化与 HF 无关。排除在富集期间 BNP 增加至少 25% 的患者降低了使用阿曲生坦的 HF 风险（HR：1.02；95% CI：0.66-1.56），同时保留了肾保护作用（HR：0.58；95% CI：0.44-0.78）。

结论

在患有 2 型糖尿病和 CKD 的患者中，基线 BNP 和响应阿曲生坦的 BNP 早期变化与 HF 住院相关，突出了在开始阿曲生坦治疗时监测利钠肽的重要性。（阿曲生坦对糖尿病肾病的研究 [SONAR]；NCT01858532）