可溶性鸟苷酸环化酶激活剂鲁卡西呱可显著改善慢性肾脏病患者的蛋白尿：一项随机安慰剂对照临床试验。

The soluble guanylate cyclase activator runcaciguat significantly improves albuminuria in patients with chronic kidney disease: a randomized placebo-controlled clinical trial.

作者信息

Gansevoort Ron T, Wheeler David C, Debén Francisco Martínez, Speeckaert Marijn, Thomas Dirk, Berger Mario, Klein Stefan, Friedrichs Frauke, Paraschin Karen, Schmieder Roland E

机构信息

Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands.

Department of Renal Medicine, University College London Medical School, London, UK.

出版信息

Nephrol Dial Transplant. 2025 May 30;40(6):1147-1160. doi: 10.1093/ndt/gfae261.

BACKGROUND AND HYPOTHESIS

In chronic kidney disease (CKD) the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is impaired. Runcaciguat, an sGC activator, activates heme-free sGC, restoring cGMP production. This phase 2a trial studied the efficacy, safety, and tolerability of runcaciguat in CKD patients with or without sodium-glucose co-transporter-2 inhibitor (SGLT2i).

METHODS

Patients with CKD and established atherosclerotic cardiovascular disease or heart failure, plus type 2 diabetes (T2D) and/or hypertension, were enrolled. All were receiving stable maximum tolerated renin-angiotensin system inhibitors with or without SGLT2i. They were randomized 3:1 to runcaciguat once daily, titrated weekly (30-120 mg if tolerated), or placebo for 8 weeks. The primary efficacy endpoint was urine albumin-to-creatinine ratio (UACR) (average of post-randomization Days 22, 29, and 57 vs baseline). CONCORD was separately powered for CKD and T2D with stable SGLT2i comedication, CKD and T2D without SGLT2i, and non-diabetic CKD.

RESULTS

Of 243 patients randomized, 229 were included in the full analysis set (FAS) and 170 in the per-protocol set (PPS). In the PPS, UACR decreased by -45.2% versus placebo with runcaciguat in patients with CKD without SGLT2i (P < 0.001) and by -48.1% versus placebo in patients with CKD taking SGLT2i (P = 0.02) In the FAS, the relative reductions were -46.9% (P < 0.001) and -44.8% (P = 0.01), respectively. No significant difference was observed between patients with or without SGLT2i. In non-diabetic CKD, UACR was reduced versus baseline with runcaciguat, but the change was not statistically significant (P = 0.10). Serious treatment-emergent adverse events were reported in 7% of patients receiving runcaciguat and 8% receiving placebo.

CONCLUSION

Runcaciguat improved albuminuria in patients with CKD, irrespective of concomitant SGLT2i. Runcaciguat was well tolerated. sGC activation may represent a novel kidney-protective treatment in CKD patients (funded by Bayer AG; ClinicalTrials.gov number, NCT04507061).

背景与假设

在慢性肾脏病（CKD）中，一氧化氮（NO）-可溶性鸟苷酸环化酶（sGC）-环磷酸鸟苷（cGMP）途径受损。瑞卡吉古特是一种sGC激活剂，可激活无血红素的sGC，恢复cGMP的生成。这项2a期试验研究了瑞卡吉古特在接受或未接受钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）的CKD患者中的疗效、安全性和耐受性。

方法

纳入患有CKD且已确诊动脉粥样硬化性心血管疾病或心力衰竭，同时患有2型糖尿病（T2D）和/或高血压的患者。所有患者均接受稳定的最大耐受量肾素-血管紧张素系统抑制剂，部分患者联合使用SGLT2i。他们被随机分为3:1两组，分别接受每日一次的瑞卡吉古特治疗（如果耐受，每周滴定剂量，30 - 120mg）或安慰剂治疗，为期8周。主要疗效终点是尿白蛋白与肌酐比值（UACR）（随机分组后第22、29和57天的平均值与基线值比较）。CONCORD试验分别针对联合稳定使用SGLT2i的CKD和T2D患者、未使用SGLT2i的CKD和T2D患者以及非糖尿病CKD患者进行了功效分析。

结果

243例随机分组的患者中，229例纳入全分析集（FAS），170例纳入符合方案集（PPS）。在PPS中，未使用SGLT2i的CKD患者使用瑞卡吉古特后UACR较安慰剂组降低了-45.2%（P < 0.001），使用SGLT2i的CKD患者中这一数值为-48.1%，较安慰剂组（P = 0.02）。在FAS中，相对降低幅度分别为-46.9%（P < 0.001）和-44.8%（P = 0.01）。使用或未使用SGLT2i的患者之间未观察到显著差异。在非糖尿病CKD患者中，瑞卡吉古特使UACR较基线值降低，但变化无统计学意义（P = 0.10）。接受瑞卡吉古特治疗的患者中有7%报告了严重的治疗突发不良事件，接受安慰剂治疗的患者中这一比例为8%。