Gansevoort Ron T, Wheeler David C, Debén Francisco Martínez, Speeckaert Marijn, Thomas Dirk, Berger Mario, Klein Stefan, Friedrichs Frauke, Paraschin Karen, Schmieder Roland E
Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands.
Department of Renal Medicine, University College London Medical School, London, UK.
Nephrol Dial Transplant. 2025 May 30;40(6):1147-1160. doi: 10.1093/ndt/gfae261.
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).
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.
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.
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).
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。
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。
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%。
无论是否联合使用SGLT2i，瑞卡吉古特均可改善CKD患者的蛋白尿。瑞卡吉古特耐受性良好。sGC激活可能代表了一种针对CKD患者的新型肾脏保护治疗方法（由拜耳公司资助；ClinicalTrials.gov编号，NCT04507061）。
