Steno Diabetes Center Copenhagen, Gentofte and University of Copenhagen, Copenhagen, Denmark.
Terveystalo Oulu, Oulu, Finland.
Nephrol Dial Transplant. 2021 Dec 2;36(12):2263-2273. doi: 10.1093/ndt/gfaa299.
The protease chymase generates multiple factors involved in tissue remodelling including angiotensin II (Ang II) and has been implicated in the pathophysiology of diabetic kidney disease (DKD). This study investigated the effects of the chymase inhibitor fulacimstat on albuminuria in patients with Type II diabetes mellitus and a clinical diagnosis of DKD.
In this double-blind, randomized, placebo-controlled trial, patients were on the maximum tolerated dose of either an Ang II receptor blocker or an Ang-converting enzyme inhibitor since at least 3 months before the screening visit. Eligible patients were randomized in a 2:1 ratio to treatment with either 25 mg fulacimstat (n = 99) or placebo (n = 48) twice daily on top of standard of care.
The randomized patients had a mean urine albumin-creatinine ratio (UACR) of 131 mg/g (range: 29-2429 mg) and a mean (standard deviation) estimated glomerular filtration rate of 60.8 ± 16.9 mL/min/1.73 m2 before treatment start. Fulacimstat was safe and well tolerated, and achieved mean total trough concentrations that were ∼9-fold higher than those predicted to be required for minimal therapeutic activity. UACR increased by 27.4% [coefficient of variation (CV) 86%] and 3% (CV 88.9%) after 24 weeks of treatment with placebo or fulacimstat, respectively. Analysis of covariance revealed a least square mean UACR ratio (fulacimstat/placebo) of 0.804 (90% CI 0.627-1.030, P = 0.1477), indicating a statistically non-significant UACR reduction of 19.6% after fulacimstat treatment compared with placebo.
Fulacimstat was safe and well tolerated but did not reduce albuminuria in patients with DKD. These findings do not support a therapeutic role for chymase inhibition in DKD.
糜酶可产生多种参与组织重塑的因子，包括血管紧张素 II（Ang II），并与糖尿病肾病（DKD）的病理生理学有关。本研究调查了糜酶抑制剂 fulacimstat 对 2 型糖尿病和临床诊断为 DKD 的患者蛋白尿的影响。
在这项双盲、随机、安慰剂对照试验中，患者在筛选前至少 3 个月开始服用最大耐受剂量的血管紧张素 II 受体阻滞剂或血管紧张素转换酶抑制剂。符合条件的患者以 2:1 的比例随机分为 fulacimstat（n=99）或安慰剂（n=48）组，每日两次，在标准治疗的基础上进行治疗。
随机分组的患者平均尿白蛋白/肌酐比值（UACR）为 131mg/g（范围：29-2429mg），平均（标准差）估算肾小球滤过率为 60.8±16.9mL/min/1.73m2，在开始治疗前。Fulacimstat 安全且耐受良好，达到的平均总谷浓度约为预测的最小治疗活性所需浓度的 9 倍。安慰剂和 fulacimstat 治疗 24 周后，UACR 分别增加了 27.4%[变异系数（CV）86%]和 3%（CV 88.9%）。协方差分析显示，least square mean UACR 比值（fulacimstat/placebo）为 0.804（90%置信区间 0.627-1.030，P=0.1477），表明与安慰剂相比，fulacimstat 治疗后 UACR 降低了 19.6%，但统计学上无显著性差异。
Fulacimstat 安全且耐受良好，但不能降低 DKD 患者的蛋白尿。这些发现不支持糜酶抑制在 DKD 中的治疗作用。
