Efficacy and Safety of Tangshen Formula on Patients with Type 2 Diabetic Kidney Disease: A Multicenter Double-Blinded Randomized Placebo-Controlled Trial

Background
Persons with diabetes are at high risk of developing diabetic kidney disease (DKD), which is associated with high morbidity and mortality. Current drug therapies for DKD, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are not entirely satisfactory. This study aimed to evaluate the additional benefit and safety of the Chinese herbal granule Tangshen Formula (TSF) in treating DKD.
Methods
The study was designed as a six-center randomized, double-blind, placebo-controlled trial. From April 2007 through December 2009, 180 patients with DKD were enrolled. In addition to conventional treatment with ACEIs or ARBs, 122 participants were randomly assigned to receive TSF and 58 participants to receive placebo for 24 weeks. Primary outcome was urinary protein level, measured by urinary albumin excretion rate (UAER) for participants with microalbuminuria, 24-hour urinary protein (24h UP) for participants with macroalbuminuria. Secondary outcomes included renal function, serum lipids, quality of life, symptoms, and adverse events.
Findings
After 24 weeks of treatment, no statistically significant difference in UAER (TSF −19.53 μg/min compared with placebo −7.01 μg/min, with a mean difference of −12.52 μg/min; 95%CI, −68.67 to 43.63, P = 0.696) was found between TSF and placebo groups. However, TSF displayed a statistically significant decrease in 24h UP (TSF−0.21 g compared with placebo 0.36 g, with a mean difference of −0.57g; 95%CI, −1.05 to −0.09, P = 0.024). Estimated glomerular filtration rate (eGFR) was improved in both patients with microalbuminuria and macroalbuminuria, with a mean difference of 15.51 ml/min/1.73 m2 (95%CI, 3.71 to 27.31), 9.01 ml/min/1.73 m2 (95%CI, −0.10 to 18.13), respectively. Other secondary outcomes showed no statistically significant difference between groups or in the incidence of adverse events.
Conclusions
Based on conventional treatments, TSF appears to provide additional benefits compared with placebo in decreasing proteinuria and improving eGFR in DKD patients with macroalbuminuria. Nevertheless, further study is needed to evaluate TSF treating patients with microalbuminuria.
Trial Registration
Chinese Clinical Trial Registry ChiCTR-TRC-10000843

背景
糖尿病患者罹患糖尿病肾病（DKD）的风险较高，该病伴随较高的发病率与死亡率。当前针对DKD的药物治疗方案，如血管紧张素转换酶抑制剂（ACEIs）与血管紧张素Ⅱ受体拮抗剂（ARBs），疗效尚未完全令人满意。本研究旨在评估中药颗粒剂糖肾方（TSF）用于治疗DKD的额外获益与安全性。

方法
本研究为一项6中心随机双盲安慰剂对照试验。2007年4月至2009年12月期间，共纳入180例DKD患者。在接受ACEIs或ARBs常规治疗的基础上，122例受试者被随机分配至TSF组，58例分配至安慰剂组，治疗周期均为24周。本研究的主要结局指标为尿蛋白水平：微量白蛋白尿患者采用尿白蛋白排泄率（UAER）评估，大量白蛋白尿患者采用24小时尿蛋白定量（24h UP）评估。次要结局指标包括肾功能、血脂、生活质量、临床症状以及不良事件。

结果
治疗24周后，TSF组与安慰剂组的UAER水平无统计学显著性差异（TSF组较基线变化为-19.53μg/min，安慰剂组为-7.01μg/min，组间均数差为-12.52μg/min；95%置信区间：-68.67~43.63，P=0.696）。但TSF组的24h UP水平较安慰剂组出现统计学显著性降低（TSF组较基线变化为-0.21g，安慰剂组为0.36g，组间均数差为-0.57g；95%置信区间：-1.05~-0.09，P=0.024）。微量白蛋白尿与大量白蛋白尿患者的估算肾小球滤过率（eGFR）均有所改善，组间均数差分别为15.51ml/min/1.73m²（95%置信区间：3.71~27.31）与9.01ml/min/1.73m²（95%置信区间：-0.10~18.13）。其余次要结局指标以及不良事件发生率在两组间均无统计学显著性差异。

结论
在常规治疗基础上，相较于安慰剂，TSF可降低大量白蛋白尿型DKD患者的蛋白尿水平并改善其eGFR，展现出额外获益。但仍需开展进一步研究以评估TSF用于微量白蛋白尿型DKD患者的疗效。

试验注册
中国临床试验注册中心，注册号ChiCTR-TRC-10000843