澳大利亚悉尼新南威尔士大学Vlado Perkovic研究团队领衔的一项临床试验研究了卡格列净(Canagliflozin)对2型糖尿病肾病的疗效。该研究成果发表在2019年出版的《NEJM》杂志上。

研究证实全球范围内2型糖尿病是导致肾衰竭的主要原因，但长期有效的治疗方法很少。在心血管试验中，探索性结果表明钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂可以改善2型糖尿病患者的肾病转归。

在这项双盲随机比对试验中，研究组指定2型糖尿病合并蛋白尿的慢性肾病患者每日口服100毫克剂量的SGLT2抑制剂Canagliflozin或安慰剂。要求所有患者估测的肾小球滤过率(GFR)在30至90毫升以内/ min / 1.73 m²体表面积，蛋白尿（白蛋白[mg]与肌酐[g]的比例）在300以上至5000之间，并接受肾素-血管紧张素系统阻断治疗。前期研究得到的是包括终末期肾病(透析、移植或持续GFR < 15 ml / min / 1.73 m²)，血清肌酐水平增加一倍，或死于肾病或心血管疾病在内的复合性结果。对预先指定的次级研究进行了分层测试。在对数据进行有计划地间断分析及安全监测委员会的建议下，该试验提前停止。当时，4401名患者进入随机分组，平均随访时间为2.62年。Canagliflozin组主要结果的相对风险比安慰剂组低30%，1000例病人随访年的事件发生率分别为43.2和61.2 (风险比0.70; 95%置信区间[CI]，0.59~0.82; P = 0.00001)。终末期肾病、肌酐水平倍增或因肾脏死亡等肾脏特异性复合终点的相对风险降低34% (风险比0.66; 95% CI, 0.53~0.81; P < 0.001)，终末期肾病的相对风险降低32% (风险比0.68; 95% CI, 0.54~0.86; P = 0.002)。Canagliflozin组心血管死亡、心肌梗死或中风 (风险比，0.80; 95% CI, 0.67~0.95, P=0.01)及心衰住院治疗 (危险比0.61; 95% CI, 0.47~0.80; P<0.001)的风险也较低。截肢和骨折的发生率没有显著差异。在2型糖尿病和肾病患者中，Canagliflozin组肾衰竭和心血管事件的风险低于安慰剂组，中位随访时间2.62年。

附：英文原文

Title: Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Author:Vlado Perkovic, M.B., B.S., Ph.D., Meg J. Jardine, M.B., B.S., Ph.D., Bruce Neal, M.B., Ch.B., Ph.D., Severine Bompoint, B.Sc., Hiddo J.L. Heerspink, Pharm.D., Ph.D., David M. Charytan, M.D., Robert Edwards, M.P.H., Rajiv Agarwal, M.D., George Bakris, M.D., Scott Bull, Pharm.D., Christopher P. Cannon, M.D., George Capuano, Ph.D., Pei-Ling Chu, Ph.D., Dick de Zeeuw, M.D., Ph.D., Tom Greene, Ph.D., Adeera Levin, M.D., Carol Pollock, M.B., B.S., Ph.D., David C. Wheeler, M.D., Yshai Yavin, M.B., Ch.B., Hong Zhang, M.D., Ph.D., Bernard Zinman, M.D., Gary Meininger, M.D., Barry M. Brenner, M.D., and Kenneth W. Mahaffey, M.D. 

Issue&Volume:VOL. 380 NO. 24, 2019

Abstract:

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.

METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.

RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture.

CONCLUSIONSIn patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.

DOI: DOI: 10.1056/NEJMoa1811744

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1811744gdui