The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
The George Institute for Global Health, UNSW Sydney, Sydney, Australia; Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.
Am J Kidney Dis. 2022 Feb;79(2):244-256.e1. doi: 10.1053/j.ajkd.2021.05.005. Epub 2021 May 23.
RATIONALE & OBJECTIVE: Canagliflozin reduced the risk of kidney failure and related outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. This analysis of CREDENCE trial data examines the effect of canagliflozin on the incidence of kidney-related adverse events (AEs).
A randomized, double-blind, placebo-controlled, multicenter international trial.
SETTING & PARTICIPANTS: 4,401 trial participants with T2DM, CKD, and urinary albumin-creatinine ratio >300-5,000 mg/g.
Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.
Rates of kidney-related AEs were analyzed using an on-treatment approach, overall and by screening estimated glomerular filtration rate (eGFR) strata (30-<45, 45-<60, and 60-<90 mL/min/1.73 m).
Canagliflozin was associated with a reduction in the overall incidence rate of kidney-related AEs (60.2 vs 84.0 per 1,000 patient-years; hazard ratio [HR], 0.71 [95% CI, 0.61-0.82]; P < 0.001), with consistent results for serious kidney-related AEs (HR, 0.72 [95% CI, 0.51-1.00]; P = 0.05) and acute kidney injury (AKI; HR, 0.85 [95% CI, 0.64-1.13]; P = 0.3). The rates of kidney-related AEs were lower with canagliflozin relative to placebo across the 3 eGFR strata (HRs of 0.73, 0.60, and 0.81 for eGFR 30-<45, 45-<60, and 60-<90 mL/min/1.73 m, respectively; P = 0.3 for interaction), with similar results for AKI (P = 0.9 for interaction). Full recovery of kidney function within 30 days after an AKI event occurred more frequently with canagliflozin versus placebo (53.1% vs 35.4%; odds ratio, 2.2 [95% CI, 1.0-4.7]; P = 0.04).
Kidney-related AEs including AKI were investigator-reported and collected without central adjudication. Biomarkers of AKI and structural tubular damage were not measured, and creatinine data after an AKI event were not available for all participants.
Compared with placebo, canagliflozin was associated with a reduced incidence of serious and nonserious kidney-related AEs in patients with T2DM and CKD. These results highlight the safety of canagliflozin with regard to adverse kidney-related AEs.
The CREDENCE trial and this analysis were funded by Janssen Research & Development, LLC, and were conducted as a collaboration between the funder, an academic steering committee, and an academic research organization, George Clinical.
The CREDENCE trial was registered at ClinicalTrials.gov with identifier number NCT02065791.
卡格列净可降低伴有慢性肾脏病（CKD）的 2 型糖尿病（T2DM）患者的肾衰竭及相关结局风险。CREDENCE（卡格列净与伴有明确肾脏疾病的 2 型糖尿病患者的肾脏事件临床评估）试验对卡格列净进行了分析，该试验数据检查了卡格列净对肾脏相关不良事件（AE）发生率的影响。
这是一项随机、双盲、安慰剂对照、多中心国际试验。
4401 例 T2DM、CKD 且尿白蛋白与肌酐比值＞300-5000mg/g 的试验参与者。
参与者被随机分配接受卡格列净 100mg/d 或安慰剂治疗。
采用治疗方法分析肾脏相关 AE 的发生率，总体分析和按筛查估计肾小球滤过率（eGFR）分层（30-＜45、45-＜60 和 60-＜90ml/min/1.73m ）进行分析。
与安慰剂相比，卡格列净与肾脏相关 AE 的总体发生率降低（每 1000 例患者-年分别为 60.2 与 84.0；风险比[HR]，0.71[95%CI，0.61-0.82]；P＜0.001），严重肾脏相关 AE（HR，0.72[95%CI，0.51-1.00]；P=0.05）和急性肾损伤（AKI；HR，0.85[95%CI，0.64-1.13]；P=0.3）的结果一致。卡格列净组各 eGFR 分层的肾脏相关 AE 发生率均低于安慰剂组（eGFR 为 30-＜45、45-＜60 和 60-＜90ml/min/1.73m 的 HR 分别为 0.73、0.60 和 0.81；P=0.3 用于交互作用），AKI 的结果相似（P=0.9 用于交互作用）。与安慰剂相比，卡格列净更频繁地使 AKI 事件后肾功能在 30 天内完全恢复（53.1%与 35.4%；比值比，2.2[95%CI，1.0-4.7]；P=0.04）。
包括 AKI 在内的肾脏相关 AE 是由研究者报告的，并在没有中心裁决的情况下收集的。未测量 AKI 和结构管状损伤的生物标志物，并且并非所有参与者都有 AKI 事件后的肌酐数据。
与安慰剂相比，卡格列净可降低 T2DM 和 CKD 患者严重和非严重肾脏相关 AE 的发生率。这些结果强调了卡格列净在肾脏相关不良事件方面的安全性。
CREDENCE 试验和本分析由 Janssen Research & Development，LLC 资助，由资助者、学术指导委员会和学术研究组织 George Clinical 合作进行。
CREDENCE 试验在 ClinicalTrials.gov 注册，标识符为 NCT02065791。
