From the George Institute for Global Health, University of New South Wales Sydney (V.P., M.J.J., B.N., S. Bompoint), the Royal North Shore Hospital (V.P.), Concord Repatriation General Hospital (M.J.J.), and the Charles Perkins Centre, University of Sydney (B.N.), Sydney, and the Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW (C.P.) - all in Australia; Imperial College London (B.N.) and the Department of Renal Medicine, UCL Medical School (D.C.W.) - both in London; the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H., D.Z.); the Nephrology Division, NYU School of Medicine and NYU Langone Medical Center, New York (D.M.C.); Baim Institute for Clinical Research (D.M.C., C.P.C., B.M.B.), the Cardiovascular Division (C.P.C.) and the Renal Division and Department of Medicine (B.M.B), Brigham and Women's Hospital, and Harvard Medical School (B.M.B.) - all in Boston; Janssen Research and Development, Raritan, NJ (R.E., S. Bull, G.C., P.-L.C., Y.Y., G.M.); Indiana University School of Medicine and Veterans Affairs Medical Center, Indianapolis (R.A.); the Department of Medicine, University of Chicago Medicine, Chicago (G.B.); the Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City (T.G.); the Division of Nephrology, University of British Columbia, Vancouver (A.L.), and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto (B.Z.) - all in Canada; the Renal Division, Peking University First Hospital, Beijing (H.Z.); and the Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA (K.W.M.).
N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14.
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.
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 <90 ml per minute per 1.73 m of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >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 m), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.
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.
In 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. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).
2 型糖尿病是全球范围内导致肾衰竭的主要原因，但目前可用的有效长期治疗方法却寥寥无几。在钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂的心血管试验中，探索性结果表明，此类药物可能改善 2 型糖尿病患者的肾脏结局。
在这项双盲、随机试验中，我们将患有 2 型糖尿病和白蛋白尿性慢性肾病的患者随机分为卡格列净组（每日 100 mg，口服 SGLT2 抑制剂）或安慰剂组。所有患者的肾小球滤过率（GFR）估计值（eGFR）均为 30 至<90 ml/min/1.73 m2，且白蛋白尿（白蛋白[mg]与肌酐[g]比值，>300 至 5000），并接受肾素-血管紧张素系统阻断剂治疗。主要终点是终末期肾病（透析、移植或持续 eGFR<15 ml/min/1.73 m2）、血清肌酐水平加倍或因肾脏或心血管原因死亡的复合终点。预先设定的次要终点按层次进行检验。
在数据和安全监测委员会的建议下，提前对中期分析进行了计划干预，随后试验停止。当时，4401 名患者接受了随机分组，中位随访时间为 2.62 年。卡格列净组的主要终点事件风险比安慰剂组低 30%，分别为每 1000 名患者年 43.2 例和 61.2 例（风险比，0.70；95%置信区间 [CI]，0.59 至 0.82；P=0.00001）。肾脏特异性复合终点事件（终末期肾病、肌酐水平加倍或肾脏原因死亡）的风险降低了 34%（风险比，0.66；95%CI，0.53 至 0.81；P<0.001），终末期肾病的风险降低了 32%（风险比，0.68；95%CI，0.54 至 0.86；P=0.002）。卡格列净组的心血管死亡、心肌梗死或中风（风险比，0.80；95%CI，0.67 至 0.95；P=0.01）和心力衰竭住院（风险比，0.61；95%CI，0.47 至 0.80；P<0.001）的风险也较低。截肢或骨折的发生率没有显著差异。
在中位随访 2.62 年的情况下，与安慰剂组相比，卡格列净组 2 型糖尿病合并肾病患者的肾衰竭和心血管事件风险更低。（由杨森研发资助；CREDENCE 临床试验。gov 编号，NCT02065791。）
