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Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial
The Lancet Diabetes & Endocrinology ( IF 44.0 ) Pub Date : 2021-10-04 , DOI: 10.1016/s2213-8587(21)00243-6
Niels Jongs 1 , Tom Greene 2 , Glenn M Chertow 3 , John J V McMurray 4 , Anna Maria Langkilde 5 , Ricardo Correa-Rotter 6 , Peter Rossing 7 , C David Sjöström 5 , Bergur V Stefansson 5 , Robert D Toto 8 , David C Wheeler 9 , Hiddo J L Heerspink 10 ,
Affiliation  

Background

Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial.

Methods

DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m2 and 75 mL/min per 1·73 m2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150.

Findings

Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI –33·1 to –25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of −35·1% (95% CI −39·4 to −30·6; p<0·0001) in patients with type 2 diabetes and −14·8% (−22·9 to −5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (pinteraction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change –3·06, 95% CI –5·20 to –0·90; p=0·0056).

Interpretation

In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria.

Funding

AstraZeneca.



中文翻译:

达格列净对合并和不合并 2 型糖尿病的慢性肾脏病患者尿白蛋白排泄的影响:来自 DAPA-CKD 试验的预设分析

背景

白蛋白尿的减少与随后慢性肾病患者肾衰竭风险的降低有关。SGLT2 抑制剂达格列净可显着降低肾功能正常或接近正常的 2 型糖尿病患者的蛋白尿。这种影响在患有或不患有 2 型糖尿病的慢性肾病患者中是否持续尚不清楚。我们在 dapagliflozin 和预防慢性肾病 (DAPA-CKD) 试验中评估了 dapagliflozin 对伴和不伴 2 型糖尿病的慢性肾病患者白蛋白尿的影响。

方法

DAPA-CKD 是一项多中心、双盲、安慰剂对照、随机试验,在 21 个国家的 386 个地点进行。患有慢性肾病的患者符合本试验的条件,其定义为估计肾小球滤过率 (eGFR) 介于 25 mL/min/1·73 m 2和 75 mL/min/1·73 m 2 之间尿白蛋白与肌酐比 (UACR) 介于 200 毫克/克和 5000 毫克/克之间(22·6 到 565·6 毫克/毫摩尔)。参与者被随机分配到每天一次 dapagliflozin 10 mg(阿斯利康;哥德堡,瑞典)或匹配的安慰剂,按照隔离的固定随机化时间表,使用平衡块以确保大约 1:1 的比例。白蛋白尿的变化是 DAPA-CKD 的预先指定的探索性结果。UACR 阶段的回归,定义为从大量白蛋白尿 (≥300 mg/g) 过渡到微量白蛋白尿或正常白蛋白尿 (<300 mg/g),以及 UACR 阶段的进展,定义为从低于 3000 mg/g 过渡到 3000 mg /g 或更大,是额外的离散端点。该试验已在 ClinicalTrials.gov 注册,NCT03036150。

发现

2017 年 2 月 2 日至 2020 年 4 月 3 日期间,招募了 4304 名患者并随机分配至达格列净 (n=2152) 或安慰剂组 (n=2152)。中值 UACR 为 949 mg/g(IQR 477 至 1885)。总体而言,与安慰剂相比,达格列净使几何平均 UACR 降低 29·3%(95% CI –33·1 至 –25·2;p<0·0001);相对于安慰剂,dapagliflozin 治疗导致 2 型糖尿病患者和 -14· 8%(-22·9 至 -5·9;p=0·0016)在随访期间没有 2 型糖尿病的患者中(p交互作用<0·0001) 在 3860 名基线时 UACR 为 300 mg/g 或更高的患者中,达格列净增加了 UACR 阶段消退的可能性(风险比 1·81,95% CI 1·60 至 2·05)。在基线时 UACR 低于 3000 mg/g 的 3820 名患者中,达格列净降低了 UACR 分期(0·41、0·32 至 0·52)的进展风险。dapagliflozin 治疗期间第 14 天 UACR 的较大降低与随后随访期间 eGFR 下降减弱显着相关(β/log 单位 UACR 变化 –3·06,95% CI –5·20 至 –0·90;p=0 ·0056)。

解释

在患有和不患有 2 型糖尿病的慢性肾脏病患者中,达格列净显着降低蛋白尿,2 型糖尿病患者的相对降低幅度更大。达格列净对 2 型糖尿病患者或非 2 型糖尿病患者临床结局的影响相似,但对 UACR 的影响不同,这表明达格列净对慢性肾病患者的部分保护作用可能是通过与蛋白尿减少无关的途径介导的。

资金

阿斯利康。

更新日期:2021-10-20
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