Background

Dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease with and without type 2 diabetes in the DAPA-CKD trial. In this pre-specified analysis, we assessed the effect of dapagliflozin on the rate of change in estimated glomerular filtration rate (eGFR)—ie, the eGFR slope.

Methods

DAPA-CKD was a randomised controlled trial that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio (UACR) of 200–5000 mg/g, and an eGFR of 25–75 mL/min per 1·73m². Participants were randomly assigned (1:1) to oral dapagliflozin 10 mg once daily or placebo, added to standard care. In this pre-specified analysis, we analysed eGFR slope using mixed-effect models with different slopes from baseline to week 2 (acute eGFR decline), week 2 to end of treatment (chronic eGFR slope), and baseline to end of treatment (total eGFR slope). DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150, and is now complete.

Findings

Between Feb 2, 2017, and April 3, 2020, 4304 participants were recruited, of whom 2152 (50%) were assigned to dapagliflozin and 2152 (50%) were assigned to placebo. At baseline, the mean age was 62 years (SD 12), 1425 (33·1%) participants were women, 2906 (67·5%) participants had type 2 diabetes. The median on-treatment follow-up was 2·3 years (IQR 1·8–2·6). From baseline to the end of treatment, dapagliflozin compared with placebo slowed eGFR decline by 0·95 mL/min per 1·73 m² per year (95% CI 0·63 to 1·27) in the overall cohort. Between baseline and week 2, dapagliflozin compared with placebo resulted in an acute eGFR decline of 2·61 mL/min per 1·73 m² (2·16 to 3·06) in patients with type 2 diabetes and 2·01 mL/min per 1·73 m² (1·36 to 2·66) in those without type 2 diabetes. Between week 2 and end of treatment, dapagliflozin compared with placebo reduced the mean rate of eGFR decline by a greater amount in patients with type 2 diabetes (mean difference in chronic eGFR slope 2·26 mL/min per 1·73 m² per year [1·88 to 2·64]) than in those without type 2 diabetes (1·29 mL/min per 1·73 m² per year [0·73 to 1·85]; p_interaction=0·0049). Between baseline and end of treatment, the effect of dapagliflozin compared with placebo on the decline of total eGFR slope in patients with type 2 diabetes was 1·18 mL/min per 1·73 m² per year (0·79 to 1·56) and without type 2 diabetes was 0·46 mL/min per 1·73 m² per year (–0·10 to 1·03; p_interaction=0·040). The total eGFR slope was steeper in patients with higher baseline HbA_1c and UACR; the effect of dapagliflozin on eGFR slope was also more pronounced in patients with higher baseline HbA_1c and UACR.

Interpretation

Dapagliflozin significantly slowed long-term eGFR decline in patients with chronic kidney disease compared with placebo. The mean difference in eGFR slope between patients treated with dapagliflozin versus placebo was greater in patients with type 2 diabetes, higher HbA_1c, and higher UACR.

Funding

AstraZeneca.

中文翻译：

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达格列净对伴有和不伴有 2 型糖尿病的慢性肾病患者肾功能下降率的影响：来自 DAPA-CKD 试验的预设分析

背景

在 DAPA-CKD 试验中，Dapagliflozin 降低了患有和不患有 2 型糖尿病的慢性肾病患者的肾衰竭风险。在这项预先指定的分析中，我们评估了达格列净对估计肾小球滤过率 (eGFR) 变化率（即 eGFR 斜率）的影响。

方法

DAPA-CKD 是一项随机对照试验，纳入年龄在 18 岁或以上、患有或不患有 2 型糖尿病、尿白蛋白与肌酐比 (UACR) 为 200–5000 mg/g、eGFR 为 25– 75 mL/min 每 1·73m ²。参与者被随机分配 (1:1) 口服 dapagliflozin 10 mg 每天一次或安慰剂，加入标准护理。在这个预先指定的分析中，我们使用混合效应模型分析了 eGFR 斜率，从基线到第 2 周（急性 eGFR 下降）、第 2 周到治疗结束（慢性 eGFR 斜率）以及从基线到治疗结束（总eGFR 斜率）。DAPA-CKD 在 ClinicalTrials.gov 注册，NCT03036150，现已完成。

发现

在 2017 年 2 月 2 日至 2020 年 4 月 3 日期间，招募了 4304 名参与者，其中 2152 名（50%）被分配到达格列净组，2152 名（50%）被分配到安慰剂组。基线时，平均年龄为 62 岁 (SD 12)，1425 (33·1%) 名参与者为女性，2906 名 (67·5%) 参与者患有 2 型糖尿病。中位治疗随访时间为 2·3 年（IQR 1·8-2·6）。从基线到治疗结束，在整个队列中，与安慰剂相比，达格列净将 eGFR 下降减缓了 0·95 mL/min/1·73 m ²每年（95% CI 0·63 至 1·27）。在基线和第 2 周之间，与安慰剂相比，达格列净导致2 型糖尿病患者的 eGFR 急性下降 2·61 mL/min/1·73 m ² （2·16 至 3·06）和 2·01 mL/min最小每 1·73 m ²(1·36 至 2·66) 在非 2 型糖尿病患者中。在第 2 周和治疗结束之间，与安慰剂相比，达格列净可显着降低 2 型糖尿病患者的平均 eGFR 下降率（慢性 eGFR 斜率的平均差异为 2·26 mL/min/1·73 m ²每年[1·88 到 2·64]）比没有 2 型糖尿病的患者（1·29 mL/min 每 1·73 m ²每年 [0·73 到 1·85]；p_相互作用=0·0049）。在基线和治疗结束之间，与安慰剂相比，达格列净对 2 型糖尿病患者总 eGFR 斜率下降的影响为 1·18 mL/min/1·73 m ²每年（0·79 至 1·56 ) 且无 2 型糖尿病的患者为 0·46 mL/min/1·73 m ²每年（–0·10 至 1·03；p_交互作用=0·040）。_{基线 HbA 1c}和 UACR较高的患者的总 eGFR 斜率更陡峭；_{在基线 HbA 1c}和 UACR较高的患者中，达格列净对 eGFR 斜率的影响也更为明显。

解释

与安慰剂相比，达格列净显着减缓了慢性肾病患者的长期 eGFR 下降。_{在 2 型糖尿病、HbA 1c}较高和 UACR较高的患者中，接受 dapagliflozin 治疗的患者与安慰剂治疗的 eGFR 斜率的平均差异更大。

资金

阿斯利康。