Department of Renal Medicine, University College London, London, UK; The George Institute for Global Health, Sydney, NSW, Australia.
Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Lancet Diabetes Endocrinol. 2021 Jan;9(1):22-31. doi: 10.1016/S2213-8587(20)30369-7.
Dapagliflozin reduces the risk of kidney failure and heart failure in patients with chronic kidney disease. We aimed to investigate the effects of dapagliflozin on kidney, cardiovascular, and mortality outcomes according to presence or absence of type 2 diabetes and according to underlying cause of chronic kidney disease, reported as diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause.
DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 study sites in 21 countries, in which participants with a urinary albumin-to-creatinine ratio of 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1·73m were randomly assigned (1:1) to dapagliflozin 10 mg once daily or matching placebo, as an adjunct to standard care. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney-related or cardiovascular death. Secondary efficacy outcomes were a kidney-specific composite (the same as the primary outcome but excluding cardiovascular death), a composite of cardiovascular death or hospital admission for heart failure, and all-cause mortality. In this study, we conducted a prespecified subgroup analysis of the DAPA-CKD primary and secondary endpoints by presence or absence of type 2 diabetes and by aetiology of chronic kidney disease. DAPA-CKD is registered with ClinicalTrials.gov, NCT03036150.
The study took place between Feb 2, 2017, and June 12, 2020. 4304 participants were randomly assigned (2152 to dapagliflozin and 2152 to placebo) and were followed up for a median of 2·4 years (IQR 2·0-2·7). Overall, 2906 (68%) participants had a diagnosis of type 2 diabetes, of whom 396 (14%) had chronic kidney disease ascribed to causes other than diabetic nephropathy. The relative risk reduction for the primary composite outcome with dapagliflozin was consistent in participants with type 2 diabetes (hazard ratio [HR] 0·64, 95% CI 0·52-0·79) and those without diabetes (0·50, 0·35-0·72; p=0·24). Similar findings were seen for the secondary outcomes: kidney-specific composite outcome (0·57 [0·45-0·73] vs 0·51 [0·34-0·75]; P=0·57), cardiovascular death or hospital admission for heart failure (0·70 [0·53-0·92] vs 0·79 [0·40-1·55]; P=0·78), and all-cause mortality (0·74 [0·56-0·98] vs 0·52 [0·29-0·93]; P=0·25). The effect of dapagliflozin on the primary outcome was also consistent among patients with diabetic nephropathy (n=2510; HR 0·63, 95% CI 0·51-0·78), glomerulonephritides (n=695; 0·43, 0·26-0·71), ischaemic or hypertensive chronic kidney disease (n=687; 0·75, 0·44-1·26), and chronic kidney disease of other or unknown cause (n=412; 0·58, 0·29-1·19; P=0·53), with similar consistency seen across the secondary outcomes. The proportions of participants in the dapagliflozin and placebo groups who had serious adverse events or discontinued study drug due to adverse events did not vary between those with and those without type 2 diabetes.
Dapagliflozin reduces the risks of major adverse kidney and cardiovascular events and all-cause mortality in patients with diabetic and non-diabetic chronic kidney disease.
AstraZeneca.
达格列净可降低慢性肾脏病患者发生肾衰竭和心力衰竭的风险。本研究旨在根据是否患有 2 型糖尿病以及慢性肾脏病的病因（糖尿病肾病、慢性肾小球肾炎、缺血性或高血压性慢性肾脏病或其他或未知原因的慢性肾脏病），评估达格列净对肾脏、心血管和死亡率结局的影响。
DAPA-CKD 是一项多中心、双盲、安慰剂对照、随机临床试验，在 21 个国家的 386 个研究地点进行，纳入尿白蛋白与肌酐比值为 200-5000mg/g 且估计肾小球滤过率（eGFR）为 25-75ml/min/1.73m²的患者，按 1:1 比例随机分配（1:1）接受每日一次达格列净 10mg 或匹配安慰剂治疗，联合标准治疗。主要复合终点为 eGFR 至少下降 50%、终末期肾病或肾脏相关或心血管死亡。次要疗效终点为肾脏特异性复合终点（与主要终点相同，但不包括心血管死亡）、心血管死亡或因心力衰竭住院的复合终点以及全因死亡率。本研究根据是否患有 2 型糖尿病以及慢性肾脏病的病因进行了 DAPA-CKD 主要和次要终点的预先指定亚组分析。DAPA-CKD 在 ClinicalTrials.gov 上注册，NCT03036150。
该研究于 2017 年 2 月 2 日至 2020 年 6 月 12 日进行，共纳入 4304 名患者，按 1:1 比例随机分配（达格列净组 2152 例，安慰剂组 2152 例），中位随访时间为 2.4 年（IQR 2.0-2.7）。总体而言，2906 名（68%）参与者患有 2 型糖尿病，其中 396 名（14%）慢性肾脏病的病因归因于除糖尿病肾病以外的其他原因。与安慰剂相比，达格列净降低了主要复合终点的风险，在患有 2 型糖尿病的患者中（HR 0.64，95%CI 0.52-0.79）和不患有糖尿病的患者中（0.50，0.35-0.72；p=0.24）风险比降低一致。次要结局也观察到相似的发现：肾脏特异性复合结局（0.57 [0.45-0.73] vs 0.51 [0.34-0.75]；P=0.57）、心血管死亡或心力衰竭住院（0.70 [0.53-0.92] vs 0.79 [0.40-1.55]；P=0.78）和全因死亡率（0.74 [0.56-0.98] vs 0.52 [0.29-0.93]；P=0.25）。在糖尿病肾病患者（n=2510；HR 0.63，95%CI 0.51-0.78）、肾小球肾炎患者（n=695；0.43，0.26-0.71）、缺血性或高血压性慢性肾脏病患者（n=687；0.75，0.44-1.26）和其他或未知原因的慢性肾脏病患者（n=412；0.58，0.29-1.19；P=0.53）中，达格列净对主要结局的影响也一致，且在次要结局中也具有相似的一致性。在有和没有 2 型糖尿病的患者中，达格列净组和安慰剂组发生严重不良事件或因不良事件停止研究药物的患者比例没有差异。
达格列净降低了伴有和不伴有 2 型糖尿病的慢性肾脏病患者发生主要不良肾脏和心血管事件以及全因死亡率的风险。
阿斯利康。
