达格列净、依普利酮及其联合应用对慢性肾脏病患者蛋白尿降低作用的随机交叉临床试验。
Albuminuria-Lowering Effect of Dapagliflozin, Eplerenone, and Their Combination in Patients with Chronic Kidney Disease: A Randomized Crossover Clinical Trial.
机构信息
Division of Nephrology, University of Campania "Luigi Vanvitelli," Naples, Italy.
Nephrology Service, Clinic University hospital, INCLIVA Health Research Institute, University of Valencia, Valencia, Spain.
出版信息
J Am Soc Nephrol. 2022 Aug;33(8):1569-1580. doi: 10.1681/ASN.2022020207. Epub 2022 Apr 19.
BACKGROUND
Sodium glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with CKD. We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and MRA eplerenone alone and in combination in patients with CKD.
METHODS
We conducted a randomized open-label crossover trial in patients with urinary albumin excretion ≥100 mg/24 hr, eGFR 30-90 ml/min per 1.73 m, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week washout periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline.
RESULTS
Of 57 patients screened, 46 were randomly assigned (mean eGFR, 58.1 ml/min per 1.73 m; median UACR, 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks of treatment with dapagliflozin, eplerenone, and dapagliflozin-eplerenone was -19.6% (95% confidence interval [CI], -34.3 to -1.5), -33.7% (95% CI, -46.1 to -18.5), and -53% (95% CI, -61.7 to -42.4; <0.001 versus dapagliflozin; =0.01 versus eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozin-eplerenone (=-0.13; =0.47; =-0.08; =0.66, respectively). Hyperkalemia was more frequently reported with eplerenone (=8; 17.4%) compared with dapagliflozin (=0; 0%) or dapagliflozin-eplerenone (=2; 4.3%; =0.003).
CONCLUSIONS
Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR-lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
European Union Clinical Trials Register, EU 2017-004641-25.
背景
钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂和盐皮质激素受体拮抗剂（MRA）可降低尿白蛋白与肌酐比值（UACR），并为 CKD 患者提供肾脏和心血管保护。我们评估了 SGLT2 抑制剂达格列净和 MRA 依普利酮单独及联合应用于 CKD 患者的疗效和安全性。
方法
我们在尿白蛋白排泄≥100mg/24 小时、eGFR 30-90ml/min/1.73m²的患者中进行了一项随机、开放标签、交叉试验，这些患者正在接受最大耐受剂量的 ACE 抑制剂（ACEi）或血管紧张素受体阻滞剂（ARB）治疗。患者被随机分配到 4 周的治疗期，每天服用达格列净 10mg、依普利酮 50mg 或两者联合治疗，每个治疗期之间有 4 周的洗脱期。主要结局是治疗之间 UACR 变化的相关性。次要结局是从基线开始的 24 小时 UACR 的百分比变化。
结果
在筛选出的 57 名患者中，46 名被随机分配（平均 eGFR，58.1ml/min/1.73m²；中位数 UACR，401mg/g）至三组。达格列净、依普利酮和达格列净-依普利酮治疗 4 周后 UACR 从基线的平均百分比变化分别为-19.6%（95%置信区间[CI]，-34.3 至-1.5）、-33.7%（95% CI，-46.1 至-18.5）和-53%（95% CI，-61.7 至-42.4；<0.001 与达格列净相比；=0.01 与依普利酮相比）。达格列净或依普利酮治疗期间的 UACR 变化与达格列净-依普利酮治疗期间的 UACR 变化不相关（=-0.13；=0.47；=-0.08；=0.66，分别）。依普利酮（=8；17.4%）较达格列净（=0；0%）或达格列净-依普利酮（=2；4.3%；=0.003）更常报告高钾血症。
结论
达格列净和依普利酮的尿白蛋白反应变化不相关，支持系统轮换这些治疗以优化治疗。达格列净与依普利酮联合使用可显著降低 UACR。需要在该人群中进行更大规模的试验以确认 SGLT2 抑制剂和 MRA 联合治疗的长期疗效和安全性。
临床试验注册名称和注册号
欧盟临床试验注册处，EU 2017-004641-25。
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