Comprehensive Heart Failure Center and Renal Division, University of Wuerzburg and Hospital, Germany (C.W.)
Biostatistics Center, George Washington University, Rockville, MD (J.M.L.).
Circulation. 2018 Jan 9;137(2):119-129. doi: 10.1161/CIRCULATIONAHA.117.028268. Epub 2017 Sep 13.
Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and established cardiovascular disease in the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. We investigated the effects of empagliflozin on clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease.
Patients with type 2 diabetes mellitus, established cardiovascular disease, and estimated glomerular filtration rate (eGFR) ≥30 mL·min·1.73 m at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. We analyzed cardiovascular death, hospitalization for heart failure, all-cause hospitalization, and all-cause mortality in patients with prevalent kidney disease (defined as eGFR <60 mL·min·1.73 m and/or urine albumin-creatinine ratio >300 mg/g) at baseline. Additional analyses were performed in subgroups by baseline eGFR (<45, 45-<60, 60-<90, ≥90 mL·min·1.73 m) and baseline urine albumin-creatinine ratio (>300, 30-≤300, <30 mg/g).
Of 7020 patients treated, 2250 patients had prevalent kidney disease at baseline, of whom 67% had a diagnosis of type 2 diabetes mellitus for >10 years, 58% were receiving insulin, and 84% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In patients with prevalent kidney disease at baseline, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.98), the risk of all-cause mortality by 24% (HR, 0.76; 95% CI, 0.59-0.99), the risk of hospitalization for heart failure by 39% (HR, 0.61; 95% CI, 0.42-0.87), and the risk of all-cause hospitalization by 19% (HR, 0.81; 95% CI, 0.72-0.92). Effects of empagliflozin on these outcomes were consistent across categories of eGFR and urine albumin-creatinine ratio at baseline and across the 2 doses studied. The adverse event profile of empagliflozin in patients with eGFR <60 mL·min·1.73 m was consistent with the overall trial population.
Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676.
钠-葡萄糖协同转运蛋白 2 抑制剂恩格列净在 EMPA-REG OUTCOME 试验（在 2 型糖尿病患者中进行的恩格列净心血管结局事件试验）中降低了 2 型糖尿病和已确诊心血管疾病患者的心血管发病率和死亡率。随着肾功能下降，恩格列净的尿糖排泄量减少，导致肾病患者的降血糖作用降低。我们研究了恩格列净对 2 型糖尿病、已确诊心血管疾病和慢性肾脏病患者的临床结局的影响。
在筛选时，有 2 型糖尿病、已确诊心血管疾病和估计肾小球滤过率（eGFR）≥30 mL·min·1.73 m 的患者被随机分配接受恩格列净 10 mg、恩格列净 25 mg 或安慰剂，每日一次，同时接受标准治疗。我们分析了基线时存在已确诊肾脏疾病（定义为 eGFR<60 mL·min·1.73 m 和/或尿白蛋白-肌酐比值>300 mg/g）患者的心血管死亡、因心力衰竭住院、全因住院和全因死亡率。在基线 eGFR（<45、45-<60、60-<90、≥90 mL·min·1.73 m）和基线尿白蛋白-肌酐比值（>300、30-≤300、<30 mg/g）亚组中进行了额外分析。
在接受治疗的 7020 名患者中，2250 名患者基线时存在已确诊肾脏疾病，其中 67%患有 2 型糖尿病>10 年，58%正在接受胰岛素治疗，84%正在服用血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂。在基线时存在已确诊肾脏疾病的患者中，与安慰剂相比，恩格列净降低了 29%的心血管死亡风险（风险比 [HR]，0.71；95%置信区间 [CI]，0.52-0.98），降低了 24%的全因死亡率风险（HR，0.76；95%CI，0.59-0.99），降低了 39%的心衰住院风险（HR，0.61；95%CI，0.42-0.87），降低了 19%的全因住院风险（HR，0.81；95%CI，0.72-0.92）。恩格列净对这些结局的影响在基线时 eGFR 和尿白蛋白-肌酐比值的各个类别以及研究的 2 个剂量组中均一致。在 eGFR<60 mL·min·1.73 m 的患者中，恩格列净的不良事件谱与整个试验人群一致。
恩格列净改善了 2 型糖尿病、已确诊心血管疾病和慢性肾脏病患者的临床结局并降低了死亡率。
