Background: 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.

Methods: Patients with type 2 diabetes mellitus, established cardiovascular disease, and estimated glomerular filtration rate (eGFR) ≥30 mL·min⁻¹·1.73 m⁻² 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⁻¹·1.73 m⁻² 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⁻¹·1.73 m⁻²) and baseline urine albumin-creatinine ratio (>300, 30–≤300, <30 mg/g).

Results: 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⁻¹·1.73 m⁻² was consistent with the overall trial population.

Conclusions: Empagliflozin improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676.

背景： Empagliflozin是一种钠-葡萄糖共转运蛋白2抑制剂，可降低2型糖尿病患者的心血管发病率和死亡率，并在EMPA-REG OUTCOME试验中确诊为心血管疾病（Empagliflozin 2型糖尿病患者的心血管结果事件试验）。依帕格列净引起的尿葡萄糖排泄随着肾功能的下降而降低，从而导致肾脏疾病患者降低葡萄糖的效力降低。我们调查了依帕列净对2型糖尿病，已确定的心血管疾病和慢性肾脏病患者的临床结局的影响。

方法：筛选出患有2型糖尿病，心血管疾病且估计肾小球滤过率（eGFR）≥30 mL·min ^-1 ·1.73 m ^-2的患者，随机接受恩帕格列净10毫克，恩帕列净25毫克或安慰剂一次除了日常护理。我们分析了患有肾脏疾病（定义为eGFR <60 mL·min ^-1 ·1.73 m ^-2和/或尿白蛋白-肌酐比值）的患者的心血管死亡，心衰住院，全因住院和全因死亡率基线时> 300 mg / g）。通过基线eGFR（<45，45– <60，60– <90，≥90mL·min ^-1 ·1.73 m ^-2进行亚组的其他分析）和基线尿白蛋白-肌酐比值（> 300、30–≤300，<30 mg / g）。

结果：在接受治疗的7020例患者中，有2250例在基线时患有肾脏疾病，其中67％的2型糖尿病被诊断为10年以上，58％的患者接受胰岛素治疗，84％的患者接受血管紧张素转换酶抑制剂或血管紧张素受体治疗阻滞剂。与安慰剂相比，在基线时患有肾脏疾病的普遍患者中，依帕格列净使心血管死亡的风险降低了29％（危险比[HR]为0.71； 95％置信区间[CI]为0.52-0.98），这是全因原因死亡率降低24％（HR，0.76； 95％CI，0.59-0.99），因心衰住院的风险降低39％（HR，0.61； 95％CI，0.42-0.87），以及全因住院的风险降低19％（HR，0.81； 95％CI，0.72-0.92）。依帕格列净对这些结局的影响在基线时以及研究的2种剂量的eGFR和尿白蛋白-肌酐比值的各个类别中均一致。eGFR <60 mL·min的依帕格列净不良反应^-1 ·1.73 m ^-2与总体试验人群一致。

结论： Empagliflozin可改善2型糖尿病，已确定的心血管疾病和慢性肾脏病易感患者的临床疗效并降低其死亡率。

临床试验注册： URL：https : //www.clinicaltrials.gov。唯一标识符：NCT01131676。