Safety and Efficacy of Empagliflozin Main intenance HD (SEED)

项目摘要 每年有超过124，000人开始血液透析，超过490，000名患者接受 在美国终末期肾病的维持性血液透析。心血管（CV）疾病 仍然是死亡的主要原因，而每个患者每年有1.6次住院治疗， 患者在30天内再次入院。开始血液透析的个体通常会进一步下降， 残余肾功能是进一步发病和死亡的潜在危险因素。尽管有巨大的负担， 发病率和道德，很少有治疗方法已经过测试，甚至更少的证明，以减少死亡的风险 在这个高危人群中。 钠-葡萄糖协同转运蛋白2抑制剂（SGLT 2 i）的开发预示着 肾病学，在慢性肾病（CKD）患者中进行的专门试验报告了显著降低 CKD进展、蛋白尿和CV结局（包括因心力衰竭住院）的风险。尽管 建议避免在中度或重度CKD患者中开始SGLT 2 i治疗的初始指南， 降糖作用减弱，多项试验以及我们自己的分析表明， 对血糖控制的作用仅介导了全部临床益处的一小部分。此外，SGLT 2 i 即使在没有糖尿病的情况下，与安慰剂相比， 安全有效地预防晚期CKD患者的发病率和死亡率。然而，安全性和 这些疗法的疗效还有待于在需要开始 血液透析。 因此，我们建议进行一项II期、随机、安慰剂对照、平行组的临床试验， 恩格列净在开始血液透析的成人患者中的安全性和疗效。我们的研究结果将 为更大规模的多中心结局试验的设计和开发提供信息，这是迫切需要解决的问题。 该人群中不可接受的高CV疾病率和相关死亡率。我们的建议 具有临床相关性、可行性、创新性，并得到非血液透析患者中稳健文献的支持， CKD。基于潜在的病理生理学、临床未满足的需求以及我们在以下方面的集体经验， 临床试验的性能，我们的建议有可能通知和改善病人的护理需要 在全球范围内启动HD。

PROJECT SUMMARY Each year over 124,000 individuals initiate hemodialysis and there are over 490,000 patients receiving maintenance hemodialysis for end-stage kidney disease in the United States. Cardiovascular (CV) disease remains the leading cause of death, while each patient has 1.6 hospitalizations annually and around 34% of patients are readmitted within 30 days. Individuals initiating hemodialysis generally experience further decline in residual kidney function, a potent risk factor for further morbidity and mortality. Despite the massive burden of morbidity and morality, few therapies have been tested, with even fewer proven, to reduce the risk of mortality in this high-risk population. The development of sodium-glucose co-transporter 2 inhibitors (SGLT2i) has heralded a paradigm-shift in nephrology, with dedicated trials in patients with chronic kidney disease (CKD) reporting substantial reductions in the risk of CKD progression, proteinuria, and CV outcomes, including hospitalization for heart failure. Despite initial guidelines suggesting avoiding initiation of SGLT2i in individuals with moderate or severe CKD, in whom the glucose-lowering effects are attenuated, multiple trials, as well as our own analyses, demonstrate that the effects on glycemic control only mediate a small portion of the overall clinical benefits. Furthermore, SGLT2i provide potent kidney and CV risk reduction compared with placebo even in the absence of diabetes, while they are safe and effectively prevent morbidity and mortality in patients with advanced CKD. However, the safety and efficacy of these therapies have yet to be tested in end stage kidney disease patients requiring initiation of hemodialysis. We therefore propose a phase II, randomized, placebo-controlled, parallel group pilot clinical trial to test the safety and efficacy of empagliflozin among adult patients initiating hemodialysis. The results of our study will inform the design and development of a larger multi-center outcomes trial, which is urgently needed to address the unacceptably high rates of CV disease and associated mortality in this population. Our proposals are clinically relevant, feasible, innovative, and are supported by robust literature in non-hemodialysis patients with CKD. Building on the underlying pathophysiology, the clinical unmet need, and our collective experience in performance of clinical trials, our proposals have the potential to inform and improve the care of patients requiring initiation of HD globally.