Safety, tolerability, and feasibility of empagliflozin therapy in dialysis-dependent ESKD

项目摘要 心血管疾病是终末期肾病(ESKD)死亡的主要原因， 占总死亡人数的55%。特别是，心脏性猝死对人类构成最大的威胁 透析人群。心力衰竭(HF)的诊断，这是一种高度流行的并发症，与 慢性透析患者三年内80%的死亡率是猝死的有力预测因素。 在ESKD中。代谢和心肌异常的聚集性，包括胰岛素抵抗，受损 心肌生物能量学、左室肥厚、心肌纤维化和舒张期功能障碍， 调节心力衰竭的发展，增加ESKD猝死的风险。遗憾的是，这是一种治疗 在ESKD中，改善CV风险的选择仍然非常有限。发展新奇高效 因此，减少心力衰竭风险和死亡的干预措施是对以下方面最大的未满足需求之一 透析人群。钠-葡萄糖共转运体2抑制剂(SGLT2 Is)--一类新型口服降糖药 减少肾脏近端小管葡萄糖重吸收的药物最近证实 减少2型和非2型患者的心衰住院和心血管死亡的效果是前所未有的 糖尿病。新出现的数据表明，SGLT2的好处包括它们缓解胰岛素的功效 增强心肌线粒体氧化能力，逆转左心室肥厚，改善舒张期 功能障碍，减少心脏纤维化。假设这些简历的好处是下游的 肾脏SGLT2抑制的后果(即血糖和钠尿)，临床试验已经排除了这些 患有晚期肾功能衰竭。然而，有令人信服的证据表明，SGLT2可能有直接影响 对心肌的作用，与其对肾脏的作用无关，以恢复心肌电生理平衡， 增强线粒体功能，减少纤维化，有可能逆转LVH，预防心衰和 心律不齐。这些数据提出了一个关键的问题，即SGLT2 IS是否可以提高ESKD的存活率。为了 进行一项全面的临床试验，以评估SGLT2 is在ESKD中的CV和生存益处，一项试点研究是 需要评估初步的安全性、耐受性和可行性。因此，我们提出了一种随机的、双重的- 75名慢性血液透析患者的盲法、安慰剂对照、三臂先导性研究，以评估(1)安全性和 选择性SGLT2抑制剂依帕格列酮的耐受性，包括稳态药代动力学(PK)研究 两种不同的每日剂量和(2)进行全面临床试验的可行性。我们的建议是第一个 到目前为止，评估SGLT2i在ESKD中的安全性和耐受性的研究，包括两项详细的PK研究 剂量以检查慢性给药的效果。积极的调查结果将(1)提供必要的 初步的安全性、耐受性和可行性数据，用于规划ESKD的更大规模、多中心临床试验，以及(2) 推动未来的研究，以调查SGLT2 IS提供心肌和代谢益处的有效性， 这可能会导致ESKD中CV风险管理的范式转变。

PROJECT ABSTRACT Cardiovascular (CV) disease is the leading cause of mortality in end-stage kidney disease (ESKD), accounting for 55% of total deaths. In particular, sudden cardiac death poses the greatest threat to the dialysis population. A diagnosis of heart failure (HF), a highly prevalent complication that is associated with an 80% mortality rate within three years in chronic dialysis patients, is a powerful predictor of sudden death in ESKD. A clustering of metabolic and myocardial abnormalities, including insulin resistance, impaired myocardial bioenergetics, left ventricular hypertrophy (LVH), myocardial fibrosis, and diastolic dysfunction, mediates development of HF and increases the risk of sudden death in ESKD. Regrettably, therapeutic options to ameliorate the CV risk remain very limited in ESKD. Development of novel and effective interventions to reduce HF risk and death, therefore, represents one of the greatest unmet needs for the dialysis population. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), a novel class of oral hypoglycemic medications that reduce glucose reabsorption in the renal proximal tubule, have recently demonstrated unprecedented efficacy to reduce HF hospitalization and CV deaths in patients with and without type 2 diabetes. Emerging data suggest that the benefits of SGLT2is include their efficacy to mitigate insulin resistance, enhance mitochondrial oxidative capacity in the heart, reverse LVH and improve diastolic dysfunction, and reduce cardiac fibrosis. Given that these CV benefits are hypothesized to be downstream consequences of renal SGLT2 inhibition (i.e. glycosuria and natriuresis), clinical trials have excluded those with advanced renal failure. There is compelling evidence, however, that SGLT2is may have direct effects on myocardium, independent of its action on the kidney, to restore myocardial electrophysiologic balance, enhance mitochondrial function, and reduce fibrosis, with a potential to reverse LVH and prevent HF and arrhythmia. These data raise a crucial question if SGLT2is may improve survival in ESKD. In order to perform a full-scale clinical trial to evaluate the CV and survival benefits of SGLT2is in ESKD, a pilot study is required to assess preliminary safety, tolerability, and feasibility. We hence propose a randomized, double- blind, placebo-controlled, 3-arm pilot study in 75 chronic hemodialysis participants to evaluate (1) safety and tolerability of empagliflozin, a selective SGLT2 inhibitor, including a steady-state pharmacokinetic (PK) study of two different daily doses and (2) feasibility of conducting a full-scale clinical trial. Our proposal is the first study to evaluate safety and tolerability of a SGLT2i in ESKD to date, including a detailed PK study of two doses to examine the effect of chronic administration. Positive findings will (1) provide the necessary preliminary safety, tolerability, and feasibility data to plan a larger, multi-center clinical trial in ESKD, and (2) promote future studies to investigate the efficacy of SGLT2is to provide myocardial and metabolic benefits, which may lead to a paradigm shift in the management of CV risk in ESKD.