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

恩格列净治疗透析依赖性 ESKD 的安全性、耐受性和可行性

• 批准号: 10686172
• 负责人: MONIQUE Eun Hee CHO
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686172
• 关键词: Accounting; Adherence; Arrhythmia; Bioenergetics; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Trials; Complication; Data; Development; Diabetes Mellitus; Diagnosis; Dialysis patients; Dialysis procedure; Disease; Dose; Double-Blind Method; Drug Kinetics; Electrophysiology (science); End stage renal failure; Equilibrium; Exclusion; Fibrosis; Functional disorder; Future; General Population; Glucose; Glycosuria; Heart; Heart failure; Hemodialysis; Homeostasis; Hospitalization; Hypoglycemia; Hypoglycemic Agents; Impairment; Insulin Resistance; Kidney; Kidney Failure; Knowledge; Left Ventricular Hypertrophy; Mediating; Metabolic; Mission; Mitochondria; Multi-Institutional Clinical Trial; Myocardial; Myocardium; National Institute of Diabetes and Digestive and Kidney Diseases; Natriuresis; Nephrons; Non-Insulin-Dependent Diabetes Mellitus; Oral; Participant; Patients; Pharmaceutical Preparations; Phase; Pilot Projects; Placebo Control; Placebos; Population; Procedures; Proximal Kidney Tubules; Questionnaires; Randomized; Reducing Agents; Renal function; Risk; Safety; Sodium; Sodium-Hydrogen Antiporter; Sudden Death; Therapeutic; Ventricular; absorption; active method; arm; cardioprotection; cardiovascular risk factor; coronary fibrosis; diabetic; effective intervention; improved; inhibitor; kidney dysfunction; mortality; non-diabetic; novel; prevent; randomized, clinical trials; recruit; response; sudden cardiac death; symporter; translational impact; treatment group

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.

项目摘要 心血管（CV）疾病是末期肾脏疾病（ESKD）死亡率的主要原因， 占总死亡的55％。特别是，突然心脏死亡对 透析人群。心力衰竭的诊断（HF），这是一种高度普遍的并发症 慢性透析患者三年内死亡率为80％，是猝死的有力预测指标 在ESKD中。代谢和心肌异常（包括胰岛素抵抗）的聚类受损 心肌生物能学，左心室肥大（LVH），心肌纤维化和舒张功能障碍， 介导HF的发展，并增加ESKD突然死亡的风险。遗憾的是，治疗性 改善简历风险的选择在ESKD中仍然非常有限。新颖有效的发展 因此，降低HF风险和死亡的干预措施代表了对 透析人群。葡萄糖共转运蛋白2抑制剂（SGLT2IS），这是一种新型的口服降血糖 减少肾脏近端小管中葡萄糖重吸收的药物最近已证明 有和没有2型患者的HF住院和CV死亡的前所未有的疗效 糖尿病。新兴数据表明，SGLT2IS的好处包括它们减轻胰岛素的功效 电阻，增强心脏的线粒体氧化能力，反向LVH并改善舒张压 功能障碍并减少心脏纤维化。假设这些简历的好处是下游 肾脏SGLT2抑制的后果（即糖尿和纳地尿症），临床试验排除了这些试验 具有高级肾衰竭。但是，有令人信服的证据表明sglt2is可能有直接影响 在心肌上，独立于对肾脏的作用，以恢复心肌生理平衡， 增强线粒体功能并降低纤维化，有可能逆转LVH并防止HF和 心律不齐。如果SGLT2IS可以提高ESKD的生存，这些数据引发了一个至关重要的问题。为了 进行全面临床试验，以评估ESKD中SGLT2IS的CV和生存益处 需要评估初步安全性，耐受性和可行性。因此，我们提出了一个随机的，双重的 在75名慢性血液透析参与者中，盲人，安慰剂对照，三臂试点研究评估（1）安全性和 Empagliflozin的耐受性，一种选择性SGLT2抑制剂，包括稳态药代动力学（PK）研究 每天两种不同的剂量和（2）进行全尺度临床试验的可行性。我们的建议是第一个 迄今为止，sglt2i评估SGLT2I的安全性和耐受性的研究，包括两个详细的PK研究 剂量检查慢性给药的作用。积极的发现将（1）提供必要的 初步的安全性，耐受性和可行性数据，以计划ESKD中更大的多中心临床试验，（2） 促进未来的研究以调查SGLT2IS提供心肌和代谢益处的功效， 这可能会导致ESKD中简历风险管理的范式转移。