SGLT-inhibitors in patients with hypertrophic cardiomyopathy

肥厚型心肌病患者的 SGLT 抑制剂

• 批准号: 10710875
• 负责人: Sharlene M Day
• 金额: $ 37.09万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10710875
• 关键词: Adoption; Aftercare; Benefits and Risks; Bioenergetics; Biological Models; Blood Pressure; Butyrates; Cardiac; Cardiovascular Diseases; Cardiovascular system; Case Report Form; Clinical Research; Clinical Trials; Clinical Trials Data Monitoring Committees; Collaborations; Cross-Over Studies; Data; Diabetes Mellitus; Disease; Disease Progression; Double-Blind Method; EFRAC; Echocardiography; Electronic Health Record; Eligibility Determination; Endocrinology; Fatty Acids; Functional disorder; Glucose; Goals; Health system; Heart; Heart Abnormalities; Heart Atrium; Heart failure; Hospitalization; Human; Hypertrophic Cardiomyopathy; Hypoglycemic Agents; Inherited; Institutional Review Boards; Ketone Bodies; Ketones; Ketoses; Ketosis; Left; Left Ventricular Outflow Obstruction; Longevity; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Metabolic; Monitor; Myocardial; Myosin ATPase; Non-Insulin-Dependent Diabetes Mellitus; Obstruction; Oxygen Consumption; Patients; Pediatric Hospitals; Pennsylvania; Pharmaceutical Preparations; Phase; Phosphocreatine; Physical Function; Placebos; Pre-Clinical Model; Preparation; Progressive Disease; Protocols documentation; Quality of Life Assessment; Radiology Specialty; Randomized; Registries; Reproducibility; Research Personnel; Safety; Sodium; Stroke Volume; Testing; Therapeutic; Training; Treatment Efficacy; Universities; Ventricular; Ventricular Arrhythmia; actigraphy; cardioprotection; cardiovascular effects; diabetic; early phase clinical trial; early phase trial; effective therapy; efficacy evaluation; exercise capacity; experience; heart rhythm; hemodynamics; human model; human subject; improved; inhibitor; manufacture; mortality; off-label use; oxidation; phase II trial; preservation; pro-brain natriuretic peptide (1-76); safety assessment; safety outcomes; saluretic; screening; spectroscopic imaging; symporter; symptomatic improvement; tool; treatment response

Project summary Patients with hypertrophic cardiomyopathy (HCM) experience a progressive disease course and bear a substantial symptomatic burden, marked by heart failure, atrial and ventricular arrhythmias and early mortality. Patients with symptomatic HCM, but without obstruction of the left ventricular outflow tract (so-called non- obstructive HCM), are a particular challenge to manage, as no treatments have proven effective at improving symptoms or impacting the trajectory of disease progression. This proposal will focus on sodium-glucose cotransporter 2 inhibitors (SGLT2i) as a potential therapeutic option for non-obstructive HCM. Initially developed as hypoglycemic drugs to treat type-2 diabetes mellitus (T2DM), SGLT2i unexpectedly conferred a remarkable cardioprotective benefit with robust reductions in cardiovascular mortality and hospitalizations for heart failure, irrespective of diabetic status or ejection fraction. While the mechanisms of action by which SGLT2i are exerting such beneficial cardiovascular effects are still unclear, an improvement in cardiac energetics has been proposed as one plausible mechanism based on evidence for increased cardiac ketone oxidation and ATP content in preclinical models of heart failure. The overall goal of this study is to determine the safety, feasibility, and preliminary efficacy of SGLT2i in patients with non-obstructive HCM. The rationale for conducting this study is based on the similarities between non-obstructive HCM and heart failure with preserved ejection fraction, and also the unique structural and functional features of HCM that make an early phase trial essential before implementation of larger phase clinical trials or adoption of “off label” use. We will perform a randomized, double-blind, cross-over study of the SGLT2i dapagliflozin vs placebo in 26 patients with non-obstructive HCM and ejection fraction >50%. Our primary safety outcomes will be rhythm monitoring and intracavitary left ventricular gradients assessed by echocardiography. Our preliminary efficacy endpoints will be change in peak oxygen consumption (VO2), left ventricular systolic and diastolic function by echocardiography, NT-proBNP, ambulatory actigraphy, and quality of life assessment. In an exploratory aim, we will test whether SGLT2i improve cardiac energetics in HCM using 31P-MR spectroscopy to quantify relative amounts of myocardial energy stores, specifically phosphocreatine and ATP. This early phase study seeks to extend the marked cardiovascular benefits of SGLT2i recently demonstrated for heart failure with reduced and preserved ejection fraction, to patients with HCM. The study team includes investigators with a strong track record in early phase clinical trials in HCM, at a high volume HCM center at the University of Pennsylvania, in collaboration with experienced clinician investigators in endocrinology and radiology at the Children's Hospital of Pennsylvania. The results of this study will provide essential preliminary data to determine if larger scale clinical trials of SGLT2i in HCM should be pursued, and explore a shift in metabolic substrate utilization as a potential mechanism of action of conferred benefit.

项目概要 肥厚型心肌病 (HCM) 患者会经历进行性病程并承受 严重的症状负担，以心力衰竭、房性和室性心律失常以及早期死亡为特征。 有症状的肥厚性心肌病但无左心室流出道梗阻的患者（所谓的非梗阻性心肌病） 阻塞性 HCM）是一个特殊的管理挑战，因为没有任何治疗方法被证明可以有效改善 症状或影响疾病进展的轨迹。该提案将重点关注钠-葡萄糖 协同转运蛋白 2 抑制剂 (SGLT2i) 作为非阻塞性 HCM 的潜在治疗选择。最初 SGLT2i 被开发为治疗 2 型糖尿病 (T2DM) 的降血糖药物，出人意料地赋予了 显着的心脏保护作用，可显着降低心血管死亡率和住院率 心力衰竭，无论糖尿病状况或射血分数如何。虽然其作用机制 SGLT2i 是否发挥这种有益的心血管作用仍不清楚，即改善心脏功能 基于心脏酮增加的证据，能量学被提议作为一种合理的机制 心力衰竭临床前模型中的氧化和 ATP 含量。本研究的总体目标是确定 SGLT2i 在非梗阻性 HCM 患者中的安全性、可行性和初步疗效。理由 进行这项研究是基于非阻塞性 HCM 和心力衰竭之间的相似性 保留的射血分数，以及 HCM 独特的结构和功能特征，使得早期 在实施更大规模的临床试验或采用“标签外”使用之前，阶段试验至关重要。我们将 对 26 名患者进行 SGLT2i 达格列净与安慰剂的随机、双盲、交叉研究 具有非阻塞性 HCM 且射血分数 >50%。我们的主要安全成果是心律监测 和通过超声心动图评估的腔内左心室梯度。我们的初步疗效终点 峰值耗氧量 (VO2)、左心室收缩和舒张功能将发生变化 超声心动图、NT-proBNP、动态体动记录仪和生活质量评估。在探索性的目标下， 我们将使用 31P-MR 波谱来量化测试 SGLT2i 是否改善 HCM 中的心脏能量学 心肌能量储存的相对量，特别是磷酸肌酸和 ATP。这项早期研究 寻求扩大最近证明的 SGLT2i 对心力衰竭的显着心血管益处 HCM 患者的射血分数降低并保持不变。研究小组包括具有以下研究能力的研究人员： 在 HCM 的早期临床试验中取得了良好的记录，在大学的一个大容量 HCM 中心进行 宾夕法尼亚州，与内分泌学和放射学领域经验丰富的临床研究人员合作 宾夕法尼亚州儿童医院。这项研究的结果将为以下方面提供重要的初步数据： 确定是否应该对 HCM 进行更大规模的 SGLT2i 临床试验，并探索代谢的转变 底物利用作为赋予益处的潜在作用机制。