Phase II Trial of Metformin for Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction

二甲双胍治疗保留射血分数的心力衰竭肺动脉高压的 II 期试验

基本信息

批准号：
10460583
负责人：
MARC A SIMON
金额：
$ 57.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460583
关键词：
Accelerometer Activities of Daily Living Acute Adenosine Monophosphate Aging Animal Model Biopsy Blinded Blood Vessels Blood capillaries Cardiac Catheterization Procedures Cardiopulmonary Cardiopulmonary Physiology Categories Cell Proliferation Characteristics Chronic Clinical Data Clinical Trials Congestive Cross-Over Trials Data Deacetylase Disease EFRAC Exercise Exercise Test Failure Formulation Glucose Transporter Heart Heart Diseases Heart Hypertrophy Heart failure Heterogeneity High Prevalence Hypoxemia Inhalation Insulin Receptor Insulin Resistance Intervention Knowledge Lead Left Liver Lung Lung diseases Measures Mediating Metabolic Metabolic Control Metabolic hormone Metabolic syndrome Metabolism Metformin Mitochondria Monitor Morbidity - disease rate Muscle Fibers Nitrites Obesity Observational Study Oral Outcome Patients Phase Phase II Clinical Trials Phenotype Phosphorylation Physiological Physiology Placebos Process Protein Kinase Public Health Pulmonary Hypertension Pulmonary Wedge Pressure Pulmonary artery structure Reporting Resistance Respiratory Failure Role Serum Signal Transduction Sirtuins Skeletal Muscle Smooth Muscle Myocytes Testing Therapeutic Clinical Trial Time Treatment Failure Venous Venous Pressure level Walking Workload adipokines adiponectin aging population base chronic thromboembolic pulmonary hypertension clinical heterogeneity diabetic disorder risk fibroblast growth factor 21 glucose metabolism glucose tolerance glucose uptake hemodynamics high risk improved improved outcome insight insulin sensitivity lung pressure mortality novel patient population phase 2 study phase II trial platelet-derived growth factor BB pre-clinical preservation pressure primary outcome programs pulmonary arterial hypertension pulmonary arterial pressure secondary endpoint sensor targeted treatment translational clinical trial vascular abnormality

项目摘要

Heart failure with preserved ejection fraction (HFpEF) is a major driver of morbidity and mortality among the aging population and is a rapidly growing public health problem. However, there are no specific therapies for HFpEF and the negative results of a growing number of clinical trials are thought to be due, in large part, to substantial clinical heterogeneity of HFpEF. This has led to a call for deeper phenotyping to better target therapeutic clinical trials. One specific HFpEF phenotype with particularly poor outcomes is pulmonary hypertension (PH), which can result from chronic congestion of the pulmonary vasculature in HFpEF. Altered glucose metabolism has also been implicated in both HFpEF and PH, as well as specifically the PH-HFpEF phenotype. Our preliminary data on the cardiopulmonary physiology of PH-HFpEF from a recent phase II clinical trial suggests abnormal aging of the pulmonary vasculature with a steep decline in its compliance. We found that PH-HFpEF patients are typically in their 60's with a high prevalence of metabolic syndrome characteristics. Further, observational research suggests metformin may be associated with improved outcomes in heart failure. Additionally, we have studied the impact of metformin in an obese animal model of PH-HFpEF and shown a reduction in pulmonary pressures associated with increased 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Increased AMKP was associated with a novel finding of upregulated sirtuin-3 (SIRT3) in skeletal muscle, but not in the lung or heart. AMPK regulates glucose uptake in skeletal muscle and is dysregulated in metabolic syndrome, heart failure, and PH. We have found decreased activation of SIRT3 in skeletal muscle biopsies from HFpEF patients and that skeletal muscle activation of SIRT3 drives secretion of the myokine, fibroblast growth factor 21 (FGF21). FGF21 inhibits pulmonary artery smooth muscle cell proliferation and confers systemic benefits on insulin resistance in an AMPK-dependent manner. These lines of evidence together suggest that metformin has significant promise for the specific treatment of PH-HFpEF. We propose a 12-week blinded cross over trial of metformin in PH-HFpEF to improve exercise hemodynamics, functional capacity, and glucose metabolism. This phase II clinical trial will provide detailed phenotyping and physiological data on PH-HFpEF (Aim 1). The primary outcome will be exercise mean pulmonary artery pressure. Secondary endpoints will include functional capacity as assessed by continuous work load exercise testing, activity monitoring by accelerometer, distance walked in 6 minutes, as well as cardiopulmonary hemodynamics (pulmonary artery pressures, resistance, and vascular compliance). Glucose tolerance and insulin sensitivity will be assessed. Skeletal muscle biopsies will be taken to study SIRT3-AMPK signaling, muscle fiber switch, and FGF21-adiponectin secretion (Aim 2). Results from this study will provide valuable insights into the cardiopulmonary and metabolic physiology of PH-HFpEF and may lead to novel and phenotypically specific therapy for this high-risk disease of aging.

射血分数保留的心力衰竭（HFpEF）是导致患者发病率和死亡率的主要因素人口老龄化是一个迅速增长的公共卫生问题。但目前尚无特效治疗方法 HFpEF 和越来越多的临床试验的负面结果被认为在很大程度上是由于 HFpEF 具有显着的临床异质性。这导致人们呼吁进行更深入的表型分析以更好地靶向治疗性临床试验。一种结果特别差的特定 HFpEF 表型是肺部疾病高血压 (PH)，可能是 HFpEF 中肺血管系统慢性充血所致。改变葡萄糖代谢也与 HFpEF 和 PH 相关，特别是 PH-HFpEF 表型。我们最近的 II 期研究中关于 PH-HFpEF 心肺生理学的初步数据临床试验表明肺血管系统异常老化，其顺应性急剧下降。我们发现 PH-HFpEF 患者通常在 60 多岁，代谢综合征的患病率很高特征。此外，观察性研究表明二甲双胍可能与改善心力衰竭的结果。此外，我们还研究了二甲双胍对肥胖动物模型的影响 PH-HFpEF 并显示与 5' 腺苷增加相关的肺压降低单磷酸激活蛋白激酶 (AMPK) 磷酸化。 AMKP 升高与骨骼肌中 Sirtuin-3 (SIRT3) 上调的新发现，但肺或心脏中没有上调。 AMPK 调节骨骼肌中葡萄糖的摄取，在代谢综合征、心力衰竭和肺PH中失调。我们有发现 HFpEF 患者骨骼肌活检中 SIRT3 的激活减少，并且骨骼肌 SIRT3 的激活驱动肌因子、成纤维细胞生长因子 21 (FGF21) 的分泌。 FGF21 抑制肺动脉平滑肌细胞增殖并对胰岛素抵抗产生全身益处 AMPK 依赖方式。这些证据共同表明二甲双胍在以下方面具有重大前景： PH-HFpEF的具体治疗。我们建议对二甲双胍治疗 PH-HFpEF 进行为期 12 周的盲法交叉试验改善运动血流动力学、功能能力和葡萄糖代谢。本次二期临床试验将提供 PH-HFpEF 的详细表型和生理数据（目标 1）。主要结果将是运动平均肺动脉压。次要终点将包括评估的功能能力通过连续工作负荷运动测试，通过加速度计监测活动，6分钟步行距离，以及心肺血流动力学（肺动脉压力、阻力和血管遵守）。将评估葡萄糖耐量和胰岛素敏感性。将进行骨骼肌活检研究 SIRT3-AMPK 信号传导、肌纤维开关和 FGF21-脂联素分泌（目标 2）。结果来自这项研究将为 PH-HFpEF 的心肺和代谢生理学提供有价值的见解，可能会为这种高风险的衰老疾病带来新的、表型特异性的治疗方法。