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（HFPEF）的心力衰竭是发病率和死亡率的主要驱动力人口老龄化，是一个快速增长的公共卫生问题。但是，没有特定的疗法 HFPEF和越来越多的临床试验的负面结果被认为是由于 HFPEF的实质性临床异质性。这导致呼吁进行更深入的表型以更好地靶向治疗性临床试验。肺部的一种特定的HFPEF表型是肺部高血压（pH），这可能是由于HFPEF中肺脉管系统的慢性充血而引起的。改变葡萄糖代谢也与HFPEF和PH有关，尤其是pH-HFPEF 表型。我们有关最近II期pH-HFPEF的心肺生理学的初步数据临床试验表明，肺脉管系统异常衰老，其依从性急剧下降。我们发现pH-HFPEF患者通常处于60年代，代谢综合症患病率很高特征。此外，观察性研究表明二甲双胍可能与改善有关心力衰竭的结果。此外，我们研究了二甲双胍在肥胖动物模型中的影响 pH-HFPEF并显示出与增加5'腺苷有关的肺压降低单磷酸激活的蛋白激酶（AMPK）磷酸化。增加的AMKP与骨骼肌中上调的Sirtuin-3（SIRT3）的新颖发现，而不是在肺或心脏中。 AMPK调节骨骼肌中的葡萄糖摄取，在代谢综合征，心力衰竭和pH中失调。我们有发现HFPEF患者的骨骼肌活检中SIRT3的激活减少了 SIRT3的激活驱动肌动物的分泌，成纤维细胞生长因子21（FGF21）。 FGF21抑制肺动脉平滑肌细胞增殖，并赋予全身益处胰岛素抵抗依赖AMPK的方式。这些证据共同表明二甲双胍对 pH-HFPEF的特定处理。我们在pH-hfpef中提出了一个为期12周的盲人十字架。改善运动血液动力学，功能能力和葡萄糖代谢。该II期临床试验将提供有关pH-HFPEF的详细表型和生理数据（AIM 1）。主要结果将是运动平均肺动脉压力。次要终点将包括评估的功能能力通过连续的工作负荷锻炼测试，通过加速度计监测活动，距离在6分钟内步行，以及心肺血流动力学（肺动脉压，抗性和血管遵守）。将评估葡萄糖耐受性和胰岛素敏感性。将进行骨骼肌活检研究SIRT3-AMPK信号传导，肌肉纤维开关和FGF21-辅导蛋白分泌（AIM 2）。结果这项研究将为PH-HFPEF和可能会导致这种高危衰老疾病的新颖和表型特定的治疗。