Improve PAD PERformance with METformin. The PERMET Trial

使用 METformin 改善 PAD 性能。

基本信息

批准号：
9236746
负责人：
Mary McGrae McDermott
金额：
$ 81.26万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-09 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9236746
关键词：
4 hydroxynonenal 5&apos -AMP-activated protein kinase Autophagocytosis Biguanides Biochemical Biogenesis Biopsy Blood Vessels Blood capillaries Citrate (si)-Synthase DNA Diabetes Mellitus Double-Blind Method Human Impairment Ischemia Lower Extremity Measures Mediating Medical Metformin Mitochondria Mitochondrial Proteins Muscle Non-Insulin-Dependent Diabetes Mellitus Nuclear Outcome Oxidative Stress PINK1 gene PPAR gamma Participant Patients Performance Perfusion Peripheral arterial disease Pharmaceutical Preparations Physical Function Placebo Control Placebos Pre-Clinical Model Property Proteins Quality of life Questionnaires Randomized Randomized Clinical Trials Randomized Controlled Clinical Trials Reactive Oxygen Species Reperfusion Therapy Reporting Skeletal Muscle Therapeutic Time Tissues Walking Work brachial artery capillary density enzyme activity follow-up functional decline functional disability improved improved functioning pre-clinical prevent primary outcome protein expression repaired secondary outcome treadmill

项目摘要

PROJECT SUMMARY Improve PAD PERformance with METformin: The PERMET Trial. Our work and that of others has established that people with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and increased rates of mobility loss compared to people without PAD. However, few therapies are available that improve functioning or prevent functional decline in people with PAD. Metformin is an inexpensive, widely available, well tolerated biguanide medication and the most commonly prescribed drug for Type 2 diabetes mellitus worldwide. Recent pre-clinical and preliminary human evidence suggest that metformin has previously unrecognized therapeutic properties. Therapeutic properties of metformin in pre-clinical models that may benefit people with PAD include: calf skeletal muscle increases in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) (a major regulator of mitochondrial biogenesis), calf skeletal muscle increases in mitochondrial protein expression and activity, increases in capillary density in ischemic tissue, reductions in oxidative stress, increased autophagy (repair of cellular damage), and improved endothelial function. These therapeutic properties target pathophysiologic conditions present in PAD. Therefore, we hypothesize that metformin will improve lower extremity functioning in people with PAD, by facilitating favorable changes in calf skeletal muscle and by increasing calf skeletal muscle perfusion. No randomized clinical trials have studied whether metformin improves lower extremity functioning in PAD. A definitive trial is needed. We propose a placebo controlled double-blind randomized clinical trial to establish whether metformin (2,000 mgs daily) improves and/or prevents decline in walking performance in people with PAD. Participants will be 212 people with PAD who do not have diabetes mellitus, since metformin is a first-line therapy for Type 2 diabetes. Our primary outcome is change in six-minute walk at 6-month follow-up. Secondary outcomes are 6-month changes in treadmill walking performance, brachial artery flow-mediated dilation, calf skeletal muscle biopsy measures, patient-reported walking performance, and quality of life. Calf muscle outcomes consist of changes in PGC-1α abundance, mitochondrial quantity, mitochondrial enzyme activity, capillary density, reactive oxygen species (ROS)-induced tissue damage, and autophagy. If metformin improves functional performance and prevents functional decline in PAD, this widely available, inexpensive, and well tolerated medication will have a major impact on preventing mobility loss and improving quality of life in the large and growing number of people with PAD.

项目概要使用 METformin 提高 PAD 性能：PERMET 试验。我们和其他人的工作已经证实，患有下肢外周动脉疾病的人 (PAD) 具有更大的功能障碍、更快的功能衰退以及更高的活动能力丧失率然而，与没有 PAD 的人相比，很少有治疗方法可以改善功能或预防 PAD。 PAD 患者的功能下降。二甲双胍是一种廉价、广泛使用、耐受性良好的双胍类药物，也是最有效的双胍类药物。世界范围内治疗 2 型糖尿病的常用药物。最近的临床前和初步人体试验。有证据表明二甲双胍具有以前未被认识的治疗特性。二甲双胍在临床前模型中的应用可能使 PAD 患者受益，包括：小腿骨骼肌增加过氧化物酶体增殖物激活受体 γ 共激活剂 1-α (PGC-1α)（线粒体生物发生），小牛骨骼肌线粒体蛋白表达和活性增加，缺血组织毛细血管密度增加，氧化应激减少，自噬增加（修复细胞损伤），并改善内皮功能，这些治疗特性针对病理生理学。因此，我们认为二甲双胍可以改善下肢功能。对于 PAD 患者，通过促进小腿骨骼肌的有利变化并增加小腿骨骼的没有随机临床试验研究二甲双胍是否可以改善肌肉灌注。需要进行明确的试验来确定 PAD 的肢体功能。我们提出了一项安慰剂对照双盲随机临床试验，以确定二甲双胍是否（每天 2,000 毫克）改善和/或预防 PAD 参与者的步行能力下降。将有 212 名没有糖尿病的 PAD 患者，因为二甲双胍是 2 型糖尿病的一线治疗药物 2 糖尿病。我们的主要结果是 6 个月随访时六分钟步行的变化。跑步机行走表现、肱动脉血流介导的扩张、小腿骨骼肌的 6 个月变化活检指标、患者报告的步行表现和小腿肌肉结果包括： PGC-1α丰度、线粒体数量、线粒体酶活性、毛细血管密度、活性氧（ROS）诱导的组织损伤和自噬。如果二甲双胍可以改善 PAD 的功能表现并防止功能下降，那么这将广泛可用、廉价且耐受性良好的药物将对预防行动能力丧失和改善大量且不断增加的 PAD 患者的生活质量。