Improve PAD PERformance with METformin. The PERMET Trial

使用 METformin 改善 PAD 性能。

• 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
• 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' -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

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.

项目摘要 通过二甲双胍提高PAD性能：Permet试验。 我们的工作和其他工作已经确定下肢外周动脉疾病的人 （PAD）具有更大的功能障碍，更快的功能下降和移动损失率提高 与没有垫子的人相比。但是，很少有疗法可改善功能或预防 PAD患者的功能下降。 二甲双胍是一种便宜，可用的，耐受性良好的Biguanide药物，最多 全世界通常开处方的2型糖尿病药物。最近的临床前和初步人类 有证据表明，二甲双胍以前没有识别的治疗特性。 可能受益于PAD的人的临床前模型中的二甲双胍包括：小腿骨骼肌肉增加 过氧化物体增生剂激活受体伽马共振剂1-α（PGC-1α）（PGC-1α）（主要调节剂 线粒体生物发生），小腿骨骼肌在线粒体蛋白表达和活性中增加 缺血组织中毛细血管密度的增加，氧化应激的减少，自噬增加（修复 细胞损伤），并改善了内皮功能。这些治疗特性靶向病理生理学 垫中存在的条件。因此，我们假设二甲双胍将改善下肢功能 在有垫子的人中，通过促进小腿骨骼肌的良好变化并增加小腿骨骼 肌肉灌注。没有随机临床试验有研究二甲双胍是否改善较低 肢体在垫子中发挥作用。需要确定的试验。 我们提出了一项安慰剂控制的双盲随机临床试验，以确定二甲双胍是否是 （每天2,000毫克）改善和/或防止患有PAD的人的步行性能下降。参与者 将是212人患有糖尿病的人，因为二甲双胍是一种类型的一线疗法 2个糖尿病。在6个月的随访中，我们的主要结果在步行六分钟的步行路程中发生了变化。次要结果是 跑步机步行性能，臂动脉流介导的扩张，小腿骨骼肌的6个月变化 活检措施，患者报告的步行表现和生活质量。小腿肌肉结局包括 PGC-1α抽象，线粒体量，线粒体酶活性，毛细管密度， 活性氧（ROS）诱导的组织损伤和自噬。 如果二甲双胍改善功能性能并防止PAD的功能下降，则可以广泛 可用，廉价且耐受性良好的药物将对防止出行损失和 改善了大量和越来越多的垫子的生活质量。