Metformin, Muscle Energetics, and Vascular Function in Older Adults With Peripheral Artery Disease
Metformin, Muscle Energetics, and Vascular Function in Older Adults With Peripheral Artery Disease
The investigators are doing this research study to find out if taking Metformin improves
 walking ability in patients with peripheral arterial disease (PAD). In PAD the arteries
 (blood vessels) in the legs are narrowed because of the build up of plaque. The leg muscle
 can hurt in patients with PAD and this is usually described as a cramp or tiredness. This
 pain is called intermittent claudication. Metformin is an FDA approved medication for the
 treatment of diabetes. The investigators believe that Metformin may help your leg muscles
 work better.

 The investigators will enroll up to 100 subjects in order to find 60 subjects with PAD at
 Brigham and Women's Hospital (BWH).
Peripheral artery disease (PAD) is a manifestation of atherosclerosis that affects more than
 7 million adults in the US. The prevalence of PAD increases with age and is estimated to be
 15 20% among individuals 65 years of age and older. Patients with PAD have limited functional
 capacity; they walk more slowly and have less walking endurance than persons who do not have
 PAD, irrespective of whether they have classic symptoms of intermittent claudication or
 critical limb ischemia. This functional impairment adversely affects quality of life.
 Although flow limitation due to atherosclerotic stenosis is necessary for the development of
 symptoms in PAD, the lack of correlation between walking capacity and the degree of
 hemodynamic compromise raises the possibility that alternative mechanisms contribute to
 functional limitations in these patients. Putative mechanisms include inadequate skeletal
 muscle glucose uptake, altered skeletal muscle energetics, and impaired vasomotor tone and
 nutrient delivery mediated by endothelial dysfunction. Metformin, via AMPactivated protein
 kinase (AMPK)-dependent and independent mechanisms, can favorably affect skeletal muscle
 metabolic functions including glucose uptake, fatty acid oxidation, mitochondrial function,
 and consequently cellular energetics, and it also may have a direct salutary effect on
 vascular function via regulation of nitric oxide synthase. It is intriguing, therefore, to
 consider the possibility that metformin would improve skeletal muscle metabolic and vascular
 function in older patients with PAD and translate into functional benefits. Accordingly, the
 investigators seek to elucidate molecular mechanisms through which metformin affects skeletal
 muscle energetics and hypothesize that metformin will lead to advantageous metabolic,
 vascular, and physical functional changes in older patients with PAD.
Inclusion Criteria:

 -  Age 40 years or greater

 -  Intermittent claudication for 6 months or greater

 -  Maximal walk time between 1-20 minutes on all ETTs

 -  Resting ABI ≤ 0.9 in index leg at baseline

 -  ABI falls ≥ 20% in index leg 1 minute post baseline ETT

 -  MWT variability < 20%

 Exclusion Criteria:

 -  Type 1 or Type 2 Diabetes

 -  Limb-threatening ischemia (rest pain, ulceration, gangrene)

 -  Peripheral vascular surgery or PCI within 6 months

 -  MI or CABG within 6 months

 -  Carotid endarterectomy (CEA) within 6 months

 -  Cerebrovascular accident or TIA within 6 months

 -  Uncontrolled hypertension (SBP > 140 mmHg, DBP >90 mmHg)

 -  Pentoxifylline/Cilostazol added/changed within 3 months

 -  HMG-CoA reductase inhibitor added/changed within 3 months

 -  Exercise limitations other than claudication (heart failure, angina, COPD, arthritis,
 neuropathy, etc.)

 -  Serum creatinine ≥ 1.5 mg/dL

 -  Pregnant or plans to become pregnant

 -  2 hour Oral Glucose Tolerance Test (OGTT) > 200 mg/dL