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.

Eligibility Criteria:
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