PERMET

The PERMET trial will determine whether metformin daily for six months improves six-minute walk performance in individuals with peripheral artery disease compared to placebo.

Inclusion Criteria:

All participants will have PAD. PAD will be defined as follows:

• First, an ankle brachial index (ABI) 0.90 but ≤ 1.00 and experience a 20% or higher drop in ABI after heel-rise exercise will be eligible.

• Third, potential participants with an ABI > 0.90 who have vascular lab evidence of PAD or angiographic evidence of PAD who have ischemic symptoms during the six-minute walk and/or treadmill exercise stress test will be eligible.

• Fourth, potential participants with a history of lower extremity revascularization who do not meet the criterion above and have an ABI > 0.90 with a 20% or higher drop in ABI after heel-rise exercise will be eligible.

Exclusion Criteria:

• Above* or below-knee amputation.

• Critical limb ischemia.

• Wheelchair-bound or requiring a walker to ambulate.

• Walking is limited by a symptom other than PAD.

• Current foot ulcer on bottom of foot.

• Diabetes mellitus defined as one or more of a) patient report of physician diagnosed diabetes mellitus, b) use of one or more diabetes medications, c) two baseline hemoglobinA1C values of >6.5, d) two fasting glucose values >126 mg/dl. [NOTE: the second fasting glucose value and hemoglobin A1C values will be at the discretion of the principal investigator. For example, if the first glucose value is >300 or the first A1C value is >6.9, then investigators may decide not to repeat the value.]

• Chronic kidney disease defined as GFR 45, the participant may be included.]

• Chronic liver disease defined as two or more hepatic function tests >=2.0 times the upper limit of normal. [NOTE: participants who meet this criterion may undergo a re-test of hepatic function tests to determine whether initially elevated hepatic enzymes represented a transient or spurious phenomenon.]

• Failure to successfully complete the 2-week study run-in, defined as unable to tolerate metformin and/or failing to take the medication daily for 10 or more days in the two-week period.

• Planned lower extremity revascularization, orthopedic surgery, or other major surgery during the next six months.

• Lower extremity revascularization, orthopedic surgery, cardiovascular event, coronary revascularization, or other major surgery in the previous three months.

• Major medical illness including renal disease requiring dialysis, lung disease requiring oxygen, Parkinson's disease, a life-threatening illness with life expectancy less than six months, or cancer requiring treatment in the previous two years. [NOTE: potential participants may still qualify if they have had treatment for an early stage cancer in the past two years and the prognosis is excellent. Participants who only use oxygen at night may still qualify.]

• Mini-Mental Status Examination (MMSE) score