Relation of Inflammation and Insulin Resistance to Peripheral Arterial Disease

BACKGROUND:

Patients with peripheral artery disease (PAD) frequently have functional limitations and
symptoms of claudication that impact adversely on their quality of life. Some patients
progress to critical limb ischemia and require revascularization. Vascular inflammation and
insulin resistance are two important and interdependent conditions that are associated with
atherosclerosis. Moreover, both inflammation and insulin resistance cause abnormalities in
vascular function, and insulin resistance interferes with skeletal muscle metabolism.
Therefore, inflammation and insulin resistance provide attractive targets for therapy that
could potentially ameliorate the development of symptomatic PAD or improve the function and
clinical outcomes of patients with PAD. This study will determine whether inflammation and
insulin resistance contribute to the functional and clinical consequences of PAD.

DESIGN NARRATIVE:

This study will test the hypothesis that inflammation and insulin resistance contribute to
reduced walking distance in patients with IC by impairing vascular reactivity and skeletal
muscle metabolic function. Pain-free and maximum treadmill walking time will be measured
before and after 12 weeks of treatment with pioglitazone, atorvastatin, or placebo in a 2
times 2 factorial design protocol. Endothelium-dependent and independent vasodilation
(assessed by vascular ultrasonography), and plasma markers of inflammation and insulin
resistance will also be measured before and after drug intervention. A sub-set of patients
may opt to participate in a sub-study of skeletal muscle glucose utilization, assessed (by
[18F] fluorodeoxyglucose [FDG] positron emission tomography[PET]).

A separate group of patients with PAD scheduled to undergo elective percutaneous
revascularization will be enrolled, and will undergo pre- and post-intervention FDG/PET
scanning, to ascertain whether skeletal muscle glucose utilization changes with anticipated
improvements in blood flow following intervention.

Patients will be recruited from the vascular medicine, surgery, and cardiology clinics at
Brigham and Women's Hospital. All study visits take place in the Vascular Medicine Research
Center. After two preliminary visits, patients are randomized to one of four drug
interventions. Outcome measurements of the study will include insulin resistance, skeletal
muscle glucose utilization by PET, systemic inflammatory markers, circulating and local
adipocyte markers of peroxisome proliferator-activated receptor (PPAR) activation, in vivo
vascular function by ultrasonography, ankle/brachial index (ABI), and treadmill walking
time.