Relation of Inflammation and Insulin Resistance to Peripheral Arterial Disease

Study ID	NCT00225940
Status	Recruiting
Phase	3
Source	ClinicalTrials.gov

Started	Sep 1 2003
Last Updated	Jul 28 2009
Estimated Completion	Jul 28 2009

About this clinical study

Summary

This study will test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in patients with intermittent claudication (IC) by impairing vascular reactivity and skeletal muscle metabolic function.

Condition / Disease

Cardiovascular Diseases
Peripheral Artery Disease
Inflammation
Insulin Resistance

Therapy

Atorvastatin
Pioglitazone
Placebo

Study Outcomes

Pain free and maximal treadmill walking time
Insulin resistance
Skeletal muscle glucose utilization
Systemic inflammatory markers
Circulating and local adipocyte markers of PPAR activation
In vivo vascular function by ultrasonography
Change in ankle/brachial index (ABI)

Description

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.

Overview

Gender	male, female

Target Enrollment	240

Recruiting Healthy Volunteers	No

Locations

Brigham and Women's Hospital

Boston

2 mi

Criteria

Inclusion Criteria:

IC group inclusion criteria are as follows:

1. Lower extremity PAD and IC

2. Stable IC (as defined by the San Diego Claudication Questionnaire) for at least 6 months prior to study entry

3. Resting ABI of less than or equal to 0.90

4. Maximal walking time (MWT) between 1 and 20 minutes and post-exercise ABI drop by greater than or equal to 20% (as measured by an exercise treadmill test at the baseline visit, with assessment of pain free walking time [PFWT], MWT, and measurement of the ABI in the index [most symptomatic] leg within 1 minute of concluding exercise)

Revascularization group inclusion criteria are as follows:

1. PAD

2. Scheduled to undergo lower extremity percutaneous revascularization

Control group participants will have no known medical problems and a normal cardiovascular exam

Exclusion Criteria:

Myocardial infarction or coronary artery bypass surgery within 6 months prior to study entry

Transient ischemic attack or ischemic stroke 6 months prior to study entry

Pregnancy

Uncontrolled hypertension, defined as a systolic pressure greater than 180 mm Hg and/or diastolic pressure greater than 100 mm Hg

Serum creatinine greater than 2.5

Hepatic transaminases greater than 3 times upper limit of normal

Creatine kinase greater than 5 times upper limit of normal

IC group exclusion criteria are as follows:

1. Must discontinue treadmill exercise for reasons other than muscular leg pain (e.g., shortness of breath, chest pain, back pain)

2. Type 1 or insulin-dependent Type 2 diabetes

3. Lower extremity revascularization (surgical or percutaneous intervention) within 6 months prior to study entry

4. Fasting glucose greater than 110 mg/dL

5. Hypersensitivity to HMG-CoA reductase inhibitors

6. Low-density lipoprotein levels greater than 190 mg/dL, after HMG-CoA reductase inhibitors discontinuation (patients treated with HMG-CoA reductase inhibitors [statins] must discontinue therapy for 4 weeks prior to the baseline screening visit, and remain off treatment throughout the study [maximum of 15 weeks])

Revascularization group will exclude patients with an active infection

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