ARREST PAD (Peripheral Arterial Disease)

Phase 2

Completed

Conditions: Intermittent Claudication
Insulin Resistance
Arterial Occlusive Disease

Interventions: Drug: atorvastatin and pioglitazone
Drug: atorvastatin/placebo
Drug: pioglitazone/placebo
Drug: placebo/placebo

Registration Number: NCT00153166

Lead Sponsor: Brigham and Women's Hospital

Brief Summary: This trial will test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in subjects with intermittent claudication by impairing vascular reactivity and skeletal muscle metabolic function.

Detailed Description: People with peripheral arterial disease (PAD), an important clinical manifestation of atherosclerosis, often suffer symptoms of intermittent claudication that impair their walking ability and adversely affect their quality of life. People with PAD are also at increased risk for adverse cardiovascular events, including myocardial infarction, stroke and death. Unfortunately, medical therapies directed to the functional and limb-threatening manifestations are limited. Little attention has been paid to the biologic processes that cause PAD, and to atherogenic mechanisms that may preferentially affect the peripheral circulation.

Vascular inflammation and insulin resistance are two important and interdependent conditions that are associated with atherosclerosis. Subjects in this trial (160 adults with stable intermittent claudication who are not taking insulin or insulin-sensitizing medications, such as thiazolidinediones) will be randomized in a placebo-controlled, parallel design manner, to atorvastatin 80 mg orally daily (to reduce inflammation) and pioglitazone 45 mg orally once daily (to improve insulin sensitivity). Forty healthy adult subjects, age and gender-matched to a subset of the study group, will be enrolled to serve as a control population. Primary and secondary study endpoints include: treadmill walking time, endothelium-dependent vasodilation, and insulin-mediated skeletal muscle glucose uptake.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 76

Inclusion Criteria

symptomatic intermittent claudication for >= 6 months
resting ankle/brachial index (ABI) <=0.90
maximal treadmill walking time between 1-20 minutes
>= 20% decrease in ABI post treadmill exercise
4 week statin wash-out prior to initial study testing (if applicable)

Exclusion Criteria

myocardial infarction or coronary artery bypass surgery within past 6 months
lower extremity revascularization (surgical or percutaneous) within past 6 months
transient ischemic attack or ischemic stroke within past 6 months
pregnancy
uncontrolled hypertension (systolic pressure > 180mmHg and/or diastolic pressure > 100mmHg
serum creatinine >2.5
hepatic transaminases (AST, ALT) > 3x upper limit of normal (ULN)
creatine kinase > 5x ULN
known hypersensitivity to HMG-CoA reductase inhibitors
insulin dependent Type 2 diabetes
current treatment with thiazolidinedione

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Patients with PAD (Including diabetics)	atorvastatin and pioglitazone	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
Patients with PAD (Including diabetics)	pioglitazone/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
PAD (Excluding Diabetics)	atorvastatin and pioglitazone	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
Patients with PAD (Including diabetics)	atorvastatin/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
Patients with PAD (Including diabetics)	placebo/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
PAD (Excluding Diabetics)	pioglitazone/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
PAD (Excluding Diabetics)	placebo/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
Healthy Controls	atorvastatin and pioglitazone	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
PAD (Excluding Diabetics)	atorvastatin/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
Healthy Controls	atorvastatin/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
Healthy Controls	pioglitazone/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.
Healthy Controls	placebo/placebo	Randomized to either atorvastatin and pioglitazone, atorvastatin/placebo, pioglitazone/placebo, or placebo/placebo.

Primary Outcome Measures

Name	Time	Method
Lower Extremity Skeletal Muscle Glucose Uptake	60 minutes	Net calf skeletal muscle glucose uptake determined by Patlak modeling.

Secondary Outcome Measures

Name	Time	Method
'M' = Whole Body Insulin Sensitivity	every 5 minutes for 20 minutes	A hyperinsulinemic-euglycemic clamp was performed prior to and during FDG-PET imaging to measure insulin sensitivity and to standardize metabolic conditions. Subjects were required to fast for 8 hours prior to the study. Patients were given a primed insulin infusion of 2 mU/kg/min. Serum glucose measurements were made at five-minute intervals from an arterialized venous sample achieved by placing the hand in a warming box at 50°C. Blood glucose levels are checked every 5 minutes and 20% dextrose infusion is adjusted to maintain a serum glucose level of approximately 80 mg/dL. Subjects were considered to have achieved steady state when the dextrose infusion rate required to maintain a serum glucose level of 80 mg/dL varied by no greater than 5%. To compute the steady-state glucose disposal rate, we averaged the glucose infusion rates over the last 20 minutes of the clamp and applied a "space correction" to account for small changes in serum glucose levels over that time period.