Arterial Occlusive Disease, Insulin Resistance, Intermittent Claudication
Conditions
Keywords
peripheral arterial disease, intermittent claudication
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.
Interventions
DRUGatorvastatin and pioglitazone
atorvastatin 80 mg orally once daily (to reduce inflammation) and pioglitazone 30 mg orally once daily (to improve insulin sensitivity)
DRUGatorvastatin/placebo
atorvastatin 80 mg orally once daily and matching placebo orally twice daily
DRUGpioglitazone/placebo
pioglitazone 30 mg orally once daily and matching placebo orally once daily
DRUGplacebo/placebo
placebo orally three times daily
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lower Extremity Skeletal Muscle Glucose Uptake | 60 minutes | Net calf skeletal muscle glucose uptake determined by Patlak modeling. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| '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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Controls Healthy individuals, non-smokers, normal CV examination. | 11 |
| Patients With PAD Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. | 37 |
| PAD Without Diabetes Patients with PAD and stable intermittent claudication with a resting ABI of 0.90 or less. These patients do not have diabetes. | 28 |
| Total | 76 |
Baseline characteristics
| Characteristic | Patients With PAD | PAD Without Diabetes | Healthy Controls | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 31 Participants | 22 Participants | 8 Participants | 61 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 3 Participants | 15 Participants |
| Age, Continuous | 66 years STANDARD_DEVIATION 8.7 | 64.6 years STANDARD_DEVIATION 8.8 | 60.5 years STANDARD_DEVIATION 6 | 64.2 years STANDARD_DEVIATION 9.5 |
| Region of Enrollment United States | 37 participants | 28 participants | 11 participants | 76 participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 31 Participants | 25 Participants | 5 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 19 | 0 / 18 | 0 / 20 | 0 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 | 0 / 20 | 0 / 19 |
Outcome results
Primary
Lower Extremity Skeletal Muscle Glucose Uptake
Net calf skeletal muscle glucose uptake determined by Patlak modeling.
Time frame: 60 minutes
Population: Baseline Characteristics were collected according to the clinical diagnosis of the patients and not according to randomization. Participants were grouped at Baseline and are presented here irrespective of randomization because the primary intention was to compare the different types of patients regardless of interventions received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Controls | Lower Extremity Skeletal Muscle Glucose Uptake | 62.9 umol/kg/min | Standard Deviation 21 |
| Patients With PAD | Lower Extremity Skeletal Muscle Glucose Uptake | 48.6 umol/kg/min | Standard Deviation 15 |
| PAD (Excluding Diabetes) | Lower Extremity Skeletal Muscle Glucose Uptake | 49.5 umol/kg/min | Standard Deviation 3.1 |
Secondary
'M' = Whole Body Insulin Sensitivity
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.
Time frame: every 5 minutes for 20 minutes
Population: Baseline Characteristics were collected according to the clinical diagnosis of the patients and not according to randomization. Participants were grouped at Baseline and are presented here irrespective of randomization because the primary intention was to compare the different types of patients regardless of interventions received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Controls | 'M' = Whole Body Insulin Sensitivity | 5.0 mg/kg/min |
| Patients With PAD | 'M' = Whole Body Insulin Sensitivity | 3.4 mg/kg/min |
| PAD (Excluding Diabetes) | 'M' = Whole Body Insulin Sensitivity | 3.4 mg/kg/min |