Effect of Statins on Oxidative Stress and Endothelial Progenitor Cells

Phase 2

Completed

Conditions: Hypercholesterolemia
Diabetes Mellitus
Metabolic Syndrome X

Interventions: Drug: Pravastatin
Drug: Atorvastatin

Registration Number: NCT00166036

Lead Sponsor: Emory University

Brief Summary: Thirty-six subjects with hyperlipidemia and metabolic syndrome and/or diabetes were randomized in a double-blind manner to either pravastatin 80 mg or atorvastatin 10 mg daily. Oxidative stress (dROMs assay that measures lipid hydroperoxides, plasma thiobarbituric acid reactive substances \[TBARS\], and aminothiol levels) and brachial artery flow-mediated dilation (FMD) were measured at baseline and after 12 weeks of statin therapy.

Detailed Description: Individuals with a high cholesterol level, diabetes or metabolic syndrome (collection of abnormalities such as high blood pressure, high triglyceride levels \[fat\], obesity, high blood glucose level) have an increased risk of developing a hardening of the arteries and heart disease.

A group of medications called statins, commonly used worldwide to lower cholesterol levels, are known to reduce the risk of heart disease through their effects on reducing cholesterol levels. These medications also have effects beyond the lowering of cholesterol that may help mediate their beneficial effects on the heart and blood vessels.

These include a reduced production of molecules that harm the arteries such as reactive oxygen species (ROS) and increasing the number of stem cells that help repair vessels, called endothelial progenitor cells (EPCs).

Recent studies have shown that different statins might have different effects on protecting people from developing heart disease. These differences may be due to differences in these non-cholesterol lowering processes, and are the subject of this study.

Standard of Care:

The two statins that will be used in this study, pravastatin (Pravachol ®) and atorvastatin (Lipitor®), are approved for use in people with a high cholesterol level or heart disease. These medications are generally very well tolerated with minimal side effects. They are not approved for use in patients to increase the level of EPCs or to reduce the production of ROS, and therefore are considered experimental for this indication. Currently there are no drugs that are specifically approved for these indications.

How the Problem Will be Studied:

These statins will be given to patients who have high cholesterol and either diabetes or the metabolic syndrome once a day for 12 weeks. We, the investigators at Emory, will measure the level of EPCs and ROS before and during the administration of the statin. We will also investigate how well the blood vessels dilate in response to these medications by performing an imaging study of the forearm artery using ultrasound.

The study is blinded and there is an equal chance of receiving either atorvastatin 10mg or pravastatin 80mg which are likely to lower cholesterol level by a similar amount.

How Research Will Advance Scientific Knowledge:

The goal of this study is to determine if atorvastatin will increase the number of circulating EPCs and reduce the production of ROS more than pravastatin. This may help explain the differences between these drugs that have been observed in some recently published trials.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

Inclusion Criteria

Males or females without child bearing potential aged 21-80 years
Fasting low-density lipoprotein (LDL) level > 120mg/dL.
Either known to be diabetic or have at least 3 components of metabolic syndrome that are defined below:
- Hypertension defined as blood pressure (BP) > 140 systolic or > 90 mmHg diastolic, or stable medical therapy for documented hypertension;
- Fasting glucose > 110 mg/dL;
- Waist > 40 inches in males, and > 35 inches in females;
- Triglycerides > 150mg/dL; or
- High-density lipoprotein (HDL) cholesterol < 40 mg/dL in males and < 50 mg/dL in females.
Able to provide written informed consent
Non-smoker

Exclusion Criteria

On any oral antioxidants or lipid lowering medications in the previous 8 weeks
Age < 21 or > 80 years
Premenopausal females with potential for pregnancy
LDL cholesterol level < 120 mg/dl
Initiation or change in dose of any concomitant medical therapy within 2 months before the study
Uncontrolled hypertension with BP > 180 mmHg systolic and > 120 mmHg diastolic
Current smoker
Previous intolerance or allergy to statins
Acute infection in previous 4 weeks
History of substance abuse
Uninterpretable Brachial Artery Reactivity Study
Current neoplasm
Chronic renal failure (creatinine > 2.5 mg/dL) or liver failure (liver enzymes > 2X normal)
Acute coronary syndrome, heart failure, cerebrovascular accident (CVA), or coronary intervention within 3 months
Known aortic stenosis, hypertrophic cardiomyopathy, or symptomatic heart failure.
Inability to give informed consent
Inability to return to Emory for follow-up

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pravastatin 80mg	Pravastatin	-
Atorvastatin 10MG	Atorvastatin	-

Primary Outcome Measures

Name	Time	Method
Change in Plasma Thiobarbituric Acid Reactive Substance (TBARS) Levels	Baseline &12 Weeks	Oxidative stress was assessed with plasma thiobarbituric acid reactive substance (TBARS) levels (an index of lipid peroxidation).Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage.We hypothesized that equipotent doses of these two statins will have divergent effects on markers of oxidative stress and endothelial function.

Secondary Outcome Measures

Name	Time	Method
Change in Flow-mediated Dilatation (FMD)	Baseline & 12 Weeks	Flow-mediated dilatation (FMD) of the brachial artery was used to asses Endothelial Function. The endothelium, by releasing nitric oxide (NO), promotes vasodilation and inhibits inflammation, thrombosis, and vascular smooth muscle cell proliferation.We hypothesized that equipotent doses of these two statins will have divergent effects on markers of oxidative stress and endothelial function.