Diabetes Mellitus, Hypercholesterolemia, Metabolic Syndrome X
Conditions
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.
Interventions
DRUGAtorvastatin
12 Weeks of Oral Atorvastatin 10 mg therapy.
DRUGPravastatin
12 Weeks of Oral Pravastatin 80 mg therapy.
Sponsors
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Pre-assignment details
Previous statin or other lipid lowering medications will be discontinued for 2 months. Subjects will be on stable medical therapy for at least 2 months before recruitment.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin 10 mg Subject treated with oral Atorvastatin 10 mg for 12 Weeks. | 17 |
| Pravastatin 80 mg Subject treated with oral Pravastatin 80 mg for 12 Weeks. | 19 |
| Total | 36 |
Baseline characteristics
| Characteristic | Atorvastatin 10 mg | Pravastatin 80 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 18 Participants | 34 Participants |
| Age, Continuous | 54.2 years STANDARD_DEVIATION 6.6 | 51.7 years STANDARD_DEVIATION 10.8 | 52.9 years STANDARD_DEVIATION 9.1 |
| Sex: Female, Male Female | 09 Participants | 14 Participants | 23 Participants |
| Sex: Female, Male Male | 08 Participants | 05 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 17 | 0 / 19 |
| serious Total, serious adverse events | 0 / 17 | 0 / 19 |
Outcome results
Primary
Change in Plasma Thiobarbituric Acid Reactive Substance (TBARS) Levels
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.
Time frame: Baseline &12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin 10 mg | Change in Plasma Thiobarbituric Acid Reactive Substance (TBARS) Levels | 2.1 nmol/mL | Standard Error 0.8 |
| Pravastatin 80 mg | Change in Plasma Thiobarbituric Acid Reactive Substance (TBARS) Levels | 2.5 nmol/mL | Standard Error 1 |
Secondary
Change in Flow-mediated Dilatation (FMD)
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.
Time frame: Baseline & 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin 10 mg | Change in Flow-mediated Dilatation (FMD) | 5.9 Percentage of brachial artery diameter | Standard Error 2.9 |
| Pravastatin 80 mg | Change in Flow-mediated Dilatation (FMD) | 6.0 Percentage of brachial artery diameter | Standard Error 2.3 |