Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00534014 |
| Other study ID # |
04-319B |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 2006 |
| Est. completion date |
May 2007 |
Study information
| Verified date |
March 2024 |
| Source |
University of New Mexico |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Study Goal #1: Determine the optimal oral dose of vitamin C to reduce surrogate markers of
atherosclerosis (blockages in blood vessels) following the consumption of an atherogenic high
fat lunch in type 2 diabetic individuals.
Study Goal #2: After conducting the original study, we found that vitamin E was not effective
in reducing the markers of oxidative stress, hypercoagulation, inflammation, and metabolic
parameters in patients with type 2 diabetes.
To date, data from randomized trials have largely demonstrated no significant benefit of
vitamin E supplementation on the prevention of primary and/or secondary cardiovascular
disease as once thought. Therefore, we decided to amend our current protocol to add a Part B
to study only the effects of vitamin C at the following doses: 500 mg, 1000 mg, and 2000 mg
daily (and include a placebo arm, as well.
Description:
More than 70% of type 2 diabetic individuals will die of atherosclerotic disease (1). This is
partially explained by the abnormal lipid profile frequently observed in type 2 diabetes.
These patients are also frequently afflicted with "Syndrome X," an assortment of risk factors
for atherosclerosis, including hypertension, abdominal obesity, hyperuricemia, prothrombotic
and proinflammatory states, and increased plasminogen activator inhibitor type I (PAI-1) (2).
Several approaches have been suggested to reduce the risk of atherosclerosis in type 2
diabetic individuals. Changes in lifestyle leading to increased exercise and weight loss will
result in the reduction of adipose stores (and restore tissue sensitivity to insulin).
However, this approach is very difficult for many individuals to achieve. For them, this can
be supplemented with medications such as aspirin, angiotensin inhibitors, angiotensin
receptor blockers, and the statins. Unfortunately, each of these medications is either
expensive and/or includes undesirable side effects (3). In addition, clinical experience
shows that many patients are against taking medication for cultural reasons and/or fear of
long-term unknown consequences.
For these reasons, there is great interest in using vitamins to reduce atherogenic risk. More
than half of the U.S. adult population consumes vitamins on a regular basis. They are
inexpensive and easily accessible in grocery stores and health food stores. The FDA does not
consider them as "drugs" and they undergo a less rigorous approval procedure (4,5). Vitamins
are natural compounds found in the body, and many individuals do not consider them drugs, but
feel they are simply fortifying their bodies against disease.
There is currently a focus on vitamins that are antioxidants, including vitamin C. Patients
with diabetes usually have a decreased antioxidant status, which leads to increased oxidative
stress and vascular dysfunction (6,7). Oxidative stress refers to the excessive production of
oxygen free radical species, which damage their surrounding molecules, and this leads to the
increased release of inflammatory mediators, oxidation of low-density lipoproteins (LDL), and
increased coagulation (7).
Vitamin C, another antioxidant, has been shown to regenerate Vitamin E, and in patients with
increased oxidative stress (i.e. patients with conditions such as diabetes mellitus, coronary
artery disease, and hypercholesterolemia), it restores endothelium-dependent artery
vasodilation, and may reverse endothelial dysfunction in peripheral arteries (6). It has been
hypothesized that supplementation of vitamin C may be more effective than vitamins taken
together.
The hypothesis that atherosclerosis may be prevented by blocking the oxidative metabolism of
LDL cholesterol, hence decreasing its uptake into the arterial lumen, is what incited the
interest in vitamin C for treating coronary heart disease (CHD). Basic science and animal
studies had shown beneficial effects of vitamin C on several different stages of the
atherosclerotic process. This was followed by several observational studies on patients with
no initial coronary artery disease, which suggested that vitamin C lowered the risk of future
CHD. However, this was followed by several large randomized control trials, the majority of
which showed no benefit of vitamin C in the prevention of CHD in patients with at least one
coronary risk factor. However, this did not answer the question of whether vitamin C was
beneficial in differeing doses.
In 2002, Fang et al. published a study that investigated the efficacy of vitamins C and E on
the prevention of transplant-associated arteriosclerosis (another highly oxidative state).
The primary outcome was change in average intimal index (plaque area divided by vessel area),
which was measured with intavascular ultrasonography (IVUS). The vitamin C and E plasma
concentrations were measured at baseline and at 1-year follow-up. At follow-up the placebo
group showed a significant increase but the treatment group showed no change. The authors
concluded that early progression of transplant-associated coronary arteriosclerosis is
delayed with combined vitamin C and E therapy (6,10). In 2003, Salonen et al. published the
six-year effects of combined vitamin C and E from the ASAP (Antioxidant Supplementation in
Atherosclerosis Prevention) study, which studied the effects of supplemented doses on the
progression of common carotid atherosclerosis in middle-aged high-risk men and women, using
high-resolution ultrasound to assess this outcome. The group receiving combined vitamins
showed a decrease in rate of progression of carotid intimal thickness, but this effect was
limited to men only (8,10). In the Heart Protection Study (2002), a combination of synthetic
vitamin E, vitamin C, and beta-carotene daily had no effect on the incidence of
cardiovascular events in a group of approximately 20,000 high-risk individuals (10).
Therefore, not all studies showed positive benefits. Vitamin C has been shown to reduce
overall oxidative stress by scavenging free readicals within the body (11). Some trials
failed to report antioxidant levels, making compliance difficult to measure (8) (except
through pill counting - and unfortunately, volunteers can dispose medications prior to visit,
in order to give the image of compliance). Some trials used suboptimal timing regarding
administration of antioxidant vitamins in relation to meals (1). Also, it is not known just
what exactly is the optimal dosage of vitamins C is. The doses of vitamin C has differed in
these trials (8); some investigators hypothesize that at least 500 mg/day of vitamin C are
effective for slowing the progression of atherosclerosis, but speculation is rampant (7,8).
Based on the data from these studies (1,7,8), we believe that only sufficient doses of
vitamins C will be effective for slowing the progression of atherosclerosis. It is our goal
to find the optimal dosing combination. We will use a high-risk population (diabetic
volunteers) because they are known to have high oxidative stress and may benefit tremendously
from this therapy.
