Trial Information

The Effect of Vitamin D Supplementation on Arterial Stiffness, Blood Pressure, Oxidative Stress and Inflammation in Diabetic Patients

Background:

The incidence of type 2 Diabetes Mellitus is increasing at an alarming rate worldwide, with
more than 1 million new cases per year diagnosed in the United States alone. [1] Diabetes is
the fifth leading cause of death in the United States, and it is also a major cause of
significant morbidity.

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes.

The risk of Cardiovascular disease (CVD) mortality in type 2 diabetic patients is more than
double compared with that in age-matched subjects. [2] Therefore, reducing cardiovascular
risk in diabetic patients is of great importance.

Vitamin D3 (cholecalciferol), the most powerful form of vitamin D, is synthesized in the
skin from 7-dehydrocholesterol by action of sunlight (ultraviolet B radiation). Vitamin D3
is biologically inert. In the hepatic parenchyma, vitamin D3 is converted to
25-hydroxyvitamin D3 (25OHD3) and must be converted to the active hormone 1,25-dihydroxy
vitamin D (calcitriol). 25OHD is the most plentiful and stable metabolite of vitamin D. As
such, the 25OHD level in the serum is the best indicator of vitamin D level. [3]

The major and most well known function of Vitamin D is to maintain calcium and phosphorus
homeostasis and promote bone mineralization. It is well understood that vitamin D deficiency
leads to osteomalacia and osteoporosis in adults. [4]

However, recently, increasing amount of evidence suggests that vitamin D may also influence
various nonskeletal medical conditions, including cardiovascular disease, hypertension,
diabetes, cancer, autoimmune disorders and more [4, 5] An evolving data indicates that
vitamin D deficiency is much more prevalent than previously recognized. In the United
States, as well as in other parts of the world, the mean population serum 25OHD levels have
decreased in the last decade. The best example of this drop comes from the National Health
and Nutrition Examination Survey (NHANES) population showing near doubling in the number of
subjects in the American population from 1994 to 2004 with 25OHD levels less than 30
ng/ml.[6]

The possible explanations for this dramatic decrease in vitamin D level are: downward in
milk consumption, upward in sun protection and upward in obesity. [7]

All cause and cardiovascular mortality:

The NHANES III database clearly shows an increase in adjusted all cause mortality as the
serum 25OHD level falls to less than 30 ng/ml, especially in woman, and peak protection from
death with a 25OHD level in the 35-40 ng/ml range. The prevalence of coronary artery
disease, heart failure, and peripheral artery disease is significantly increased in a
stepwise fashion as the serum 25OHD level drops to less than 30 and then 20 ng/ml
(insufficiency and deficiency, respectively). [8]

A recent meta-analysis of 18 trials comprising 57,311 randomly assigned participants, found
that vitamin D supplementation >500 IU/day reduced all cause mortality by 7%, in part by
decreasing CV deaths.[9] Deficient or insufficient serum 25(OH) D levels have been
documented in patients with myocardial infarction .[10] A correlation between vitamin D
deficiency and subsequent major adverse CV events was found among the 1739 Framingham
Offspring Study participants who were free of CV disease at baseline. In this prospective
observational study, 25(OH) D levels were measured at baseline and subjects were followed up
for a mean of 5.4 years. The rate of a composite CV end point (fatal or nonfatal MI,
ischemia, stroke, or heart failure) was 53% to 80% higher in people with low vitamin D
levels.[11]

The reason for this association between all cause mortality, CVD and vitamin D
insufficiency/deficiency is unclear. It is also unclear whether vitamin D supplementation
will normalize the CVD risk in these patients.

In a recent systemic review Wang et al found no completed trials that have tested the effect
of vitamin D and calcium supplementation on CVD as the primary end point. [12]

Vitamin D and diabetes Inspection of the recent vitamin D insufficiency/deficiency
epidemiological literature has brought to light the striking inverse correlation of
the25OHDlevel not only to cardiovascular disease but also to essentially all of the elements
of the human metabolic syndrome: hypertension; obesity; insulin resistance and glucose
Intolerance [3] Likewise, in cross sectional studies, inverse associations between serum
25(OH) D and presence of type 2 diabetes have been reported in a variety of cohorts. [13-15]

One example is the analysis of data from participants who attended the morning examination
of the Third National Health and Nutrition Examination Survey (1988-1994) that showed an
inverse association between vitamin D status and diabetes.[13]

This observations regarding the high prevalence of vitamin D deficiency among type 2 DM
patients do not establish causative relationship between the two.

In the women's Health Study, an intake of 511 IU/d of vitamin D or more was associated with
lower risk of incidence type 2 DM compared with low intake [16]

Vitamin D and Arterial stiffness Augmentation pressure, reflecting the pulsatile component
of blood pressure and thus arterial stiffness, is a well-known risk factor for
cardiovascular disease and outcome.[17-21] Augmentation index (AIx), a non invasive measure
of arterial stiffness, has been shown to predict coronary artery disease (CAD) in the
general population and in patients with type 2 diabetes [20, 22, 23] The differential
effects on arterial stiffness may be responsible for the different impact of diverse
antihypertensive drug/treatments on CAD.[21] Different drugs have been proved to improve
arterial stiffness. One example is the beneficial effect of statins on AIx, a result that is
independent of their cholesterol lowering effect. [24] Andrade et al found that Lower
1,25-OH2D3 levels were associated with higher Aix in 131 outpatients identified from
individual cardiac or kidney disease clinics. [25] Vitamin D regulates the renin-angiotensin
system (RAS) in experimental animals. Recently data in humans suggest that low plasma
25-hydroxyvitamin D levels may result in upregulation of the RAS in otherwise healthy
humans. [26] No studies to date examined the effect of vitamin D supplementation on blood
pressure and arterial stiffness as primary end point.

The purpose of this trial is to investigate the effect of vitamin D supplementation on 24
hours blood pressure monitoring, arterial stiffness, oxidative stress and inflammation in
vitamin D deficient diabetic patients.