The Effect of Vitamin D Supplementation on Arterial Stiffness in Diabetic Patients
Condition: Diabetes
Study type: Interventional

Summary: 
      The incidence of type 2 Diabetes Mellitus is increasing at an alarming rate worldwide.

      Cardiovascular disease is the leading cause of death in patients with type 2 diabetes.

      Recently, increasing amount of evidence suggests that vitamin D may influence various
      nonskeletal medical conditions, including cardiovascular disease, hypertension, diabetes,
      cancer, autoimmune disorders and more. 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.
    

Detailed description: 
      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.
    

Intervention name(s): Baby D3 drops
Intervention type(s): Drug
Intervention description(s): 2000-4000 iu per day
Other intervention name(s): vitamin D
Intervention MeSH terms: Vitamin D
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment