Vitamin D Supplementation in Patients With Diabetes Mellitus Type 2
Condition: Diabetes Mellitus Type 2; Vitamin D Deficiency
MeSH terms: Diabetes Mellitus; Vitamin D Deficiency; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      Background and Objectives :

      The presence of vitamin D deficiency in patients with type 2 diabetes mellitus (T2DM) is
      associated with an increased risk of cardiovascular disease (CVD). We aim to see whether
      supplementation of vitamin D in these patients helps to improve the endothelial function (EF)
      a surrogate marker of CVD risk.

      Hypothesis: Vitamin D supplementation in patients with T2DM and low serum 25(OH) D
      concentrations (<30ng/ml) will improve EF as measured by the Endo-PAT machine by 0.4 units
      (30% improvement over baseline) and/or will result in a increase of EPCs (CD133+/KDR+) and
      CD45dim CD34+/KDR.

      The investigators will test this hypothesis by comparing 2 groups of T2DM patients randomized
      to placebo or vitamin D3 for 16 weeks.

      Methods:

      This is a 16 weeks trial in which 120 T2DM patients will be screened with the aim to recruit
      60 T2DM patients with vitamin D deficiency or insufficiency. Out of these 60 patients , 30
      patients will be started on vitamin D supplementation and 30 patients will be given a matched
      placebo. Endothelial function (EF) will be checked before and after supplementation to see a
      change in EF.

      Significance of Project:

      If this study shows a significant improvement of EF, it would justify larger scale studies to
      show that vitamin D supplementation in patients with T2DM mitigates CVD risk and vitamin D
      supplementation in patients with T2DM and vitamin D deficiency to improve CVD risk.
    

Detailed description: 
      Overall Aims: Type 2 Diabetes Mellitus (T2DM) is increasingly more prevalent in Singapore and
      is a high cardiovascular diseases (CVD) risk factor (1,2). The presence of low serum 25(OH)D
      concentrations (<30ng/ml) has also been classified as an independent predictor of CVD(3,4)
      and has been seen to be more prevalent in T2DM (5-7). We aim to see whether replacement with
      vitamin D in these patients helps to mitigate CVD risk. Since endothelial dysfunction is one
      of the earliest manifestations of CVD and is a very robust surrogate marker, we aim to
      measure the endothelial function (EF) before and after vitamin D supplementation to evaluate
      for beneficial impact on this endpoint.

      Specific Aims: Although, there are some small scale studies done with a single high dose
      replacement of vitamin D2/D3, no studies have been done using regular daily supplementation
      with vitamin D3 and with measurement of EF using the Endo-PAT machine or measurement of
      endothelial progenitor cells (EPCs).We are doing this pilot study to see whether replacement
      with vitamin D results in an improvement of EF as measured using the Endo-PAT and estimation
      of EPCs and some biomarkers as independent established surrogate markers of CVD risk. The
      estimation of endothelial progenitor cells has been proposed as a surrogate marker of
      vascular dysfunction and is known to be reduced in patients with cardiovascular risk factors
      (8). The no. of circulating endothelial cells (CECs) and endothelial microparticles have been
      seen to be elevated in patients with cardiovascular risk factors and DM and has also been
      proposed as a effective surrogate marker. We aim to quantify the no. of endothelial
      progenitor cells (EPCs) staining positive for CD133+/KDR (kinase insert domain-containing
      receptor),CD34+/KDR and CD45dim CD34+/KDR , CECs (CD 146+/CD45- ) and EMPs derived from
      endothelial progenitors (CD45-/CD146+/CD34+/CD117+) and from mature endothelial cells
      (CD45-/CD146+/CD34+/CD117-).using flow cytometry.

      Primary Hypothesis:

      Vitamin D supplementation in patients with T2DM and low serum 25(OH) D concentrations
      (<30ng/ml) will improve EF as measured by the Endo-PAT machine by 0.4 units (30% improvement
      over baseline) and/or will result in a increase of EPCs (CD133+/KDR+) and CD45dim CD34+/KDR.
      The investigators will test this hypothesis by comparing 2 groups of T2DM patients randomized
      to placebo or vitamin D3 for 16 weeks.

      Secondary Objectives:

      To explore the prevalence of low serum 25(OH) D concentrations (<30ng/ml) in T2DM patients
      and evaluate the difference in the EF in the two groups. To see whether vitamin D
      supplementation helps to further improve other parameters such as biomarkers, blood pressure,
      BMI, urine albumin-to-creatinine ratio (ACR), lipid profile of T2DM patients.
    

Intervention name(s): Vitamin D supplementation; Placebo Pill
Intervention type(s): Drug; Drug
Intervention description(s): Vitamin D3 marketed by oneNine57; Placebo pill supplied by oneNine 57 imported to Singapore with approval and import licence from HSA.
Other intervention name(s): Vitamin D3-Cholecalciferol 1000units per tablet.; Placebo
Intervention MeSH terms: Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: 25(OH)Vitamin D; Diabetes mellitus; Endothelial Function