Effect of Saxagliptin on EPCs as a Cellular Biomarker for Evaluating Endothelial Dysfunction in Early T2DM Patients
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      Type 2 diabetes is a national epidemic. Diabetes has undesirable effects on blood vessels
      which may contribute to heart disease. Endothelial Progenitor Cells(EPCs) are found in the
      blood . Research has shown that improving the survival of these special blood cells may
      decrease the harmful effects of diabetes on blood vessels and reduce or reverse heart
      disease. Saxagliptin is an FDA(Food and Drug Administration) approved prescription medicine
      used along with diet and exercise to lower blood sugar in people with Type 2 diabetes. It is
      in a class of diabetes medication called DPP-4 inhibitors. DPP-4 inhibitors have been shown
      to increase EPCs in patients with Type 2 diabetes.

      Hypothesis: We believe poor viability and function of EPCs in early diabetes ultimately
      affects the repair and regeneration of the endothelium and that prompt intervention using
      saxagliptin with another oral hypoglycemic agent, Metformin, may reduce or reverse
      cardiovascular risk by improving EPC survival and function above and beyond adequate glucose
      metabolism control.
    

Detailed description: 
      Type 2 diabetes is a national epidemic 1,2 with significant macro and microvascular
      complications. Insulin resistance in prediabetes and early and late diabetes are associated
      with endothelial dysfunction.

      A few studies indicate that EPCs can act as a suitable bio-marker for monitoring
      cardiovascular morbidity. In this proposal we suggest that EPCs or CD34 positive cells can
      act as a suitable cellular biomarker for estimating and following endothelial dysfunction in
      early type 2 diabetes patients.

      EPCs have been used as a regenerative tool in ischemic myocardium and diabetic wound healing.
      Endothelial dysfunction with associated inflammation may be a consequence of excess
      super-oxide presence in a setting of diabetes which is a pro-oxidative stress condition
      causing EPC dysfunction and senescence. Therefore monitoring EPC number, function and gene
      expression may serve as a very useful cellular bio-marker for cardiovascular complications in
      early type 2 diabetes.

      Though lifestyle modification has been proposed as a main stay for prevention and treatment
      of early type 2 diabetes, several new therapies for diabetes have been developed in recent
      years. Incretins and incretin mimetics appear to hold promise. Oral DPP-4 inhibitors have
      been shown to increase EPCs in patients with type 2 diabetes reportedly via SDF-1 alpha
      up-regulation. Interestingly, up-regulation of SDF-1 alpha and vascular endothelial growth
      factor (VEGF), both chemotactic factors increase mobilization and recruitment of EPCs in the
      face of acute ischemic injury for repair and regeneration.

      Several studies have shown positive effect of incretins (Glucagon like peptide, GLP-1) and
      incretin receptor agonists (GLP-1 receptor agonists) on cardiovascular risk factors in type 2
      diabetes patients and even in patients with chronic heart failure and left ventricular
      dysfunction who do not have diabetes.

      DPP-4 Inhibitors may have cardio-protective effects of their own, as they increase
      bio-availability of endogenous GLP-1. They improve blood flow and nitric oxide production in
      endothelium. These are unique properties not demonstrated by other oral diabetes medications.
      The mechanism underlying these effects may be mediated by increased nitric oxide
      bioavailability but is not completely known. It is possible that Saxagliptin, a member of
      DPP-4 inhibitor group of drugs may be able to improve number and function of CD34+
      endothelial progenitor cells by up-regulating chemotactic agent SDF1 alpha (DPP-4 degrades
      SDF-1) and its receptor CXCR47, 20, 21, 30, 31.

      Poor viability and function of EPCs in early diabetes may ultimately affect the repair and
      regeneration of the endothelium and prompt intervention may reduce or reverse cardiovascular
      risk by improving EPC survival and function above and beyond adequate glucose metabolism
      control.

      Therefore we would like to explore the effect of saxagliptin in addition to lifestyle
      intervention, on number and function and gene expression of EPC and impact on endothelial
      dysfunction in type 2 diabetes.
    

Intervention name(s): Saxagliptin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 5 mg tablet once daily for 12 weeks; 1 tablet daily for 12 weeks
Other intervention name(s): Onglyza
Intervention MeSH terms: Saxagliptin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: endothelial cells; cellular biomarker; endothelial dysfunction