Linagliptin's Effect on CD34+ Stem Cells
Condition: Type 2 Diabetes; Impaired Renal Function
MeSH terms: Renal Insufficiency; 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. Linagliptin is an Food and Drug Administration (FDA) approved prescription medicine
      used along with insulin or with oral medications to lower blood sugar in people with Type 2
      diabetes. It is in a class of diabetes medication called Dipeptidyl peptidase-4 (DPP-4)
      inhibitors. DPP-4 inhibitors have been shown to increase EPCs in patients with Type 2
      diabetes.

      Hypothesis: Both type 2 diabetes and Chronic Kidney Disease (CKD) are associated with poor
      stem cell number and function. Poor viability and function of EPCs in CKD and diabetes The
      investigators hypothesize that use of Linagliptin (along with Insulin) may help reduce
      cardiovascular risk by improving EPC survival and function above and beyond adequate glucose
      metabolism control
    

Detailed description: 
      Type 2 diabetes is a national epidemic with significant macro and microvascular
      complications. Insulin resistance in pre-diabetes and overt diabetes are associated with
      endothelial dysfunction.

      A few studies indicate that stem cells particularly EPCs can act as a suitable bio-marker for
      monitoring cardiovascular morbidity. In this proposal the investigators suggest that EPCs or
      CD34 positive cells (defined as CD34/vascular endothelial growth factor receptor 2 (VEGFR2+)
      cells) can act as a suitable cellular biomarker for estimating and following endothelial
      dysfunction in early type 2 diabetes patients with CKD. EPCs have been shown to be
      dysfunctional in both CKD patients and type 2 Diabetes Mellitus (DM) patients.

      Linagliptin (TRADJENTA) tablets are indicated as an adjunct to diet and exercise to improve
      glycemic control in adults with type 2 diabetes mellitus. No dose adjustment is recommended
      for patients with renal impairment.

      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
      intra-cellular super-oxide presence in a setting of diabetes which is a pro-oxidative stress
      condition ultimately leading to poor EPC function and senescence.

      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. Mechanism of positive effect
      of exercise and oral hypoglycemic agents can be very different.

      DPP-4 inhibitors have been shown to increase EPCs in patients with type 2 diabetes reportedly
      via stromal cell-derived factor 1 (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. However these beneficial effects appear to be
      independent of glycemia reduction.

      It is however unknown whether Linagliptin will have any positive effect on human EPC function
      where two prominent cardiovascular risk factors co-exist such as CKD and type 2 diabetes.

      Therefore the investigators plan to investigate if Linagliptin can alter function and gene
      expression of CD34+ cells in a setting of CKD and type 2 diabetes. The investigators choose
      to look at non geriatric adult population with early type 2 diabetes (less than 10 years of
      duration) at an early phase of renal impairment (stages 1-3).
    

Intervention name(s): Linagliptin; 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): TRADJENTA
Intervention MeSH terms: Linagliptin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diabetes Mellitus, Type 2; Endothelial cells; Cellular biomarker; endothelial dysfunction; CD34+; Impaired renal function