Effect of Sitagliptin on Endothelial Progenitor Cells

Study Overview
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Brief Summary
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Endothelial progenitor cells (EPCs) are involved in cardiovascular homeostasis, through angiogenesis and endothelial healing. Diabetic patients have a high risk of cardiovascular events and low levels of circulating EPCs. Sitagliptin is an oral DPP-IV antagonist, approved for the treatment of type 2 diabetes. It increases the bioavailability of endogenous incretins, thus improving insulin and glucagon secretion. SDF-1, one of the major EPC regulators, is also a substrate of DPP-IV. This study tests the hypothesis that sitagliptin increases the levels of circulating EPCs in type 2 diabetic patients.

Detailed Description
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Diabetic patients suffer an elevated wirk of cardiovascular events, which strongly impact on morbidity and mortality. The mechanisms that lead to cardiovascular disease in diabetes include alterations in the endothelial layer, due to hyperglycemia, oxidative stress and other associated abnormalities. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in endothelial repair after injury, and they have been found to be reduced in diabetic patients. Thus, reduced EPCs in diabetes may be another mechanism of vascular disease induction. Reduction of EPCs in diabetes is attributable at least in part to the impairment of bone marrow mobilization, which is regulated by the chemokine SDF-1alpha, among others. The oral hypoglycemia agent sitagliptin is a dipeptidyl dipeptidase-IV inhibitor, which prevents degradation of endogenous incretins (GIP and GLP-1), thus re-equilibrating insulin and glucagon secretion. Sitagliptin may also increase the concentrations of SDF-1alpha, which is another substrate of DPP-IV. The hypothesis is that sitagliptin may increase circulating EPC levels, through SDF-alpha. This is going to be a pilot, non-randomized controlled 4-week trial of 100 mg oral sitagliptin therapy added to metformin/sulphonylureas in poorly controlled type 2 diabetic patients. At baseline and 4 weeks after the initiation of therapy blood samples will be drawn for the determination of circulating EPC levels, and concentrations of SDF-1alpha. EPCs will be defined as CD34+KDR+ cells and measured by flow cytometry as previously described in detail. SDF-1alpha will be measured using ELISA kits according to the manufacturer's instructions. Changes between baseline and 4 weeks will be evaluated using two-tailed paired Student's t test and statistical significance accepted at p<0.05.

Official Title
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Effects of 4-week Sitagliptin Therapy on Endothelial Progenitor Cells in Type 2 Diabetic Patients. A Non-randomized Controlled Open-label Pilot Trial.

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sitagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes; Both genders Age 40-80 fasting c-peptide >=1.0 ng/L Therapy with metformin or sulphonylureas HbA1c >7.0% No contraindications to sitagliptin use Exclusion Criteria: Type 1 diabetes Age <40 or >80 fasting c-peptide <1.0 ng/L Therapy with TZD HbA1c <=7.0% Acute concomitant diseases Immunological disorders Recent (within 3 months) cardiovascular events or surgery Pregnancy and lactation Inability to provide informed consent

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Sitagliptin 100 mg once daily for 4 weeks | Drug: Sitagliptin<br>* 100 mg once daily for 4 weeks<br>* Other names: Januvia; Xelevia; Tesavel;|
| No Intervention: Control<br>No change in anti-diabetic treatment regimen for at least 4 weeks. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in circulating CD34+KDR+ endothelial progenitor cells |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in SDF-1alpha concentrations |  | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes, endothelium, stem cells