Effect of Sitagliptin on Endothelial Progenitor Cells

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.

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