Role of Canagliflozin on function of CD34+ endothelial progenitor cells (EPC) in patients with type 2 diabetes

Abstract Background: Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Effect of sodium glucose channel inhibitors (SGLT2 inhibitors) such as Canagliflozin (CG) on a cellular CVD risk indicator such as CD34+ve cells, in patients with T2DM with established CKD has not been explored,Methods: 29 subjects taking metformin and/or Insulin were enrolled in a 16 weeks, double blind, randomized placebo matched trial, with a low dose 100 mg CG compared to placebo. Type 2 diabetes subjects (30–70 years old), HbA1c of 7–10%,. CD34+ cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 8 and 16. A mixed model regression analysis was done with p value less than 0.05 were considered significant.Results: Gene expression analysis of CD34+ve cells showed increase in antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX). A significant increase in gene expression of endothelial markers PECAM1 (p=0.002), VEGF-A(p= 0.04) and CXCR4 receptor (p= 0.06) followed by an increase in migratory function of CD34+ve cells is observed in Canagliflozin treated group as compared to placebo group. A significant reduction in glucose (p=0.01) levels was observed along with improved systolic and diastolic blood pressure in the CG group. Significant increase in adiponectin (p=0.02) was also noted in treatment group. Urinary exosomal protein examining podocyte health (podocalyxin, Wilm’s tumor and nephrin) showed improvement.Conclusion: We conclude that Canagliflozin on addition to metformin and/or Insulin, in subjects with type 2 diabetes demonstrates a functional improvement of CD34+ Endothelial Progenitor Cell function and gene expression and improves endothelial function