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

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 (SGLT2i) such as Canagliflozin (CG) on a cellular biomarker such as CD34+ve progenitor cells, which may help predict CVD risk, in patients with T2DM with established CKD has not been explored. This is a pilot study where 29 subjects taking metformin and/or Insulin were enrolled in a 16 week, double blind, randomized placebo matched trial, with a low dose 100 mg CG as the intervention group compared to matched placebo. Type 2 diabetes subjects (30-70 years old), with hemoglobin A1c (HbA1c) of 7-10%, were enrolled. CD34+ve cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, serum biochemistry pertaining to cardio-metabolic health, resting energy expenditure and body composition were measured. Data were collected at week 0, 8 and 16. A mixed model regression analysis was done and p value less than 0.05 was considered statistically significant. A significant expression of CXCR4 receptor with a concomittant increase in migratory function of CD34+ve cells was observed in CG treated group as compared to placebo group. Gene expression analysis of CD34+ve cells showed an increase in expression of antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and notable endothelial markers (PECAM1, VEGF-A, and NOS3). A significant reduction in glucose and HbA1c levels were observed along with improved systolic and diastolic blood pressure in the CG group. A significant increase in adiponectin (p = 0.006) was also noted in treatment group. Urinary exosomal protein leak in urine, examining podocyte health (podocalyxin, Wilm's tumor and nephrin) showed reduction with CG CONCLUSION: Low dose Canagliflozin has a beneficial effect on CD34+ cell function, serum biochemistry and urinary podocyte specific exosomes in type 2 diabetes.