Abstract
BackgroundEndothelial 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.MethodsThis 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.ResultsA 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 CGConclusionLow dose Canagliflozin has a beneficial effect on CD34+ cell function, serum biochemistry and urinary podocyte specific exosomes in type 2 diabetes.
Highlights
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
In our previous studies using two di-peptylpeptidase inhibitors (DPP4i) such as saxagliptin and linagliptin in type 2 diabetes mellitus (T2DM) patients [43, 44] we have demonstrated that CD34+ve cells are responsive to a change in therapy or intervention within 2–4 weeks using CD34+ as a biomarker and CD34+ cell based assays can be used as a reliable non serum based cellular bio-marker
Our non cellular outcome measures were focused on parameters that are agreed to be indicators of endothelial function such as arterial stiffness, serum inflammatory markers and markers of renal podocyte health. In this 16-week intervention study we investigated the synergistic effect of canagliflozin, a SGLT2 inhibitor and metformin, on number and function of CD34+ve EPCs while adjusting for variables that may affect stem cell number and function such as hemoglobin A1c (HbA1C), body mass index (BMI), gender and age
Summary
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. Use of a sodiumglucose linked transporter inhibitor (SGLT-2i) has shown promise in improving glycemic control, weight reduction, hypertension and even changes in circulating renin– angiotensin–aldosterone system (RAAS) and nitric oxide (NO) [5, 6]. Whether these group of drugs have any effect on cardiovascular disease (CVD) risk modification or on endothelial cell or endothelial progenitor cells, is unclear. It is extremely important to evaluate improvement, especially cardiovascular and endothelial health of the patient after administration of diabetic drugs
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