Comparison Between Linagliptin and Canagliflozin Effect on Inflammatory Markers, CD34+ Cell Gene Expression and Urine Exosomes in Type 2 Diabetes Subjects

Introduction: Peripheral blood derived CD34 +ve Endothelial progenitor cells (EPCs) has been shown to help vascular regeneration and are dysfunctional in subjects with type 2 diabetes mellitus (T2DM) leading to poor endothelial cell function (ECF). We conducted two separate clinical trials using Canagliflozin, an SGLT2 inhibitor and Linagliptin, a DPP4 inhibitor where these medications or matched placebo was added to other oral antidiabetic medication such Metformin and Insulin. Our goal was to do a comparative analysis based on the effect of the medications on CD34+ve hematopoetic progenitor cell function such as migration, colony formation and podocyte specific urine exosome analysis. Methods: Approximately 30 subjects were enrolled in the two studies 29 subjects were enrolled in this 12–16 weeks, double-blind, two-arm, randomized placebo matched trial, with 100 mg Canagliflozin (Cana, low dose) compared to placebo AND Linagliptin (Lina 5mg), compared to placebo. T2DM (30–70 years old), HbA1c of 7–10%, were included. Peripheral blood derived CD34+ cell number, migratory function, mRNA gene expression along with cardiometabolic parameters such as arterial stiffness, biochemistry, resting energy expenditure, and body composition were measured. Data were collected at weeks 0 (baseline), 6 or 8 (mid-point), and 12 or 16 (final). A mixed model regression analysis was done with a p-value <0.05 considered significant. Results: We found a statistically significant reduction in systolic (p=0.008) and diastolic (p=0.038) blood pressure in cana group. There was a statistically significant increase in adiponectin (p=0.0062) and trend level reduction in IL6 (p=0.16), indicating an anti-inflammatory effect of canagliflozin on endothelium, not seen in Lina group. There was an increase in mRNA expression of genes associated with endothelial function in CD34+ cells such as VEGFA, PECAM-1, a mature endothelial marker and NOS3 (or eNOS) with both Cana and Lina. There was improvement in CD34+ numbers by direct counting (not statistically significant) with both medications. Data on urine podocyte specific exosomal protein indicates an advantage with Cana compared to Lina, though it did not reach stat significance. Conclusions: Our study indicates that Canagliflozin improves several components of vascular function by improving adiponectin, reducing inflammatory cytokines, and by increasing expression of endothelium specific genes in CD34+ progenitor cells compared to Linagliptin.