Linagliptin, when compared to placebo, improves CD34+ve Endothelial Progenitor Cells in Type 2 diabetes subjects with chronic kidney disease taking metformin and/or insulin, a randomized controlled trial.

Abstract

Introduction: Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both Type 2 Diabetes 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. Cellular mechanisms of DPP4 inhibitors such as Linagliptin (LG) on CVD risk, in patients with Type 2 Diabetes with established CKD has notbeen established. Hypothesis : Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD) population. Methods : 31 subjects taking metformin and/or Insulin were enrolled in this 12 weeks, double blind, randomized placebo matched trial, with 5 mg LG compared to placebo. Type 2 diabetes subjects (30-70 years old), HbA1c of 6.5-10%, CKD Stage 1-3 were included. 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, 6 and 12. A mixed model regression analysis was done with p value <0.05 considered significant. Results : A double positive CD34/CD184 cell count had a statistically significant increase (p<0.02) as determined by flow cytometry in LG group where CD184 is SDF1a cell surface receptor. Though mRNA differences in CD34+ve was more pronounced CD34- cell mRNA analysis showed increase in antioxidants (SOD2, Catalase and CPX) and prominent endothelial markers (PECAM1, VEGF-A, vWF and NOS3). Arterial stiffness measures such as augmentation Index (AI) (p<0.04) and pulse wave analysis (PWV) were improved (reduced in stiffness) in LG group. A reduction in LDL: HDL ratio was noted in treatment group (p <0.04). Urinary exosome protein examining podocyte health (Podocalxyin, Wilms tumor and Nephrin) showed reduction or improvement. Conclusions : In DKD subjects, Linagliptin promotes an increase in CXCR4 expression on CD34+ progenitor cells with a concomitant improvement in vascular and renal parameters at 12 weeks

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

“…Our recent study using Linagliptin showed protection from renal injury with patients taking Linagliptin for a duration of 12 weeks [44]. However the difference between Linagliptin and placebo was not picked up by urine albumin: creatine ratio but was noted on assessing urinary exosome podocyte markers.…”

“…Arterial stiffness assays also help define endothelial function independent of serum assays but corelates well to standard biochemical assays that are used to define endothelial function [41,42]. 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. The same is true for of a prediabetes population with an aerobic exercise intervention, where changes in gene expression are quite fast [29].…”