92-LB: Linagliptin Improves CD34+ Progenitor Cells and Urine Exosomes

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. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Cellular mechanisms of DPP-4 inhibitors such as Linagliptin (LG) on CVD risk in patients with type 2 diabetes with established CKD has not been established.

Hypothesis: Linagliptin, a DPP-4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD)

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 DM subjects (30-70 years old), A1c 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 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.