Acute effects of linagliptin on progenitor cells, monocyte phenotypes, and soluble mediators in type 2 diabetes

Abstract

Context: Circulating cells, incluDing endothelial progenitor cells (EPCs) and monocyte subtypes, are involved in diabetic complications. Modulation of these cells may mediate additional benefits of glucose-lowering medications. Objective: We assessed whether the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin acutely modifies EPCs and monocyte subsets in patients with type 2 diabetes. Design: This was a randomized, crossover, placebo-controlled trial. Setting: The study was conducted at a tertiary referral diabetes outpatient clinic. Patients: Forty-six type 2 diabetes patients with (n18) or without (n28) chronic kidney disease (CKD) participated in the study. Intervention: Intervention included a 4-day treatment with linagliptin 5mg or placebo during two arms separated by a 2-week washout. Main Outcome Measures: Before and after each treatment,wedetermined the levels of circulating progenitor cells (CD34, CD133, KDR) and monocyte subtypes (CD14/CD16, chemokine and scavenger receptors) and the concentrations of soluble mediators. Results: Compared with placebo, linagliptin increased CD34CD133 progenitor cells (placebo subtracted effect 40.4 α 18.7/106; P .036), CD34KDR EPCs (placebo subtracted effect 22.1 α 10.2/106; P .036), and CX3CR1bright monocytes (placebo subtracted effect 1.7 α 0.8%; P .032). Linagliptin abated DPP-4 activity by greater than 50%, significantly increased active glucagon-like peptide-1andstromal cell-derived factor-1,andreducedmonocytechemotactic protein-1, CCL22, and IL-12. Patients with CKD, as compared with those without, had lower baseline CD133 and CD34CD133 cells and had borderline reduced CD34 and CD34KDR cells. The effects of linagliptin on progenitor cells and monocyte subtypes were similar in patients with or without CKD. Fasting plasma glucose, triglycerides and free fatty acids were unaffected. Conclusions: DPP-4 inhibition with linagliptin acutely increases putative vasculoregenerative and antiinflammatory cells. Direct effects of DPP-4 inhibition may be important to lower vascular risk in diabetes, especially in the presence of CKD.