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

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 (n = 18) or without (n = 28) 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, we determined 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 CD34(+) CD133(+) progenitor cells (placebo subtracted effect 40.4 +/- 18.7/10(6); P = .036), CD34(+) KDR+ EPCs (placebo subtracted effect 22.1 +/- 10.2/10(6); P = .036), and CX(3)CR1(bright) monocytes (placebo subtracted effect 1.7 +/- 0.8%; P = .032). Linagliptin abated DPP-4 activity by greater than 50%, significantly increased active glucagon-like peptide-1 and stromal cell-derived factor-1 alpha, and reduced monocytechemotactic protein-1, CCL22, and IL-12. Patients with CKD, as compared with those without, had lower baseline CD133(+) and CD34(+) CD133(+) cells and had borderline reduced CD34(+) and CD34(+) KDR+ 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.