Effects of the DPP-4 inhibitor linagliptin on renal endothelial function in type-2 diabetes

Background: Animal and human studies indicate increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in type-2 diabetes. The exaggerated NO production, compensatory to the increased oxidative stress in diabetes, lead to early hemodynamic changes characterized by hyperfiltration, hyperperfusion and increased vascular permeability.

Methods: In this randomized, double-blind, investigator-initiated trial, 62 patients (57 ± 9.3 years) with type-2 diabetes were randomly assigned to linagliptin 10 mg (n = 30) or placebo (n = 32) for a 6 weeks treatment period. Endothelial function of the renal vasculature was assessed by constant-infusion input-clearance technique with p-aminohippurate and inulin, as well as urinary albumin creatinine ratio (UACR), both assessed before and after blockade of NOS with systemic infusion of N ^G-monomethyl-L-arginine (L-NMMA).

Results: Renal plasma flow (RPF) and glomerular filtration rate (GFR) did not change after linagliptin and placebo, without any difference between the groups. The absolute [percental] change in RPF due to L-NMMA (primary objective), was lower (-46.8 ± 34 [-7.61 ± 5.3] ml/min [%] than in the placebo group (-65.1 ± 36 [-10.4 ± 5.6] ml/min [%], p = 0.045 (0.046)), indicating a lower basal NO activity after treatment with linagliptin. Consistently, after 6 weeks of treatment UACR due to L-NMMA did not clearly change in linagliptin group (22.2 (11.6 – 40.3) versus 28.2 (16.5 – 50.3)mg/g, p = 0.061), but increased significantly in the placebo group (13.5 (8.6 – 25.9) versus 20.9 (15.9 – 33.5)mg/g, p < 0.001), pointing to upregulation of NO activity in the untreated placebo group.

Conclusion: Thus, our data suggest that linagliptin normalizes increased renal endothelial function, and hence NOS-dependency of vascular tone, in patients with type-2 diabetes.