Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial

Abstract

Aims/hypothesis Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature. Methods In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion inputclearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS withResults Treatment with linagliptin for 4 weeks reduced fasting, postprandial blood glucose and HbA 1c , although not significantly; no change occurred with placebo. Renal plasma flow (RPF) did not change after linagliptin or placebo. After 4 weeks the absolute change in RPF due to L-NMMA was smaller in the linagliptin group than in the placebo group (−46.8 ± 34 vs −65.1 ± 36 ml/min, p = 0.045), indicating a lower basal NO activity after treatment with linagliptin. Consistently, the response of UACR to L-NMMA increased in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), pointing to an upregulation of NO activity in the placebo group. No clinically meaningful safety concerns were evident. Conclusions/interpretation Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes. Trial registration: ClinicalTrials.gov NCT01835678 Funding: This study was funded by Boehringer Ingelheim.

The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

“…A mechanistic, parallel-group, randomized clinical study in 62 patients with early type 2 diabetes suggested that 4 weeks of treatment with linagliptin prevented impairment of renal endothelial function, as measured by changes in basal renal endothelial nitric oxide activity [153]. The glomerular hyperfiltration that characterizes early diabetic nephropathy is associated with increased basal nitric oxide activity [154,155].…”

A review of dipeptidyl peptidase‐4 inhibitors. Hot topics from randomized controlled trials

“…Thus, in studies in overweight patients with T2DM and normal renal function, 12 weeks treatment with the DPP-4 inhibitor DEACON sitagliptin (or the GLP-1 agonist liraglutide) had no effect on renal haemodynamic variables or GFR compared to placebo, 60 while neither renal plasma flow nor GFR was affected by 4 weeks treatment with linagliptin. 61 A similar lack of effect on GFR was also noted in MARLINA-T2D, a 24-week study specifically designed to evaluate any renal effects of DPP-4 inhibition with linagliptin compared to placebo in individuals at early stages of DKD. 62 Moreover, there was no impact of sitagliptin 40 or vildagliptin 42 on GFR, even when renal function was already moderately/severely impaired.…”

“…Data from clinical studies investigating whether DPP‐4 inhibitors alter the progression of diabetic nephropathy damage are still relatively sparse, but where it has been measured, GFR appears not to be altered. Thus, in studies in overweight patients with T2DM and normal renal function, 12 weeks treatment with the DPP‐4 inhibitor sitagliptin (or the GLP‐1 agonist liraglutide) had no effect on renal haemodynamic variables or GFR compared to placebo, while neither renal plasma flow nor GFR was affected by 4 weeks treatment with linagliptin . A similar lack of effect on GFR was also noted in MARLINA‐T2D, a 24‐week study specifically designed to evaluate any renal effects of DPP‐4 inhibition with linagliptin compared to placebo in individuals at early stages of DKD .…”

A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes

“…No difference in the effect on glycaemic control was seen between the treatment groups. Similarly, linagliptin was shown to normalise increased renal endothelial function after 6 weeks’ treatment in a randomised placebo-controlled trial in 62 patients with T2D [37]. Most recently, a randomised placebo-controlled, parallel-group study found that 12 weeks of treatment with linagliptin had no effect on macrovascular function, as measured by flow-mediated vasodilation and nitroglycerin-mediated vasodilation, but exhibited a trend towards improving microvascular function [38].…”