Favorable effect of linagliptin on renal endothelial functions in patients with type 2 diabetes mellitus

Introduction

Linagliptin is an oral antidiabetic drug that inhibits the enzyme dipeptidyl peptidase 4 (DPP-4) and thereby increases and prolongs the effect of incretin hormones, particularly glucagon-like peptide 1 (GLP-1 − glucagon-like peptide 1). Linagliptin penetrates tissues very well.

Results of in vitro studies and animal models

Administration of GLP-1 infusion led to the return of aortic tone to nearly normal values in a rat model of diabetes mellitus. In in vitro studies, it was shown that DPP-4 is expressed in endothelial cells, and its inhibition reduces microvascular tone through the influence of the nitric oxide (NO) system. In an animal model of diabetes, obese Zucker rats, administration of linagliptin increased vascular relaxation, and in hypertensive Dahl rats, administration of linagliptin improved vascular functions and diabetic nephropathy. Experiments on animal models and humans showed that in the early stages of type 2 diabetes, there is an increase in NO activity and the expression of endothelial NO synthase (NOS).

Study objectives

Increased albumin permeability through the glomerular filtration barrier indicates that a key pathogenetic mechanism in the early stages of diabetic nephropathy development is endothelial dysfunction. Therefore, an appropriate therapeutic approach would be early intervention to prevent structural kidney damage. The study aimed to determine whether administration of linagliptin to patients with type 2 diabetes in the early stages of the disease can improve vascular endothelial function in the kidneys.

Methodology

In a randomized double-blind study with a parallel group design, 62 patients with type 2 diabetes mellitus were assigned to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to evaluate endothelial function in the renal vessels by measuring clearance using constant inulin and p-aminohippurate (PAH) levels induced by continuous intravenous infusion and by determining the albumin/creatinine (ACR) ratio in urine before and after NOS inhibition with N^G-monomethyl-L-arginine (L-NMMA).

Results

Four-week administration of linagliptin reduced fasting and postprandial glycemia and HbA_1c levels, but the results were not statistically significant. In the placebo group, no changes were observed in these parameters. Renal plasma flow (RPF) did not change in either group. The absolute change in RPF induced by L-NMMA administration was smaller after 4 weeks of treatment in the linagliptin group than in the placebo group (−46.8 ± 34 vs. −65.1 ± 36 ml/min; p = 0.045), indicating that linagliptin treatment reduced basal NO activity. Similarly, the change in ACR in urine in response to L-NMMA administration was higher in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), indicating upregulation of NO activity in the placebo group.

Conclusion

In patients with type 2 diabetes mellitus, four-week administration of the DPP-4 inhibitor linagliptin prevented the worsening of hyperglycemia-induced endothelial dysfunction.

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Source: Ott C., Kistner I., Keller M. et al. Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial. Diabetologia 2016; 59 (12): 2579–2587.