Impact of Liraglutide on Endothelial Function and Microvascular Blood Flow in Type 2 Diabetes Mellitus

Overview

The trial is a phase IV clinical trial investigating the impact of Liraglutide on endothelial function and microvascular blood flow in 44 patients with type 2 diabetes mellitus aged 30-65 and HbA1c ranging from ≥ 5.5% ≤ 7.0%. The patients will be randomized into two study arms, one arm will be treated with Metformin monotherapy, the second arm will be treated with Metformin and Liraglutide at an increasing dose (0.6 mg/day to 1.8 mg/day.)

Type 2 Diabetes Mellitus (DM) is associated with increased cardiovascular risk and the majority of type 2 diabetic patients die due to the vascular complications of Diabetes Mellitus. In type 2 diabetic patients, an early marker in the biogenesis of atherosclerosis and cardiovascular disease is the occurrence of endothelial dysfunction with subsequent deterioration in micro- and macrovascular blood flow and tissue supply. Also several mechanistic pathways linking Diabetes Mellitus with endothelial dysfunction and cardiovascular complications are postulated. Recent studies aimed to investigate the vasoprotective effect of strict glycaemic control using conventional treatment algorithms failed to reduce cardiovascular risk in patients with Diabetes Mellitus type 2. Numerous pharmacological drugs are available to reduce blood glucose levels in type 2 diabetic patients. Beside comparable glucose lowering efficacy, some of them evolve limited or even adverse effects on vascular function and cardiovascular risk. Therefore, ideally new treatments in Diabetes Mellitus type 2 provide more than just reducing blood glucose values. Future treatments in type 2 Diabetes Mellitus will be judged on their potency to affect the cardiovascular risk profile in patients with Diabetes Mellitus type 2. Liraglutide is a Glucagon-like peptide-1 (GLP-1) analogue shown to be effective in the treatment of type 2 Diabetes Mellitus. Liraglutide was shown to improve blood glucose levels not only by stimulating insulin secretion from the β cell, but also by improving the conversion of intact proinsulin into insulin and C-peptide in the granula of the β cell. While in rodents, GLP-1 and its analogues showed an increase in β cell regeneration and an inhibitory effect on β cell apoptosis, the effect of GLP-1 analogues on β cell mass in humans is less clear. Beyond its effects on β cells, Liraglutide and other GLP1 analogues were shown to suppress the glucagon release from α cells and to evolve a supportive effect on weight reduction by central and probably peripheral effects. Beside these effects of GLP-1-analogues on β cell physiology and glucose metabolism, recent studies suggested several pleiotrophic effects of GLP-1 treatment which go beyond glycaemic control. Receptors for GLP-1 have been located in myocardial and endothelial cells, and GLP-1 supplementation was found to improve myocardial and endothelial function in diabetic and in non-diabetic subjects. In endothelial cells, isolated from human coronary arteries, GLP-1 rapidly activates endothelial nitric oxide synthase (eNOS) and stimulates nitric oxide (NO) production, promotes cell proliferation and inhibits glucolipoapoptosis. In addition, in transformed vascular endothelial cells, GLP-1 protects endothelial dysfunction incurred by tumor necrosis factor-α (TNF-α) through the modulation of the expression of vascular adhesion molecules and plasminogen activator inhibitor-1 (PAI-1). Chronic administration of GLP-1 analogues is associated with a significant reduction in blood pressure. Therefore it seems conceivable, that in patients with Diabetes Mellitus type 2, treatment with the GLP-1 analog Liraglutide might improve the cardiovascular risk profile beyond glucose control by stimulating endothelial NO release and by improving endothelial function. The goal of our study is to investigate the vascular and endothelial effects of adding Liraglutide treatment to type 2 diabetic patients previously treated with Metformin.

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Outcomes