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

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.

Inclusion criteria

• Diabetes Mellitus type 2
• HbA1c ≥ 5.5% and ≤ 7.0%
• Treatment with Metformin (daily dose 500 - 3000 mg monotherapy, the past 3 months)
• Age 30 - 65 years

Exclusion criteria

• Pre-treatment with PPAR gamma agonists or DPP IV inhibitors or GLP-1 analogues within the last three months
• History of type 1 Diabetes Mellitus
• No full legal mental and physical ability to give informed consent
• Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg)
• Anamnestic acute and chronic infections
• Inflammatory bowel disease and/or diabetic gastroparesis
• Anamnestic history of epilepsy
• Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures
• History of severe or multiple allergies
• Treatment with any other investigational drug within 3 months before trial entry
• Progressive fatal disease
• History of drug or alcohol abuse in the past 2 years
• Liver disease with ASAT or ALAT above 3 times the upper normal limit
• Serum potassium > 5.5 mmol/L
• Moderate to Severe Kidney disease with a GFR ≤ 60 ml/min
• Pregnancy or breast feeding
• Sexually active woman of childbearing potential not practicing a highly effective method of birth control as defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, hormonal IUDs, sexual abstinence or vasectomised partner
• Have had more than one unexplained episode of severe hypoglycaemia (defined as requiring assistance of another person due to disabling hypoglycaemia) within 6 months prior to screening visit
• History of dehydration, diabetic precoma, diabetic ketoacidosis or diabetic gastroparesis
• Acute (within the previous 2 days) or scheduled investigation with iodine containing radiopaque material
• Acute myocardial infarction, open heart surgery or cerebral event (stroke/TIA) within the previous 6 months
• Anamnestic uncontrolled unstable angina pectoris, pericarditis, myocarditis, endocarditis, haemodynamic relevant aortic stenosis, aortic aneurysma or heart insufficiency NYHA III or IV
• Anamnestic recent pulmonary embolism or pulmonary insufficiency
• Smoking within the last 6 months (> 1 cigarette/day)
• Planned change in antidiabetic, lipid lowering or blood pressure medication