Effects of Agonists of Glucagon Like Peptide - 1 Receptors (GLP-1R) on Arterial Stiffness, Endothelial Glycocalyx and Coronary Flow Reserve in Patients With Coronary Artery Disease and Patients With Diabetes Mellitus
Condition: Type 2 Diabetes Mellitus; Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      Arterial stiffness is associated with increased risk for cardiovascular disease. Moreover,
      the integrity of endothelial glycocalyx plays a vital role in vascular permeability,
      inflammation and elasticity. Agonists of Glucagon like peptide - 1 receptors (GLP-1R) used in
      the treatment of type 2 diabetes mellitus (T2DM). This category includes exenatide and
      liraglutide. These drugs lower glucose levels by inhibiting the secretion of glucagon,
      promoting the release of insulin in response to hyperglycemia, slowing gastric emptying, and
      augmenting satiety. Clinical studies have shown that GLP-1R agonists have beneficial effects
      on cardiovascular function in both diabetic patients and healthy subjects. The purpose of
      this study is to investigate in patients with T2DM without coronary artery disease (CAD),
      patients with T2DM and CAD and obese patients with abnormal oral glucose tolerance test
      (OGTT), changes in arterial stiffness, endothelial glycocalyx thickness and coronary reserve
      flow (CFR) after treatment with metformin or agonist GLP-1R.
    

Detailed description: 
      The investigators will study three groups matched for age and sex: 30 patients with type 2
      diabetes mellitus (T2DM) without coronary artery disease (CAD), 30 patients with T2DM and CAD
      and 30 obese patients (BMI >30 Kg/m²) with abnormal oral glucose tolerance test (OGTT). It
      will be a randomized study with metformin or GLP-1R agonist treatment for 1 year. All
      subjects will receive for 1 year: (a) GLP-1R agonist or (b) metformin. At 0, 3, 6 and 12
      months, where 0 is the starting point of treatment, blood samples will be collected.

      At 0, 3, 6 and 12 months the investigators will measure:

        1. Carotid-femoral pulse wave velocity (PWV, m/sec) using tonometry by Complior (SP ALAM)
           and augmentation index (AI, %) by the method of arteriography (Arteriograph, TensioMed)

        2. Perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels
           (ranged from 5-25 micrometers) using Sideview Darkfield imaging (Microscan, Glycocheck).
           Increased PBR is considered an accurate non invasive index of reduced endothelial
           glucocalyx thickness.

        3. Coronary flow reserve (CFR) in the left anterior descending artery after infusion of
           adenosine using Doppler echocardiography.

        4. Determination of the following parameters in blood: glucose, insulin, free fatty acids,
           triglycerides, glycerol, C reactive protein (CRP), transforming growth factor-b (TGF-b),
           Lipoprotein-Associated Phospholipase A2 (LP-LPA2), tumor necrosis factor-a (TNF-a),
           interleukins 6 and 10 (IL6 and IL10), propeptide of type I procollagen (PIP), propeptide
           of procollagen type III (PIIINP), matrix metallopeptidases 9 and 2 (MMP),
           macrophage-colony stimulating factor (MCSF), growth differentiation factor-15 (GDF-15),
           N-terminal pro b-type natriuretic peptide (NT-proBNP) and galectin-3.
    

Intervention name(s): Liraglutide; Metformin
Intervention type(s): Drug; Drug
Intervention description(s): Stimulation of Glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8mg once daily as a subcutaneous injection; Antidiabetic drug-biguanide class (Glucophage) 1000mg twice daily per os
Other intervention name(s): Victoza (liraglutide); Glucophage (Metformin)
Intervention MeSH terms: Metformin; Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Arterial stiffness; Endothelial glycocalyx; Coronary flow reserve