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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

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ClinicalTrials.gov Identifier: NCT03010683
Recruitment Status : Recruiting
First Posted : January 5, 2017
Last Update Posted : January 9, 2017
Sponsor:
Information provided by (Responsible Party):
Ignatios Ikonomidis, University of Athens

Brief 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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Coronary Artery Disease Drug: Liraglutide Drug: Metformin Not Applicable

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : November 2015
Estimated Primary Completion Date : June 2017
Estimated Study Completion Date : December 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: liraglutide Drug: Liraglutide
Stimulation of Glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8mg once daily as a subcutaneous injection
Other Name: Victoza (liraglutide)

Active Comparator: Metformin Drug: Metformin
Antidiabetic drug-biguanide class (Glucophage) 1000mg twice daily per os
Other Name: Glucophage (Metformin)




Primary Outcome Measures :
  1. Differences in pulse wave velocity at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R. [ Time Frame: Baseline, 3 months, 6 months and 12 months ]
    Differences in carotid-femoral pulse wave velocity (PWV, m/sec) using tonometry at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.

  2. Differences in augmentation index at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R. [ Time Frame: Baseline, 3 months, 6 months, and 12 months. ]
    Differences in augmentation index (AI, %) using oscillometry at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.

  3. Differences in coronary flow reserve at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R. [ Time Frame: Baseline, 3 months, 6 months, and 12 months. ]
    Differences in coronary flow reserve (CFR) using Doppler echocardiography at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.

  4. Differences in endothelial glycocalyx thickness at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R. [ Time Frame: Baseline, 3 months, 6 months, and 12 months. ]
    Differences in endothelial glycocalyx thickness as assessed by perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R. High PBR values represent reduced glycocalyx thickness.


Secondary Outcome Measures :
  1. Endothelial glycocalyx and pulse wave velocity. [ Time Frame: Baseline, 3 months, 6 months, and 12 months. ]
    Association of endothelial glycocalyx thickness as assessed by perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels with pulse wave velocity (PWV, m/sec) at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.

  2. Endothelial glycocalyx and coronary flow reserve. [ Time Frame: Baseline, 3 months, 6 months, and 12 months. ]
    Association of endothelial glycocalyx thickness as assessed by perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels with coronary flow reserve (CFR) using Doppler echocardiography at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patients with type 2 diabetes mellitus (T2DM) without coronary artery disease (CAD)
  • Patients with T2DM and CAD.
  • Obese patients (BMI >30 Kg/m²) with abnormal oral glucose tolerance test (OGTT)

Exclusion Criteria:

  • valvular heart disease
  • congestive heart failure
  • peripheral vascular disease
  • liver or kidney failure
  • history of alcohol or drug abuse

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03010683


Contacts
Contact: Ignatios Ikonomidis, MD 00302105831264 ignoik@otenet.gr
Contact: John Lekakis, MD 00302105831264 lekakisster@gmail.com

Locations
Greece
''Attikon'' University General Hospital Recruiting
Haidari, Athens, Attiki, Greece, 12462
Principal Investigator: Ignatios Ikonomidis, MD         
Sponsors and Collaborators
University of Athens
Investigators
Principal Investigator: Ignatios Ikonomidis, MD 2nd Cardiology Department, University of Athens, Greece
Principal Investigator: George Pavlidis, MD 2nd Cardiology Department, University of Athens, Greece
Principal Investigator: Vaia Lambadiari, MD 2nd Department of Internal Medicine, University of Athens, Greece
Principal Investigator: Fotini Kousathana, MD 2nd Department of Internal Medicine, University of Athens, Greece
Principal Investigator: George Dimitriadis, MD 2nd Department of Internal Medicine, University of Athens, Greece
Principal Investigator: John Lekakis, MD 2nd Cardiology Department, University of Athens, Greece

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Ignatios Ikonomidis, Associate Professor in Cardiology, University of Athens
ClinicalTrials.gov Identifier: NCT03010683     History of Changes
Other Study ID Numbers: GLP1-DM-ATTIKON
First Posted: January 5, 2017    Key Record Dates
Last Update Posted: January 9, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Ignatios Ikonomidis, University of Athens:
Arterial stiffness
Endothelial glycocalyx
Coronary flow reserve

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Metformin
Liraglutide
Glucagon-Like Peptide 1
Glucagon
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Gastrointestinal Agents