Clinical trial NCT03010683: 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
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes Mellitus
Coronary Artery Disease
Keywords: Arterial stiffness
Endothelial glycocalyx
Coronary flow reserve
Lead sponsor: University of Athens
Sponsor class: OTHER
First posted: 2017-01-05
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
timeFrame: Baseline, 3 months, 6 months and 12 months
measure: Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
timeFrame: Baseline, 3 months, 6 months, and 12 months.
measure: Differences in Coronary Flow Reserve at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
timeFrame: Baseline, 3 months, 6 months, and 12 months.
measure: Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
timeFrame: Baseline, 3 months, 6 months, and 12 months.
Secondary outcomes:
measure: Endothelial Glycocalyx and Pulse Wave Velocity.
timeFrame: Baseline, 3 months, 6 months, and 12 months.
measure: Endothelial Glycocalyx and Coronary Flow Reserve.
timeFrame: Baseline, 3 months, 6 months, and 12 months.
Other outcomes:
Locations:
city: Athens
country: Greece
facility: ''Attikon'' University General Hospital
state: Attiki
Study officials:
affiliation: 2nd Cardiology Department, University of Athens, Greece
name: Ignatios Ikonomidis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: 2nd Cardiology Department, University of Athens, Greece
name: George Pavlidis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: 2nd Department of Internal Medicine, University of Athens, Greece
name: Vaia Lambadiari, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: 2nd Department of Internal Medicine, University of Athens, Greece
name: Fotini Kousathana, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: 2nd Department of Internal Medicine, University of Athens, Greece
name: George Dimitriadis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: 2nd Cardiology Department, University of Athens, Greece
name: John Lekakis, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gnesin F, Thuesen ACB, Kahler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Jun 5;6(6):CD012906. doi: 10.1002/14651858.CD012906.pub2.
citation: Lambadiari V, Pavlidis G, Kousathana F, Varoudi M, Vlastos D, Maratou E, Georgiou D, Andreadou I, Parissis J, Triantafyllidi H, Lekakis J, Iliodromitis E, Dimitriadis G, Ikonomidis I. Effects of 6-month treatment with the glucagon like peptide-1 analogue liraglutide on arterial stiffness, left ventricular myocardial deformation and oxidative stress in subjects with newly diagnosed type 2 diabetes. Cardiovasc Diabetol. 2018 Jan 8;17(1):8. doi: 10.1186/s12933-017-0646-z.