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

NCT ID: NCT03010683

Last Updated: 2021-03-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-11-30
• Study Completion Date: 2017-12-31

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.

Conditions

Type 2 Diabetes Mellitus; Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

liraglutide

Group Type: ACTIVE_COMPARATOR

Liraglutide

Intervention Type: DRUG

Stimulation of Glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8mg once daily as a subcutaneous injection

Metformin

Group Type: ACTIVE_COMPARATOR

Metformin

Intervention Type: DRUG

Antidiabetic drug-biguanide class (Glucophage) 1000mg twice daily per os

Interventions

Liraglutide

Stimulation of Glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8mg once daily as a subcutaneous injection

Intervention Type: DRUG

Metformin

Antidiabetic drug-biguanide class (Glucophage) 1000mg twice daily per os

Intervention Type: DRUG

Other Intervention Names

Victoza (liraglutide); Glucophage (Metformin)

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Athens

OTHER

Sponsor Role: lead

Responsible Party

Ignatios Ikonomidis

Associate Professor in Cardiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ignatios Ikonomidis, MD

Role: PRINCIPAL_INVESTIGATOR

2nd Cardiology Department, University of Athens, Greece

George Pavlidis, MD

Role: PRINCIPAL_INVESTIGATOR

2nd Cardiology Department, University of Athens, Greece

Vaia Lambadiari, MD

Role: PRINCIPAL_INVESTIGATOR

2nd Department of Internal Medicine, University of Athens, Greece

Fotini Kousathana, MD

Role: PRINCIPAL_INVESTIGATOR

2nd Department of Internal Medicine, University of Athens, Greece

George Dimitriadis, MD

Role: PRINCIPAL_INVESTIGATOR

2nd Department of Internal Medicine, University of Athens, Greece

John Lekakis, MD

Role: PRINCIPAL_INVESTIGATOR

2nd Cardiology Department, University of Athens, Greece

Locations

''Attikon'' University General Hospital

Athens, Attica, Greece

Countries

Greece

References

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.

Reference Type: DERIVED

PMID: 32501595 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29310645 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

GLP1-DM-ATTIKON

Identifier Type: -

Identifier Source: org_study_id