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

• Sponsor: University of Athens (Other)
• Overall Status: Completed
• CT.gov ID: NCT03010683
• Collaborator: (none)
• Enrollment: 60
• Location: 1
• Arms: 2
• Duration (Months): 25
• Patients Per Site Per Month: 2.4

Study Details

Study Description

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	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 60 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: Nov 1, 2015
• Actual Primary Completion Date: Jun 1, 2017
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

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

Outcome Measures

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. [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. [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. [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. [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. [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. [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	''Attikon'' University General Hospital	Athens	Attiki	Greece	12462

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 22, 2016

More Information

Publications

None provided.

• Responsible Party: Ignatios Ikonomidis, Associate Professor in Cardiology, University of Athens
• ClinicalTrials.gov Identifier: NCT03010683
• Other Study ID Numbers: GLP1-DM-ATTIKON
• First Posted: Jan 5, 2017
• Last Update Posted: Mar 5, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Ignatios Ikonomidis, Associate Professor in Cardiology, University of Athens: Arterial stiffness; Endothelial glycocalyx; Coronary flow reserve
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Liraglutide

Study Results

Participant Flow

Arm/Group Title	Liraglutide	Metformin
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection	Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os
Period Title: Overall Study
STARTED	30	30
COMPLETED	30	30
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Liraglutide	Metformin	Total
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection	Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os	Total of all reporting groups
Overall Participants	30	30	60
Age (Count of Participants)
<=18 years	3 10%	3 10%	6 10%
Between 18 and 65 years	20 66.7%	20 66.7%	40 66.7%
>=65 years	7 23.3%	7 23.3%	14 23.3%
Sex: Female, Male (Count of Participants)
Female	10 33.3%	10 33.3%	20 33.3%
Male	20 66.7%	20 66.7%	40 66.7%
Race/Ethnicity, Customized (participants) [Number]
Greeks	30 100%	30 100%	60 100%
Pulse Wave Velocity (m/s) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m/s]	11.8 (2.5)	11.2 (3)	11.5 (2.8)

Outcome Measures

1. Primary Outcome

Title	Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
Description	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.
Time Frame	Baseline, 3 months, 6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Liraglutide	Metformin
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection	Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os
Measure Participants	30	30
Baseline	11.8 (2.5)	11.2 (3)
3 months	11.6 (2.8)	11.5 (2.7)
6 months	10.3 (3.3)	11 (3)
12 months	10.5 (1.9)	10.8 (2)

2. Primary Outcome

Title	Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
Description	Differences in augmentation index (AI, %) using oscillometry 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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Liraglutide	Metformin
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection	Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os
Measure Participants	30	30
Baseline	18	14
3 months	15.8	13.6
6 months	13	15
12 months	13.9	15.3

3. Primary Outcome

Title	Differences in Coronary Flow Reserve at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
Description	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.
Time Frame	Baseline, 3 months, 6 months, and 12 months.

Outcome Measure Data

Analysis Population Description

The investigators did not measure coronary flow reserve (CFR).

Arm/Group Title	Liraglutide	Metformin
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection	Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os
Measure Participants	0	0

4. Primary Outcome

Title	Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
Description	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.
Time Frame	Baseline, 3 months, 6 months, and 12 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Liraglutide	Metformin
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection	Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os
Measure Participants	30	30
Baseline	2.1 (0.29)	2.13 (0.3)
3 months	2.07 (0.3)	2.15 (0.3)
6 months	2.5 (0.2)	2.13 (0.3)
12 months	2.04 (0.2)	2.10 (0.3)

5. Secondary Outcome

Title	Endothelial Glycocalyx and Pulse Wave Velocity.
Description	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.
Time Frame	Baseline, 3 months, 6 months, and 12 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Liraglutide	Metformin
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection	Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os
Measure Participants	30	30
Baseline	0.39	0.35
3 months	0.36	0.32
6 months	0.32	0.29
12 months	0.44	0.37

6. Secondary Outcome

Title	Endothelial Glycocalyx and Coronary Flow Reserve.
Description	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.
Time Frame	Baseline, 3 months, 6 months, and 12 months.

Outcome Measure Data

Analysis Population Description

The investigators did not estimate the association between endothelial glycocalyx thickness and coronary flow reserve (CFR) because they did not measure the CFR.

Arm/Group Title	Liraglutide	Metformin
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection	Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os
Measure Participants	0	0

Adverse Events

Time Frame	12 months
Arm/Group Title	Liraglutide		Metformin
Arm/Group Description	Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection		Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os
All Cause Mortality
	Liraglutide		Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Serious Adverse Events
	Liraglutide		Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Liraglutide		Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)

Limitations/Caveats

Οur study has a modest number of subjects. Additional large scale studies are needed to expand our results.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.