Coronary Artery Disease, Type 2 Diabetes Mellitus
Conditions
Keywords
Arterial stiffness, Endothelial glycocalyx, Coronary flow reserve
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.
Interventions
DRUGLiraglutide
Stimulation of Glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8mg once daily as a subcutaneous injection
DRUGMetformin
Antidiabetic drug-biguanide class (Glucophage) 1000mg twice daily per os
Sponsors
University of Athens
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
Greece
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection | 30 |
| Metformin Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os | 30 |
| Total | 60 |
Baseline characteristics
| Characteristic | Liraglutide | Metformin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Categorical >=65 years | 7 Participants | 7 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 20 Participants | 40 Participants |
| Pulse Wave Velocity | 11.8 m/s STANDARD_DEVIATION 2.5 | 11.2 m/s STANDARD_DEVIATION 3 | 11.5 m/s STANDARD_DEVIATION 2.8 |
| Race/Ethnicity, Customized Greeks | 30 participants | 30 participants | 60 participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Male | 20 Participants | 20 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 0 / 30 | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Liraglutide | Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | Baseline | 18 percentage of the central pulse pressure |
| Liraglutide | Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 3 months | 15.8 percentage of the central pulse pressure |
| Liraglutide | Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 6 months | 13 percentage of the central pulse pressure |
| Liraglutide | Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 12 months | 13.9 percentage of the central pulse pressure |
| Metformin | Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 12 months | 15.3 percentage of the central pulse pressure |
| Metformin | Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | Baseline | 14 percentage of the central pulse pressure |
| Metformin | Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 6 months | 15 percentage of the central pulse pressure |
| Metformin | Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 3 months | 13.6 percentage of the central pulse pressure |
Primary
Differences in Coronary Flow Reserve at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
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.
Population: The investigators did not measure coronary flow reserve (CFR).
Primary
Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | Baseline | 2.1 micrometers | Standard Deviation 0.29 |
| Liraglutide | Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 3 months | 2.07 micrometers | Standard Deviation 0.3 |
| Liraglutide | Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 6 months | 2.5 micrometers | Standard Deviation 0.2 |
| Liraglutide | Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 12 months | 2.04 micrometers | Standard Deviation 0.2 |
| Metformin | Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 12 months | 2.10 micrometers | Standard Deviation 0.3 |
| Metformin | Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | Baseline | 2.13 micrometers | Standard Deviation 0.3 |
| Metformin | Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 6 months | 2.13 micrometers | Standard Deviation 0.3 |
| Metformin | Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 3 months | 2.15 micrometers | Standard Deviation 0.3 |
Primary
Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | Baseline | 11.8 m/s | Standard Deviation 2.5 |
| Liraglutide | Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 3 months | 11.6 m/s | Standard Deviation 2.8 |
| Liraglutide | Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 6 months | 10.3 m/s | Standard Deviation 3.3 |
| Liraglutide | Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 12 months | 10.5 m/s | Standard Deviation 1.9 |
| Metformin | Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 12 months | 10.8 m/s | Standard Deviation 2 |
| Metformin | Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | Baseline | 11.2 m/s | Standard Deviation 3 |
| Metformin | Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 6 months | 11 m/s | Standard Deviation 3 |
| Metformin | Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R. | 3 months | 11.5 m/s | Standard Deviation 2.7 |
Secondary
Endothelial Glycocalyx and Coronary Flow Reserve.
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.
Population: The investigators did not estimate the association between endothelial glycocalyx thickness and coronary flow reserve (CFR) because they did not measure the CFR.
Secondary
Endothelial Glycocalyx and Pulse Wave Velocity.
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Endothelial Glycocalyx and Pulse Wave Velocity. | 3 months | 0.36 Pearson correlation coefficient (r) |
| Liraglutide | Endothelial Glycocalyx and Pulse Wave Velocity. | Baseline | 0.39 Pearson correlation coefficient (r) |
| Liraglutide | Endothelial Glycocalyx and Pulse Wave Velocity. | 6 months | 0.32 Pearson correlation coefficient (r) |
| Liraglutide | Endothelial Glycocalyx and Pulse Wave Velocity. | 12 months | 0.44 Pearson correlation coefficient (r) |
| Metformin | Endothelial Glycocalyx and Pulse Wave Velocity. | 12 months | 0.37 Pearson correlation coefficient (r) |
| Metformin | Endothelial Glycocalyx and Pulse Wave Velocity. | Baseline | 0.35 Pearson correlation coefficient (r) |
| Metformin | Endothelial Glycocalyx and Pulse Wave Velocity. | 3 months | 0.32 Pearson correlation coefficient (r) |
| Metformin | Endothelial Glycocalyx and Pulse Wave Velocity. | 6 months | 0.29 Pearson correlation coefficient (r) |