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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.
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| liraglutide | Active Comparator |
| |
| Metformin | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Liraglutide | Drug | Stimulation of Glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8mg once daily as a subcutaneous injection |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline, 3 months, 6 months and 12 months |
| 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. | Baseline, 3 months, 6 months, and 12 months. |
| 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. | Baseline, 3 months, 6 months, and 12 months. |
| 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. | Baseline, 3 months, 6 months, and 12 months. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline, 3 months, 6 months, and 12 months. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ''Attikon'' University General Hospital | Athens | Attica | 12462 | Greece |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32501595 | Derived | 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. | |
| 29310645 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Liraglutide | Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection |
| FG001 | Metformin | Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 22, 2016 |
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| Metformin | Drug | Antidiabetic drug-biguanide class (Glucophage) 1000mg twice daily per os |
|
|
| 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. | Baseline, 3 months, 6 months, and 12 months. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Liraglutide | Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection |
| BG001 | Metformin | Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Race/Ethnicity, Customized | Number | participants |
| ||||||||||||||||||
| Pulse Wave Velocity | Mean | Standard Deviation | m/s |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Deviation | m/s | Baseline, 3 months, 6 months and 12 months |
|
|
| ||||||||||||||||||||||||||||||||||||
| 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. | Posted | Mean | Inter-Quartile Range | percentage of the central pulse pressure | Baseline, 3 months, 6 months, and 12 months. |
|
| |||||||||||||||||||||||||||||||||||||
| 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. | The investigators did not measure coronary flow reserve (CFR). | Posted | Baseline, 3 months, 6 months, and 12 months. |
|
| |||||||||||||||||||||||||||||||||||||||
| 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. | Posted | Mean | Standard Deviation | micrometers | Baseline, 3 months, 6 months, and 12 months. |
|
| |||||||||||||||||||||||||||||||||||||
| 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. | Posted | Number | Pearson correlation coefficient (r) | Baseline, 3 months, 6 months, and 12 months. |
|
| ||||||||||||||||||||||||||||||||||||||
| 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. | The investigators did not estimate the association between endothelial glycocalyx thickness and coronary flow reserve (CFR) because they did not measure the CFR. | Posted | Baseline, 3 months, 6 months, and 12 months. |
|
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12 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Liraglutide | Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection | 0 | 30 | 0 | 30 | 0 | 30 |
| EG001 | Metformin | Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os | 0 | 30 | 0 | 30 | 0 | 30 |
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Οur study has a modest number of subjects. Additional large scale studies are needed to expand our results.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Ignatios Ikonomidis | 2nd Cardiology Department, National and Kapodistrian University of Athens, Attikon Hospital | +30 6944805732 | ignoik@gmail.com |
| Jan 24, 2021 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D003324 | Coronary Artery Disease |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D003327 | Coronary Disease |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D000069450 | Liraglutide |
| D008687 | Metformin |
| ID | Term |
|---|---|
| D052216 | Glucagon-Like Peptide 1 |
| D004763 | Glucagon-Like Peptides |
| D052336 | Proglucagon |
| D005768 | Gastrointestinal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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| >=65 years |
|
| Male |
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| 6 months |
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| 12 months |
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