<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03010683</url>
  </required_header>
  <id_info>
    <org_study_id>GLP1-DM-ATTIKON</org_study_id>
    <nct_id>NCT03010683</nct_id>
  </id_info>
  <brief_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</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Athens</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Athens</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Arterial stiffness is associated with increased risk for cardiovascular disease. Moreover,&#xD;
      the integrity of endothelial glycocalyx plays a vital role in vascular permeability,&#xD;
      inflammation and elasticity. Agonists of Glucagon like peptide - 1 receptors (GLP-1R) used in&#xD;
      the treatment of type 2 diabetes mellitus (T2DM). This category includes exenatide and&#xD;
      liraglutide. These drugs lower glucose levels by inhibiting the secretion of glucagon,&#xD;
      promoting the release of insulin in response to hyperglycemia, slowing gastric emptying, and&#xD;
      augmenting satiety. Clinical studies have shown that GLP-1R agonists have beneficial effects&#xD;
      on cardiovascular function in both diabetic patients and healthy subjects. The purpose of&#xD;
      this study is to investigate in patients with T2DM without coronary artery disease (CAD),&#xD;
      patients with T2DM and CAD and obese patients with abnormal oral glucose tolerance test&#xD;
      (OGTT), changes in arterial stiffness, endothelial glycocalyx thickness and coronary reserve&#xD;
      flow (CFR) after treatment with metformin or agonist GLP-1R.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators will study three groups matched for age and sex: 30 patients with type 2&#xD;
      diabetes mellitus (T2DM) without coronary artery disease (CAD), 30 patients with T2DM and CAD&#xD;
      and 30 obese patients (BMI &gt;30 Kg/m²) with abnormal oral glucose tolerance test (OGTT). It&#xD;
      will be a randomized study with metformin or GLP-1R agonist treatment for 1 year. All&#xD;
      subjects will receive for 1 year: (a) GLP-1R agonist or (b) metformin. At 0, 3, 6 and 12&#xD;
      months, where 0 is the starting point of treatment, blood samples will be collected.&#xD;
&#xD;
      At 0, 3, 6 and 12 months the investigators will measure:&#xD;
&#xD;
        1. Carotid-femoral pulse wave velocity (PWV, m/sec) using tonometry by Complior (SP ALAM)&#xD;
           and augmentation index (AI, %) by the method of arteriography (Arteriograph, TensioMed)&#xD;
&#xD;
        2. Perfused boundary region (PBR, micrometers) of the sublingual arterial microvessels&#xD;
           (ranged from 5-25 micrometers) using Sideview Darkfield imaging (Microscan, Glycocheck).&#xD;
           Increased PBR is considered an accurate non invasive index of reduced endothelial&#xD;
           glucocalyx thickness.&#xD;
&#xD;
        3. Coronary flow reserve (CFR) in the left anterior descending artery after infusion of&#xD;
           adenosine using Doppler echocardiography.&#xD;
&#xD;
        4. Determination of the following parameters in blood: glucose, insulin, free fatty acids,&#xD;
           triglycerides, glycerol, C reactive protein (CRP), transforming growth factor-b (TGF-b),&#xD;
           Lipoprotein-Associated Phospholipase A2 (LP-LPA2), tumor necrosis factor-a (TNF-a),&#xD;
           interleukins 6 and 10 (IL6 and IL10), propeptide of type I procollagen (PIP), propeptide&#xD;
           of procollagen type III (PIIINP), matrix metallopeptidases 9 and 2 (MMP),&#xD;
           macrophage-colony stimulating factor (MCSF), growth differentiation factor-15 (GDF-15),&#xD;
           N-terminal pro b-type natriuretic peptide (NT-proBNP) and galectin-3.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2015</start_date>
  <completion_date type="Actual">December 2017</completion_date>
  <primary_completion_date type="Actual">June 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</measure>
    <time_frame>Baseline, 3 months, 6 months and 12 months</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</measure>
    <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
    <description>Differences in augmentation index (AI, %) using oscillometry at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Differences in Coronary Flow Reserve at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</measure>
    <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</measure>
    <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
    <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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Endothelial Glycocalyx and Pulse Wave Velocity.</measure>
    <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endothelial Glycocalyx and Coronary Flow Reserve.</measure>
    <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
    <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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Type 2 Diabetes Mellitus</condition>
  <condition>Coronary Artery Disease</condition>
  <arm_group>
    <arm_group_label>liraglutide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Metformin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Liraglutide</intervention_name>
    <description>Stimulation of Glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8mg once daily as a subcutaneous injection</description>
    <arm_group_label>liraglutide</arm_group_label>
    <other_name>Victoza (liraglutide)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Antidiabetic drug-biguanide class (Glucophage) 1000mg twice daily per os</description>
    <arm_group_label>Metformin</arm_group_label>
    <other_name>Glucophage (Metformin)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with type 2 diabetes mellitus (T2DM) without coronary artery disease (CAD)&#xD;
&#xD;
          -  Patients with T2DM and CAD.&#xD;
&#xD;
          -  Obese patients (BMI &gt;30 Kg/m²) with abnormal oral glucose tolerance test (OGTT)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  valvular heart disease&#xD;
&#xD;
          -  congestive heart failure&#xD;
&#xD;
          -  peripheral vascular disease&#xD;
&#xD;
          -  liver or kidney failure&#xD;
&#xD;
          -  history of alcohol or drug abuse&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ignatios Ikonomidis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>2nd Cardiology Department, University of Athens, Greece</affiliation>
  </overall_official>
  <overall_official>
    <last_name>George Pavlidis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>2nd Cardiology Department, University of Athens, Greece</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Vaia Lambadiari, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>2nd Department of Internal Medicine, University of Athens, Greece</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Fotini Kousathana, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>2nd Department of Internal Medicine, University of Athens, Greece</affiliation>
  </overall_official>
  <overall_official>
    <last_name>George Dimitriadis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>2nd Department of Internal Medicine, University of Athens, Greece</affiliation>
  </overall_official>
  <overall_official>
    <last_name>John Lekakis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>2nd Cardiology Department, University of Athens, Greece</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>''Attikon'' University General Hospital</name>
      <address>
        <city>Athens</city>
        <state>Attiki</state>
        <zip>12462</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Greece</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <results_first_submitted>November 3, 2020</results_first_submitted>
  <results_first_submitted_qc>March 3, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">March 5, 2021</results_first_posted>
  <last_update_submitted>March 3, 2021</last_update_submitted>
  <last_update_submitted_qc>March 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Athens</investigator_affiliation>
    <investigator_full_name>Ignatios Ikonomidis</investigator_full_name>
    <investigator_title>Associate Professor in Cardiology</investigator_title>
  </responsible_party>
  <keyword>Arterial stiffness</keyword>
  <keyword>Endothelial glycocalyx</keyword>
  <keyword>Coronary flow reserve</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Liraglutide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 22, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/83/NCT03010683/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Liraglutide</title>
          <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
        </group>
        <group group_id="P2">
          <title>Metformin</title>
          <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
                <participants group_id="P2" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
                <participants group_id="P2" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Liraglutide</title>
          <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
        </group>
        <group group_id="B2">
          <title>Metformin</title>
          <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
            <count group_id="B2" value="30"/>
            <count group_id="B3" value="60"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Greeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Pulse Wave Velocity</title>
          <units>m/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11.8" spread="2.5"/>
                    <measurement group_id="B2" value="11.2" spread="3"/>
                    <measurement group_id="B3" value="11.5" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</title>
        <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.</description>
        <time_frame>Baseline, 3 months, 6 months and 12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Liraglutide</title>
            <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
          </group>
          <group group_id="O2">
            <title>Metformin</title>
            <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
          </group>
        </group_list>
        <measure>
          <title>Differences in Pulse Wave Velocity at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</title>
          <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.</description>
          <units>m/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.8" spread="2.5"/>
                    <measurement group_id="O2" value="11.2" spread="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.6" spread="2.8"/>
                    <measurement group_id="O2" value="11.5" spread="2.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.3" spread="3.3"/>
                    <measurement group_id="O2" value="11" spread="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.5" spread="1.9"/>
                    <measurement group_id="O2" value="10.8" spread="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</title>
        <description>Differences in augmentation index (AI, %) using oscillometry at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.</description>
        <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Liraglutide</title>
            <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
          </group>
          <group group_id="O2">
            <title>Metformin</title>
            <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
          </group>
        </group_list>
        <measure>
          <title>Differences in Augmentation Index at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</title>
          <description>Differences in augmentation index (AI, %) using oscillometry at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.</description>
          <units>percentage of the central pulse pressure</units>
          <param>Mean</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18" lower_limit="-1" upper_limit="31"/>
                    <measurement group_id="O2" value="14" lower_limit="-9" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.8" lower_limit="-2" upper_limit="29"/>
                    <measurement group_id="O2" value="13.6" lower_limit="-6" upper_limit="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13" lower_limit="-2" upper_limit="31"/>
                    <measurement group_id="O2" value="15" lower_limit="-8" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.9" lower_limit="-1" upper_limit="32"/>
                    <measurement group_id="O2" value="15.3" lower_limit="-6" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Differences in Coronary Flow Reserve at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</title>
        <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.</description>
        <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
        <population>The investigators did not measure coronary flow reserve (CFR).</population>
        <group_list>
          <group group_id="O1">
            <title>Liraglutide</title>
            <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
          </group>
          <group group_id="O2">
            <title>Metformin</title>
            <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
          </group>
        </group_list>
        <measure>
          <title>Differences in Coronary Flow Reserve at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</title>
          <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.</description>
          <population>The investigators did not measure coronary flow reserve (CFR).</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</title>
        <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.</description>
        <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Liraglutide</title>
            <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
          </group>
          <group group_id="O2">
            <title>Metformin</title>
            <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
          </group>
        </group_list>
        <measure>
          <title>Differences in Endothelial Glycocalyx Thickness at Baseline and 3, 6 and 12 Months After Treatment With Metformin or Agonist GLP-1R.</title>
          <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.</description>
          <units>micrometers</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.1" spread="0.29"/>
                    <measurement group_id="O2" value="2.13" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.07" spread="0.3"/>
                    <measurement group_id="O2" value="2.15" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.5" spread="0.2"/>
                    <measurement group_id="O2" value="2.13" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.04" spread="0.2"/>
                    <measurement group_id="O2" value="2.10" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Endothelial Glycocalyx and Pulse Wave Velocity.</title>
        <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.</description>
        <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Liraglutide</title>
            <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
          </group>
          <group group_id="O2">
            <title>Metformin</title>
            <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
          </group>
        </group_list>
        <measure>
          <title>Endothelial Glycocalyx and Pulse Wave Velocity.</title>
          <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.</description>
          <units>Pearson correlation coefficient (r)</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.39"/>
                    <measurement group_id="O2" value="0.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.36"/>
                    <measurement group_id="O2" value="0.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.32"/>
                    <measurement group_id="O2" value="0.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.44"/>
                    <measurement group_id="O2" value="0.37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Endothelial Glycocalyx and Coronary Flow Reserve.</title>
        <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.</description>
        <time_frame>Baseline, 3 months, 6 months, and 12 months.</time_frame>
        <population>The investigators did not estimate the association between endothelial glycocalyx thickness and coronary flow reserve (CFR) because they did not measure the CFR.</population>
        <group_list>
          <group group_id="O1">
            <title>Liraglutide</title>
            <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
          </group>
          <group group_id="O2">
            <title>Metformin</title>
            <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
          </group>
        </group_list>
        <measure>
          <title>Endothelial Glycocalyx and Coronary Flow Reserve.</title>
          <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.</description>
          <population>The investigators did not estimate the association between endothelial glycocalyx thickness and coronary flow reserve (CFR) because they did not measure the CFR.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Liraglutide</title>
          <description>Stimulation of glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8 mg once daily as a subcutaneous injection</description>
        </group>
        <group group_id="E2">
          <title>Metformin</title>
          <description>Antidiabetic drug - biguanide class (Glucophage) 1000 mg twice daily per os</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>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. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Οur study has a modest number of subjects. Additional large scale studies are needed to expand our results.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr Ignatios Ikonomidis</name_or_title>
      <organization>2nd Cardiology Department, National and Kapodistrian University of Athens, Attikon Hospital</organization>
      <phone>+30 6944805732</phone>
      <email>ignoik@gmail.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03010683
org study id: GLP1-DM-ATTIKON
nct id: NCT03010683
lead sponsor: 
has dmc: Yes
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:

        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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Investigator)
measure: Differences in Pulse Wave Velocity 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
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.
measure: Differences in Augmentation Index 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.
description: Differences in augmentation index (AI, %) using oscillometry at baseline and 3, 6 and 12 months after treatment with metformin or agonist GLP-1R.
measure: Differences in Coronary Flow Reserve 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.
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.
measure: Differences in Endothelial Glycocalyx Thickness 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.
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.
measure: Endothelial Glycocalyx and Pulse Wave Velocity.
time frame: Baseline, 3 months, 6 months, and 12 months.
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.
measure: Endothelial Glycocalyx and Coronary Flow Reserve.
time frame: Baseline, 3 months, 6 months, and 12 months.
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.
arm group label: liraglutide
arm group type: Active Comparator
arm group label: Metformin
arm group type: Active Comparator
intervention type: Drug
intervention name: Liraglutide
description: Stimulation of Glucagon like peptide-1 receptor by liraglutide (Victoza) 1.8mg once daily as a subcutaneous injection
arm group label: liraglutide
other name: Victoza (liraglutide)
intervention type: Drug
intervention name: Metformin
description: Antidiabetic drug-biguanide class (Glucophage) 1000mg twice daily per os
arm group label: Metformin
other name: Glucophage (Metformin)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ignatios Ikonomidis, MD
role: Principal Investigator
affiliation: 2nd Cardiology Department, University of Athens, Greece
last name: George Pavlidis, MD
role: Principal Investigator
affiliation: 2nd Cardiology Department, University of Athens, Greece
last name: Vaia Lambadiari, MD
role: Principal Investigator
affiliation: 2nd Department of Internal Medicine, University of Athens, Greece
last name: Fotini Kousathana, MD
role: Principal Investigator
affiliation: 2nd Department of Internal Medicine, University of Athens, Greece
last name: George Dimitriadis, MD
role: Principal Investigator
affiliation: 2nd Department of Internal Medicine, University of Athens, Greece
last name: John Lekakis, MD
role: Principal Investigator
affiliation: 2nd Cardiology Department, University of Athens, Greece
facility: 
country: Greece
responsible party type: Principal Investigator
investigator affiliation: University of Athens
investigator full name: Ignatios Ikonomidis
investigator title: Associate Professor in Cardiology
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Metformin
mesh term: Liraglutide
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Οur study has a modest number of subjects. Additional large scale studies are needed to expand our results.
point of contact: 