The Effect of Exenatide Compared to Lantus Insulin on Vascular Function in Type 2 Diabetes
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      The main goals of the study are to evaluate the effect of Exenatide on endothelial-dependent
      vasodilation, as measured by flow mediated dilation (FMD), to evaluate the effect on
      endothelial-independent vasodilation, as measured by nitroglycerin (TNG) response, and to
      evaluate the effect on arterial stiffness, as measured by pulse wave analysis (PWA). We will
      also measure the effects on various markers of endothelial function, subclinical
      inflammation, fibrinolysis, and oxidative stress. The control group for the study will
      receive Lantus insulin, with a goal of similar glycemic control between the treatment and
      control groups.

      Specific Aims

      We will test the following hypotheses:

        1. Treatment of patients with type 2 diabetes who are inadequately controlled by
           monotherapy with a Sulfonylurea (SU) or Metformin, or on combination therapy of a SU and
           Metformin with Exenatide (GLP-1 mimetic) will result in improved endothelial dependent
           vasodilation, as measured by FMD, as compared to the control group, who will be treated
           with Lantus insulin to achieve comparable HbA1c levels.

        2. Treatment with Exenatide (GLP-1 mimetic) will result in improved arterial stiffness, as
           measured by AI by PWA, as compared to the control group, who will be treated with Lantus
           insulin to achieve comparable HbA1c levels.

        3. Endothelial dependent vasodilation, as measured by FMD, and arterial stiffness, as
           measured by AI, measured in the postprandial state (following a standard test meal) will
           be improved following treatment with Exenatide as compared to treatment with once daily
           basal insulin (Lantus).

        4. Treatment will result in no improvement in endothelial-independent vasodilation, as
           measured by a response to TNG, as compared to the control group, who will be treated
           with Lantus insulin to achieve comparable HbA1c levels.

        5. Treatment with Exenatide, compared with treatment with Lantus, will result in a
           reduction in various plasma markers of inflammation (CRP, TNFA, IL6), endothelial
           activation (ICAM, VCAM, endothelin 1), fibrinolysis (PAI-1 protein, PAI-1 activity), and
           oxidative stress (FOX2).
    

Detailed description: 
      The trial is a randomized, controlled, comparator study. Subjects and investigators will not
      be blinded due to the nature of the treatment. After providing informed consent and meeting
      the inclusion and exclusion criteria, subjects will undergo baseline studies then be
      randomized to either treatment with Exenatide or Lantus insulin to achieve comparable
      improvement in glycemic control, as measured by HbA1c. A computer program (randomization.com)
      will be utilized to randomize 72 patients to receive either Exenatide or Lantus. The
      treatment group will receive twice daily injections of Exenatide, initially of 5ug BID, and
      increased to 10ug BID after 1 month. The control group will receive daily injections of
      Lantus insulin each evening, which will be titrated to achieve blood glucose targets based on
      self monitoring of blood glucose (SMBG), as outlined by the American Diabetes Association
      (ADA) (goal: fasting 90-130, peak postprandial less than180 mg/dl). The subjects on Lantus
      should achieve this goal by week 6 of the study, so that they have six weeks of maximal
      therapy. The control group will receive Lantus with the goal of similar glycemic control
      between the groups, with a goal of HbA1c reduction of 0.5-1.5% after 3 months. Based on
      recent data, it should be feasible to accomplish similar improvements in glycemia between the
      groups.

      The trial will be preceded by a one-week screening and evaluation period, during which time
      the patient will be informed about the trial, and qualification will be determined based on
      the inclusion/exclusion criteria, as noted below. The patient will also be instructed in
      injection technique and SMBG techniques at the screening visit. Subjects will be asked to
      perform daily fasting blood glucose monitoring, and in addition on 2 days per week (1 weekday
      and 1 weekend day) to obtain 6 blood glucose measurements (fasting, 1-2hours post-breakfast,
      pre-lunch, 1-2 hours post-lunch, pre-dinner, and 1-2 hours post-dinner). Baseline studies
      will then be performed at week 0, including fasting laboratory studies, FMD, PWA, and Meal
      Challenge Test. The subject will then be randomized to receive treatment with either Lantus
      or Exenatide for 12 weeks duration. Repeat studies will then be performed at 12 weeks,
      including repeat of the baseline laboratory studies, FMD, PWA, and Meal Challenge test.

      Schedule/Flow Chart

      Visit 1 (week -1): Potential participants will be informed regarding the trial, records will
      be reviewed, and inclusion/exclusion criteria will be evaluated. Informed consent will be
      administered, and a history and physical will be performed. They will have baseline labs
      drawn, including HbA1c, glucose, lipids, CBC, chemistry, renal function, liver function, and
      urinalysis. If they are female and of reproductive age, they will also have a urine HCG
      performed. Subjects will be fasting for this visit.

      Visit 2 (week 0): Participants will come in fasting. Interval medical history and medications
      will be reviewed. Vital signs will be obtained. PWA and FMD will be performed. The patient
      will then have fasting labs drawn which will include glucose, insulin, c-peptide, lipids,
      free fatty acids (FFA), CRP, TNFA, IL-6, ICAM, VCAM, endothelin 1, PAI-1 protein, PAI-1
      activity, and FOX2. The patient will then have a mixed meal (time 0), and labs will again be
      drawn at 15, 30 minutes, 45 minutes, 60 minutes, 120 minutes, 180 minutes, and 240 minutes
      after the meal challenge measuring glucose, insulin, c-peptide, lipids, and FFA. At time 120
      minutes, FWA and FMD will be performed again along with blood samples for CRP, TNFA, IL-6,
      ICAM, VCAM, endothelin 1, PAI-1 protein, PAI-1 activity, and FOX2. At 240 minutes, PWA, FMD,
      and TNG will be performed.

      After completion of these tests, the patients will be randomized and start treatment with
      either Exenatide 5ug BID or nightly Lantus beginning the following day. Lantus dose will be
      based on clinical assessment, but starting doses will likely be between 10 and 20 units.
      Patients will be instructed in SMBG techniques, as well as injection techniques for either
      Byetta (Exenatide) or Lantus.

      Week 1: Telephone contact. Review side effects and blood glucoses (BGs), adjust Lantus if
      needed, and adjust oral hypoglycemic agents (OHA) in Exenatide treated group if clinically
      indicated.

      Week 2: Telephone contact. Review side effects and BGs, adjust Lantus if needed, and adjust
      OHA in Exenatide treated group if clinically indicated.

      Visit 3 (week 4): Patients will come in. Those in the Exenatide group will have the dose
      increased to 10ug sq BID. The patients in the Lantus group will have their fasting BGs
      reviewed and their dose adjusted. Side effects will be reviewed with all subjects. Subjects
      in the Exenatide treated group will have their OHA adjusted if clinically indicated.

      Week 6: Telephone contact. Review BGs and side effects, and adjust Lantus if needed. Lantus
      dose should be at/close to maximal dose to achieve target fasting blood glucose goal.
      Subjects in the Exenatide treated group will have their OHA adjusted if clinically indicated.

      Week 8: Telephone contact. Review side effects and BGs, adjust Lantus if needed, and adjust
      OHA in Exenatide treated group if clinically indicated.

      Week 10: Telephone contact. Review side effects and BGs, adjust Lantus if needed, and adjust
      OHA in Exenatide treated group if clinically indicated. At this time, we will discuss with
      the subjects if they are interested in continuing their study medication upon completion of
      the study. We will advise them to call their diabetes provider to then arrange for a
      prescription that will start upon study completion. We will advise them at the beginning of
      the study to set up a follow up appointment with their provider around the time of study
      completion. We will speak with their diabetes provider if the subject wishes us to do so.

      Visit 4 (week 12): Participants will come in fasting. If they are in the Exenatide group, we
      will ask them not to take their morning dose at home, but to bring it in with them so that it
      can be administered within 60 minutes of the meal tolerance test. Subjects will also be asked
      to return any unused study drug at this final visit. Interval medical history and medications
      will be reviewed. Vital signs will be obtained. PWA and FMD will be performed. The patient
      will then have fasting labs drawn which will include CBC, Chem 20, HbA1C, urinalysis,
      microalbumin, LFTs, glucose, insulin, c-peptide, lipids, FFA, CRP, TNFA, IL-6, ICAM, VCAM,
      endothelin 1, PAI-1 protein, PAI-1 activity, and FOX2. The subjects randomized to Exenatide
      will then take their morning dose, and all subjects will then have a mixed meal (time 0), and
      labs will again be drawn at 15, 30 minutes, 45 minutes, 60 minutes, 120 minutes, 180 minutes,
      and 240 minutes after the meal challenge measuring glucose, insulin, c-peptide, lipids, and
      FFA. At time 120 minutes, PWA and FMD will be performed again along with labs for CRP, TNFA,
      IL-6, ICAM, VCAM, endothelin 1, PAI-1 protein, PAI-1 activity, and FOX2. At 240 minutes, PWA,
      FMD, and TNG will be performed.

      Methods The Mixed Meal will consist of standard liquid meal, Boost, which is composed of
      61.5g of carbohydrate, 15g of protein, and 6g of fat, in 360ml, with 360 calories. The
      subjects will come in fasting. Starting at time 0, the Boost will be consumed over a five
      minute time period. The studies will then be performed on visits 2 and 4.

      Brachial artery flow mediated dilatation (FMD) evaluates endothelium-dependent reactivity in
      the macrocirculation. This is carried out in temperature-controlled room (24-26 degrees C)
      with a 30 minute acclimatization period. FMD of the brachial artery is measured at rest and
      during reactive hyperemia using a high-resolution 10.0 MHz linear array transducer and an HDI
      Ultramark 9 system. Reactive hyperemia is produced by inflating a pneumatic tourniquet
      distally to the brachial artery to 50 mmHg above the systolic BP for 5 minutes, then
      deflating it. Brachial artery diameter is measured before inflation of the cuff and 1-2
      minutes after cuff deflation and expressed as the percentage change.

      Trinitroglycerin-induced vasodilation evaluates endothelium independent vasodilation. The
      brachial artery will be scanned before and 5 minutes after sublingual administration of 400
      ug of trinitroglycerin. This will be performed only at 240 minutes, fifteen minutes after
      completion of the FMD study to allow for the brachial artery to return to baseline.

      Pulse wave analysis(PWA) is another method to evaluate the function of the vasculature. The
      shape of the arterial pressure waveform provides a measure of systemic arterial stiffness.
      All measurements will be made in the right arm using the Sphygmocore Px (Atcor Medical Blood
      Pressure Analysis System, Australia) in a temperature-controlled room. With the wrist
      slightly extended and supported on a pillow, the radial artery of the right arm is flattened
      with a high fidelity micro manometer using gentle pressure. 20 sequential waveforms are
      acquired and the system software generates an average peripheral and corresponding central
      waveform, which is then subjected to further analysis of augmentation. Two pressure peaks
      characterize the systolic part of the central waveform. The first peak results from LV
      ejection, and the second results from the wave reflection. The difference between peaks
      represents the degree to which central arterial pressure is augmented by wave reflection. AP
      is the absolute increase in pressure from the reflected wave and AI is a measure of the
      contribution that the wave reflection makes to the arterial pressure waveform, and is
      expressed as a percentage of pulse pressure. The amplitude and timing of the reflected wave
      ultimately depends on the stiffness of the small vessels and large arteries, and thus is a
      measure of systemic arterial stiffness.

      We will enroll 72 subjects to obtain 60 subjects who will complete the study. The subjects
      will have Type 2 diabetes and will be randomized to one of two treatment arms.
    

Intervention name(s): Exenatide; Glargine Insulin
Intervention type(s): Drug; Drug
Intervention description(s): Exenetide 5ug twice daily for 4 weeks, then 10ug twice daily for 8 weeks; Glargine insulin 10-20 units once daily and subsequently adjusted per protocol to achieve a fasting glucose of 100mg/dl and avoid hypoglycemia.
Other intervention name(s): Byetta; Lantus insulin
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Glargine; Exenatide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: endothelial dysfunction; subclinical inflammation; flow mediated brachial artery dilation; pulse wave analysis; glucagon like polypeptide mimetics; type 2 diabetes mellitus