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
Intervention: Exenatide; Glargine Insulin
Intervention description: 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.
Intervention MeSH terms: Insulin; Insulin, Globin Zinc; Insulin Glargine; Exenatide
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 72.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: endothelial dysfunction; subclinical inflammation; flow mediated brachial artery dilation; pulse wave analysis; glucagon like polypeptide mimetics; type 2 diabetes mellitus

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).
    

Eligibility criteria:

        Inclusion Criteria:

          -  age 18-75

          -  Type 2 Diabetes (diagnosed at least 3 months prior to study)

          -  HbA1c: above 7.0 and less than or equal to 10.0

          -  At least one HbA1c over preceding 3-6 months, and HbA1c at screening, with less than
             1% difference between lowest and highest values

          -  Stable doses of antidiabetic medications (SU and/or Metformin) for 3 months

          -  reproductive age females must have negative urine HCG at screening, and be using
             appropriate contraception during the study or be surgically sterile

          -  postmenopausal woman

          -  stable weight for 3 months prior to study (+/- 2kg)

          -  willingness to participate in the study

        Exclusion Criteria:

          -  Type 1 diabetes

          -  Type 2 diabetes less than 3 months in duration

          -  HbA1c less than 7.0 or greater than 10

          -  age less than 18 or greater than 75

          -  pregnant or planning to become pregnant during study period

          -  current insulin therapy or insulin within 6 months prior to study

          -  current use of Thiazolidinedione or within 6 months prior to study

          -  current use of Nateglinide or Repaglinide

          -  current use of an Alpha-glucosidase Inhibitor

          -  current weight loss program

          -  active smoker, or quit smoking within preceding 6 months

          -  creatinine greater than 2.0 mg/dL

          -  total cholesterol greater than 300 mg/dL

          -  triglycerides greater than 600 mg/dL

          -  blood pressure greater than 160/105 mmHg

          -  ALT/AST greater than twice the upper limit of normal

          -  any other medical condition that may interfere with trial participation or trial
             results

          -  if on Statin: Statin therapy for less than 3 months or dose change within preceding 3
             months

          -  if on ACE Inhibitor: ACE Inhibitor therapy for less than 3 months or dose change
             within preceding 3 months

          -  current use of any medication that is known to alter gastric motility