Impact of Exenatide on Cardiovascular Exercise Performance in Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      Previous research in our lab and others has established that type 2 diabetes (T2D) is
      associated with significantly impaired functional exercise capacity, a factor which is
      potentially associated with an increased risk of cardiovascular disease in those with type 2
      diabetes. Of great concern, the majority of people with type 2 diabetes are sedentary and one
      possible reason may be that exercise, even at low levels, is perceived as being a harder
      effort than for nondiabetic people. Thus, treatments that may motivate patients with type 2
      diabetes to be more physically active have great potential benefit.

      Recent observational studies suggest that glucagon-like peptide-1 agents, such as exenatide,
      may have a beneficial effect on endothelial and cardiac function. Because these two factors
      have been shown to be associated with exercise dysfunction in type 2 diabetes, the
      investigators hypothesize that exenatide may improve exercise capacity in those with type 2
      diabetes. The aims of this study are to (1) assess whether exenatide will improve functional
      exercise capacity in persons with type 2 diabetes and (2) investigate the effect of exenatide
      on specific metabolic, endothelial, cardiac and peripheral circulatory measures of function
      related to changes in exercise capacity. The Investigators primary hypothesis is that
      exenatide will improve functional exercise capacity in people with type 2 diabetes. Having a
      drug that improves exercise capacity could motivate patients to exercise more and hence be a
      significant benefit.
    

Detailed description: 
      Subjects will come for a total of seven testing visits, including two screening visits,
      during which evaluations will take place. Visits are structured as follows:

      Visits 1, 2 and 3 will be completed over a four-week period.

        1. After subjects review the study and give consent for study participation, a history and
           physical exam will be performed. In addition, the Low-level Physical Activity Recall
           (LoPAR) questionnaire, pulmonary function testing, and vital signs will be performed.

        2. Subjects will be asked to fast prior to visit 2. Blood and urine samples will be
           collected for measurement of glycosylated hemoglobin(HbA1C), fasting glucose, fasting
           insulin, free fatty acids and microalbuminuria (these measures will be covariates in the
           analyses). A dietary survey will be administered for food preferences for the three day
           study diet administered prior to visits 3, 4, 6 and 7. Dual Energy X-ray Absorptiometry
           (DXA) and body composition tests will be done to ensure that groups are weight similar
           (using fat-free mass). Autonomic nervous system testing, a resting electrocardiogram
           (EKG) and familiarization bicycle test will be performed.

        3. Subjects will receive a three day study diet prior to visit 3. A resting and exercise
           EKG will be performed on the day of the visit. Patients will have measures made of
           cardiac function and endothelial function on visit 3 as well using plethysmography and
           cardiac echo. The peak aerobic capacity (VO2max) test will be performed. Vital signs
           will be taken at rest.

        4. Randomization: Subjects will receive a three day study diet prior to visit 4. During
           visit four, arterial stiffness/endothelial function will be non-invasively measured by
           the Sphygmocor system. Subjects will have three constant-load tests to measure oxygen
           (VO2) kinetics where oxygen saturation (StO2) will be measured during exercise. A
           resting and exercise EKG and vital signs will be performed during the visit. Subjects
           will be randomized to either taking exenatide or placebo and all must have been taking
           metformin (1-2 grams /d) for at least 3 months. Exenatide will be titrated starting at 5
           mcg twice per day for two weeks then moving to 10 mcg twice per day as tolerated and the
           placebo dose will match this titration. During the treatment phase subjects will be
           given a log to keep track of their blood glucose each day. Study coordinators will
           contact each subject weekly to obtain these values which will be checked by the study
           doctors and shared with the subject's primary care physician if adjustments in other
           medications need to be made.

        5. Week 4: Visit 5 will consist of a physical exam with a clinician as well as a blood draw
           and check of vital signs during exenatide treatment.

        6. Week 12: After 3 months of exenatide or placebo administration, the procedures of Visit
           3 will be repeated as Visit 6. Additional testing to be performed during visit 6 include
           a physical exam performed by a study physician, DXA scan and body composition tests to
           monitor any changes in body composition (fat-free mass), blood work for lab tests listed
           in Visit 2 and the LoPAR questionnaire.

        7. Week 13: During visit 7, the testing performed during visit 4 will be repeated after 3
           months of exenatide or placebo administration.

      Subjects will continue exenatide or placebo treatment while completing exit testing during
      Weeks 12 and 13.
    

Intervention name(s): Exenatide; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Subcutaneous injection 2.5 micrograms (mcg) to 10 mcg twice per day (BID); Subcutaneous injection 2.5 mcg-10 mcg BID
Other intervention name(s): Byetta
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Other