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

Summary: 
      The goal of this study is to examine whether sitagliptin, an agent which enhances the action
      of hormones that control the release of insulin and is already in clinical use for type 2
      diabetes, might also improve functional exercise capacity.

      Specific aims:

      1. To test whether sitagliptin will improve functional exercise capacity in persons with type
      2 diabetes compared to glimepiride.

      1a. The primary outcome will be peak oxygen consumption (VO2peak) and oxygen uptake kinetics
      (VO2 kinetics).

      1b. Secondary outcomes include cardiac function, endothelial function and tissue oxygen
      saturation (STO2) as well as health-related quality of life.

      2. To evaluate the impact of sitagliptin on muscle mitochondrial function 2a. The primary
      outcome to address this aim will be 31P measurements (phosphocreatine, free inorganic
      phosphate, adenosine triphosphate peaks, adenosine diphosphate and pH)

      Impact: Novel approaches are needed to decrease excess cardiovascular morbidity and mortality
      in diabetes. Diabetes impairs cardiovascular fitness and thereby mortality. A demonstration
      that sitagliptin improves cardiovascular fitness, (and possibly mitochondrial function) will
      provide important new data pertinent to the management of diabetes and pre-diabetes.
    

Detailed description: 
      Subjects will come for a total of nine testing visits during which evaluations will take
      place. Visits are structured as follows:

        1. After subjects review the study and give consent for study participation, a history and
           physical exam will be performed. Ankle brachial index, autonomic nervous system function
           tests, the Low-level Physical Activity Recall questionnaire and vital signs will be
           performed.

        2. Blood drawn for measurement of hemoglobin A1C, fasting glucose, fasting insulin, free
           fatty acids and microalbuminuria, c-reactive protein, interleukin 6, adiponectin, and
           creatinine and glycerol. Additional screening labs include complete blood count (CBC),
           follicle-stimulating hormone, urine protein and a lipid panel to assess whether women
           are pre- or post-menopausal (FSH), and overall health (CBC, lipids and urine protein). A
           dietary survey will be administered for food preferences for the three day study diet
           administered prior to visits 3-5 and 7-9. Dual-energy xray absorptiometry (DEXA) and
           body composition tests will be done to ensure that groups are weight similar (using
           fat-free mass). A pulmonary function test, 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. A graded exercise test will be done to
           determine the VO2peak. Patients will have measures of cardiac function and endothelial
           function on visit 3 by plethysmography and cardiac echo. Vital signs will be taken at
           rest.

        4. Subjects will receive a three day study diet prior to visit 4. Calf muscle magnetic
           resonance spectroscopy (MRS) will be performed on a 3.0 T whole-body MRI scanner.

        5. During visit 5, arterial stiffness/endothelial function will be non-invasively measured
           by the Sphygmocor system. Subjects will also have three constant-load tests to measure
           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 taking sitagliptin plus placebo or glimepiride plus placebo and all must
           be taking metformin (1-2 grams /d) for 3 months. Sitagliptin and its placebo will be
           administered 100 mg/d. Glimepiride and its placebo will be administered 2 mg/day. During
           the treatment phase subjects will be given a log to keep track of their blood glucose
           each day.

        6. Visit 6 will consist of a physical exam with a clinician as well as a blood draw and
           check of vital signs during sitagliptin or glimepiride treatment.

        7. After 3 months of sitagliptin or glimepiride administration, Visit 3 will be repeated.
           Additional testing to be performed during visit 7 will include a physical exam performed
           by a study physician, blood work for covariate lab tests listed in Visit 2 and the
           Low-level Physical Activity Recall(LoPAR) questionnaire.

        8. During visit 8, visit 4 procedures will be repeated.

        9. During visit 9, the testing performed during visit 5 will be repeated.
    

Intervention name(s): Sitagliptin; Glimepiride; Placebo; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 100 mg sitagliptin; Active Comparator
2mg glimepiride; 2 mg placebo once daily; 100 mg placebo once daily for three months
Other intervention name(s): Januvia (sitagliptin); Amaryl; Placebo 1-sitagliptin; Placebo 2- glimepiride
Intervention MeSH terms: Sitagliptin Phosphate; Glimepiride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Other
Keywords: diabetes; type 2 diabetes; exercise; echo; heart; sitagliptin; glimepiride; cardiovascular