Impact of Sitagliptin on Cardiovascular Exercise Performance in Type 2 Diabetes

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by University of Colorado, Denver
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01951339
First received: September 19, 2013
Last updated: January 15, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention
Type 2 Diabetes
Cardiovascular Disease
Drug: Sitagliptin
Drug: Glimepiride
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: Impact of Sitagliptin on Cardiovascular Exercise Performance in Type 2 Diabetes

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • One primary outcome will be change in peak oxygen consumption (VO2peak). [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Subjects' peak oxygen consumption will be tested on a stationary bike before and after 3 months of study medication.

  • Changes from baseline in 31P measurement: phosphocreatine [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment

  • One primary outcome will be oxygen uptake kinetics (VO2 kinetics) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Oxygen uptake kinetics will be tested on a stationary bike before and after 3 months of study medication.

  • Changes from baseline in 31P measurement: free Pi [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment

  • Changes from baseline in 31P measurement: adenosine triphosphate (ATP) peaks [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment

  • Changes from baseline in 31P measurement: adenosine diphosphate (ADP) [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment

  • Changes from baseline in 31P measurement: pH [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment


Secondary Outcome Measures:
  • Changes from baseline in echocardiographic measures [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Potential change in cardiac function will be assessed by echocardiography before and after 3 months of study medication

  • Change from baseline in peak dilation of brachial artery diameter [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Change in the response of the brachial artery to hyperemia will be assessed before and after 3 months of study medication

  • Change in (non-invasively measured) deoxygenated hemoglobin concentration in the vastus lateralis during exercise [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Deoxygenated hemoglobin concentration will be measured using near-infrared spectroscopy during sub-maximal exercise before and after 3 months of study drug administration.


Estimated Enrollment: 28
Study Start Date: October 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sitagliptin plus placebo
100 mg sitagliptin plus 2 mg placebo once daily for three months
Drug: Sitagliptin
100 mg sitagliptin
Other Name: Januvia (sitagliptin)
Drug: Placebo
2 mg placebo once daily
Active Comparator: Glimepiride plus placebo
2 mg glimepiride plus 100 mg placebo once daily for three months
Drug: Glimepiride

Active Comparator

2mg glimepiride

Other Name: Amaryl
Drug: Placebo
100 mg placebo once daily for three months

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.
  Eligibility

Ages Eligible for Study:   22 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Female subjects may be pre, peri or post-menopausal.
  2. People who do not participate in a regular exercise program (> one bout of exercise per week).
  3. Presence of type 2 diabetes will be documented by chart review that will confirm the diagnosis as well as the presence of treatment for diabetes.
  4. Persons with type 2 diabetes will be accepted for study only if they have total glycosylated hemoglobin levels (HbA1C) between 7.5 and 9.5% (adequate control) on therapy.
  5. Persons who are taking metformin 1-2 g/day only to control their type 2 diabetes (T2D).

Exclusion Criteria:

  1. Females of childbearing potential who are pregnant, planning to become pregnant or breastfeeding.
  2. Persons will be excluded if they have evidence of ischemic heart disease by history or abnormal resting or exercise electrocardiogram (EKG) (> 1 mm ST segment depression), regional wall motion abnormalities, left ventricular systolic dysfunction or significant valvular disease.
  3. Persons with angina or any other cardiac or pulmonary symptoms potentially limiting exercise performance.
  4. Presence of systolic blood pressure >190 at rest or >250 with exercise or diastolic pressure >95 at rest or >115 with exercise.
  5. Subjects who have peripheral arterial disease.
  6. Subjects with proteinuria (urine protein >200 mg/dl) or a creatinine > 2 mg/dl, suggestive of renal disease.
  7. Persons with liver function impairment defined as elevated liver function tests three times the upper limit.
  8. Persons with a history of pancreatitis.
  9. Subjects more than 140% of ideal body weight.
  10. Patients on insulin therapy will not be included.
  11. Current smokers will not be accepted for study since smoking can impair cardiovascular exercise performance but people who have quit smoking for at least 1year will be accepted for study.
  12. Persons with autonomic dysfunction (>20 mm fall in upright blood pressure without a change in heart rate) will be excluded.
  13. Diabetic persons with clinically evident distal symmetrical neuropathy will be excluded from further study, because of possible effects on exercise performance, by evaluation of symptoms (numbness, paresthesia) and signs (elicited by vibration, pinprick, light touch, ankle jerks).
  14. Persons with diabetic ketoacidosis.
  15. Persons with a serious hypersensitivity to sitagliptin, sulfonylureas or sulfonamides.
  16. Inability to walk or ride a bike unassisted for a continuous 5 minutes.
  17. Subjects will be excluded if they have any implanted metal in their body.
  18. Subjects currently being treated with Digoxin.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01951339

Contacts
Contact: Shawna McMillin, MS 720-848-6689 shawna.mcmillin@ucdenver.edu
Contact: Leah Herlache, MS 303-724-2255 leah.herlache@ucdenver.edu

Locations
United States, Colorado
University of Colorado Anschutz Medical Campus Recruiting
Aurora, Colorado, United States, 80045
Principal Investigator: Judith G. Regensteiner, PhD         
Principal Investigator: Jane EB Reusch, MD         
Sponsors and Collaborators
University of Colorado, Denver
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Judith G. Regensteiner, PhD University of Colorado Anschutz Medical Campus
Principal Investigator: Jane EB Reusch, MD University of Colorado Anschutz Medical Campus
  More Information

Additional Information:
No publications provided

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01951339     History of Changes
Other Study ID Numbers: 13-2015
Study First Received: September 19, 2013
Last Updated: January 15, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Colorado, Denver:
diabetes
type 2 diabetes
exercise
echo
heart
sitagliptin
glimepiride
cardiovascular

Additional relevant MeSH terms:
Cardiovascular Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Glimepiride
Sitagliptin
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Hypoglycemic Agents
Physiological Effects of Drugs
Immunosuppressive Agents
Immunologic Factors
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 27, 2014