Impact of Sitagliptin on Cardiovascular Exercise Performance in Type 2 Diabetes

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01951339
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 36
• Location: 1
• Arms: 2
• Actual Duration (Months): 56
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief 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.

1. 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 or Disease	Intervention/Treatment	Phase
Type 2 Diabetes; Cardiovascular Disease	Drug: Sitagliptin; Drug: Glimepiride; Drug: Placebo; Drug: Placebo	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: Impact of Sitagliptin on Cardiovascular Exercise Performance in Type 2 Diabetes
• Actual Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Jun 1, 2018
• Actual Study Completion Date: Jun 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sitagliptin plus placebo 100 mg sitagliptin plus 2 mg placebo once daily for three months	Drug: Sitagliptin; 100 mg sitagliptin; Other Names: Januvia (sitagliptin) ; Drug: Placebo; 2 mg placebo once daily; Other Names: Placebo 1-sitagliptin
Active Comparator: Glimepiride plus placebo 2 mg glimepiride plus 100 mg placebo once daily for three months	Drug: Glimepiride; Active Comparator 2mg glimepiride; Other Names: Amaryl ; Drug: Placebo; 100 mg placebo once daily for three months; Other Names: Placebo 2- glimepiride

Outcome Measures

Primary Outcome Measures

1. Peak Oxygen Consumption (VO2peak). [Pre-intervention (Baseline) and post-intervention (3 months)]

   Subjects' peak oxygen consumption will be tested on a stationary bike before and after 3 months of study medication.

2. Changes From Baseline in 31P Measurement: Phosphocreatine Time Constant [Pre-intervention (Baseline) and post-intervention (3 months)]

   Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment

3. Change in Oxygen Uptake Kinetics (VO2 Kinetics) [Pre-intervention (Baseline) and post-intervention (3 months)]

   Oxygen uptake kinetics will be tested on a stationary bike before and after 3 months of study medication. VO2 kinetics is reported as the time constant associated with the change in oxygen update from rest to steady state.

4. Changes From Baseline in 31P Measurement: Free Pi Time Constant [Pre-intervention (Baseline) and post-intervention (3 months)]

   Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment. Data are represented as the change in Pi through the scan.

5. Changes From Baseline in 31P Measurement: Adenosine Triphosphate (ATP) Peaks [Pre-intervention (Baseline) and post-intervention (3 months)]

   Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment

6. Changes From Baseline in 31P Measurement: Adenosine Diphosphate (ADP) Time Constant [Pre-intervention (Baseline) and post-intervention (3 months)]

   Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment

7. Changes From Baseline in 31P Measurement: pH [Pre-intervention (Baseline) and post-intervention (3 months)]

   Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment

Secondary Outcome Measures

1. Changes From Baseline in Echocardiographic Measures (Stroke Volume) [Pre-intervention (Baseline) and post-intervention (3 months)]

   Potential change in cardiac function will be assessed by echocardiography before and after 3 months of study medication

2. Change in (Non-invasively Measured) Deoxygenated Hemoglobin Concentration in the Vastus Lateralis During Exercise [Pre-intervention (Baseline) and post-intervention (3 months)]

   Deoxygenated hemoglobin concentration will be measured using near-infrared spectroscopy during sub-maximal exercise before and after 3 months of study drug administration.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 22 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 and 9.5% (adequate control) on therapy.

5. Persons who are taking metformin 500-2000 mg/day only to control their T2D, but are not taking any other diabetes medication in addition to or instead of metformin.

6. Persons not taking medication to control diabetes.

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

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Anschutz Medical Campus	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• Merck Sharp & Dohme LLC

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 15, 2016

More Information

Additional Information:

• AcTIVe Research Lab

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01951339
• Other Study ID Numbers: 13-2015
• First Posted: Sep 26, 2013
• Last Update Posted: May 22, 2019
• Last Verified: Apr 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Product Manufactured in and Exported from the U.S.: Yes
• 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; Sitagliptin Phosphate; Glimepiride

Study Results

Participant Flow

Pre-assignment Detail	Patients underwent screening, as well as baseline data collection prior to randomization to group. Several patients withdrew from the study prior to randomization.

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Period Title: Overall Study
STARTED	15	15
COMPLETED	13	14
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo	Total
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months	Total of all reporting groups
Overall Participants	13	14	27
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 84.6%	11 78.6%	22 81.5%
>=65 years	2 15.4%	3 21.4%	5 18.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59 (2)	57 (3)	57 (8)
Sex: Female, Male (Count of Participants)
Female	7 53.8%	6 42.9%	13 48.1%
Male	6 46.2%	8 57.1%	14 51.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	1 7.7%	0 0%	1 3.7%
Black or African American	4 30.8%	1 7.1%	5 18.5%
White	8 61.5%	13 92.9%	21 77.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%	14 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Peak Oxygen Consumption (VO2peak).
Description	Subjects' peak oxygen consumption will be tested on a stationary bike before and after 3 months of study medication.
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	13	14
Pre-intervention	1893 (138)	1953 (113)
Post-intervention	1849 (135)	1881 (151)

2. Primary Outcome

Title	Changes From Baseline in 31P Measurement: Phosphocreatine Time Constant
Description	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	7	8
Pre-intervention	34.1 (7.3)	30.9 (3.9)
Post-intervention	26.6 (2.9)	29.6 (3.6)

3. Primary Outcome

Title	Change in Oxygen Uptake Kinetics (VO2 Kinetics)
Description	Oxygen uptake kinetics will be tested on a stationary bike before and after 3 months of study medication. VO2 kinetics is reported as the time constant associated with the change in oxygen update from rest to steady state.
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	13	14
Pre-intervention	56.2 (5.0)	54.2 (7.3)
Post-intervention	67.5 (8.0)	54.6 (4.3)

4. Primary Outcome

Title	Changes From Baseline in 31P Measurement: Free Pi Time Constant
Description	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment. Data are represented as the change in Pi through the scan.
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

These data are quality control measures only.

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	14	15
Pre-intervention	29.73 (10.16)	28.54 (10.44)
Post-intervention	27.94 (3.82)	26.15 (5.60)

5. Primary Outcome

Title	Changes From Baseline in 31P Measurement: Adenosine Triphosphate (ATP) Peaks
Description	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

These data are quality control measures only.

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	14	15
Pre-intervention	8.19 (0.22)	7.93 (0.58)
Post-intervention	12.66 (13.59)	8.02 (0.29)

6. Primary Outcome

Title	Changes From Baseline in 31P Measurement: Adenosine Diphosphate (ADP) Time Constant
Description	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	7	8
Pre-intervention	28.0 (5.3)	24.5 (3.5)
Post-intervention	19.4 (1.1)	21.2 (2.9)

7. Primary Outcome

Title	Changes From Baseline in 31P Measurement: pH
Description	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

These data are quality control measures only.

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	14	15
Pre-intervention	6.88 (0.05)	6.88 (0.05)
Post-intervention	6.85 (0.02)	6.89 (0.05)

8. Secondary Outcome

Title	Changes From Baseline in Echocardiographic Measures (Stroke Volume)
Description	Potential change in cardiac function will be assessed by echocardiography before and after 3 months of study medication
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	13	14
Pre-intervention	58.2 (5.5)	72.7 (6.1)
Post-intervention	64.6 (11.9)	77.8 (6.7)

9. Secondary Outcome

Title	Change in (Non-invasively Measured) Deoxygenated Hemoglobin Concentration in the Vastus Lateralis During Exercise
Description	Deoxygenated hemoglobin concentration will be measured using near-infrared spectroscopy during sub-maximal exercise before and after 3 months of study drug administration.
Time Frame	Pre-intervention (Baseline) and post-intervention (3 months)

Outcome Measure Data

Analysis Population Description

This variable was listed as a secondary outcome of the study that was later dropped by the investigators after a careful review of the literature. We decided not to pursue this outcome because it was not scientifically useful to address the original hypothesis.

Arm/Group Title	Sitagliptin Plus Placebo	Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily	2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
Measure Participants	0	0

Adverse Events

Time Frame	Adverse event data were collected during individual study participation, approximately 6 months.
Arm/Group Title	Sitagliptin Plus Placebo		Glimepiride Plus Placebo
Arm/Group Description	100 mg sitagliptin plus 2 mg placebo once daily for three months Sitagliptin: 100 mg sitagliptin Placebo: 2 mg placebo once daily		2 mg glimepiride plus 100 mg placebo once daily for three months Glimepiride: Active Comparator 2mg glimepiride Placebo: 100 mg placebo once daily for three months
All Cause Mortality
	Sitagliptin Plus Placebo		Glimepiride Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Sitagliptin Plus Placebo		Glimepiride Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Sitagliptin Plus Placebo		Glimepiride Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/15 (33.3%)		3/15 (20%)
Gastrointestinal disorders
Medication side effects	3/15 (20%)	3	1/15 (6.7%)	1
Metabolism and nutrition disorders
High blood glucose	1/15 (6.7%)	1	0/15 (0%)	0
Mild hypoglycemia	1/15 (6.7%)	1	2/15 (13.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.