Impact of Sitagliptin on Cardiovascular Exercise Performance in Type 2 Diabetes

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.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Type 2 Diabetes
• Intervention / Treatment: Drug: Sitagliptin; Drug: Placebo; Drug: Placebo; Drug: Glimepiride

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 Type: Interventional
• Enrollment (Actual): 36
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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; Drug: Placebo; 100 mg placebo once daily for three months; Other Names: Placebo 2- glimepiride
Active Comparator: Glimepiride plus placebo; 2 mg glimepiride plus 100 mg placebo once daily for three months	Drug: Placebo; 2 mg placebo once daily; Other Names: Placebo 1-sitagliptin; Drug: Placebo; 100 mg placebo once daily for three months; Other Names: Placebo 2- glimepiride; Drug: Glimepiride; Active Comparator 2mg glimepiride; Other Names: Amaryl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Oxygen Consumption (VO2peak).	Subjects' peak oxygen consumption will be tested on a stationary bike before and after 3 months of study medication.	Pre-intervention (Baseline) and post-intervention (3 months)
Changes From Baseline in 31P Measurement: Phosphocreatine Time Constant	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment	Pre-intervention (Baseline) and post-intervention (3 months)
Change in Oxygen Uptake Kinetics (VO2 Kinetics)	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.	Pre-intervention (Baseline) and post-intervention (3 months)
Changes From Baseline in 31P Measurement: Free Pi Time Constant	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.	Pre-intervention (Baseline) and post-intervention (3 months)
Changes From Baseline in 31P Measurement: Adenosine Triphosphate (ATP) Peaks	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment	Pre-intervention (Baseline) and post-intervention (3 months)
Changes From Baseline in 31P Measurement: Adenosine Diphosphate (ADP) Time Constant	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment	Pre-intervention (Baseline) and post-intervention (3 months)
Changes From Baseline in 31P Measurement: pH	Potential change in muscle mitochondrial function will be assessed after three months of study medication treatment	Pre-intervention (Baseline) and post-intervention (3 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes From Baseline in Echocardiographic Measures (Stroke Volume)	Potential change in cardiac function will be assessed by echocardiography before and after 3 months of study medication	Pre-intervention (Baseline) and post-intervention (3 months)
Change in (Non-invasively Measured) Deoxygenated Hemoglobin Concentration in the Vastus Lateralis During Exercise	Deoxygenated hemoglobin concentration will be measured using near-infrared spectroscopy during sub-maximal exercise before and after 3 months of study drug administration.	Pre-intervention (Baseline) and post-intervention (3 months)

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: 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

Publications and helpful links

General Publications

• Scalzo RL, Rafferty D, Schauer I, Huebschmann AG, Cree-Green M, Reusch JEB, Regensteiner JG. Sitagliptin improves diastolic cardiac function but not cardiorespiratory fitness in adults with type 2 diabetes. J Diabetes Complications. 2019 Aug;33(8):561-566. doi: 10.1016/j.jdiacomp.2019.05.002. Epub 2019 May 10.

Helpful Links

• AcTIVe Research Lab

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2013
• Primary Completion (Actual): June 1, 2018
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: September 19, 2013
• First Submitted That Met QC Criteria: September 23, 2013
• First Posted (Estimated): September 26, 2013

Study Record Updates

• Last Update Posted (Actual): July 12, 2023
• Last Update Submitted That Met QC Criteria: July 10, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: diabetes; exercise; type 2 diabetes; heart; sitagliptin; cardiovascular; echo; glimepiride
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate; Glimepiride
• Other Study ID Numbers: 13-2015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes