Atherosclerosis, Diabetes
Conditions
Keywords
dipeptidyl peptidase-4 inhibitor, endothelium, vascular, diabetes type 2, nitric oxide, inflammation
Brief summary
The study is being performed to determine whether sitagliptin, a dipeptidyl peptidase-4 inhibitor, both acutely and chronically improves blood vessel function. Patients with type 2 diabetes who are on metformin will be enrolled in this study for up to 22 weeks in this double blinded cross over study where they will receive a sitagliptin pill once a day for 8 weeks and during a separate 8 weeks receive a matching placebo pill. The treatment periods are divided by a 4 week period. Blood vessel function will be measured by ultrasound before and after a single dose of sitagliptin and placebo, as well as after 8 weeks of treatment with each. Blood will also be taken to measure blood markers of inflammation at each time the ultrasounds are performed.
Detailed description
We plan to recruit 38 patients with T2DM for this single center, double blind randomized, interventional crossover trial comparing sitagliptin (100 mg/day) to matching placebo. We have chosen placebo over a comparator for this study as our goal is to determine whether sitagliptin both improves glycemic control and endothelial function, properties not shared by other popular classes of agents like sulfonylureas. Subjects will be randomized with a 1:1 allocation ratio to either sitagliptin 1st or placebo 1st. The study have 5 total visits. Subjects who pass a phone screen will be invited to a screening visit for study eligibility (Visit 1) Informed consent will be reviewed; a unique study number will be assigned once written informed consent is obtained (no subject will be assigned more than 1 allocation number); relevant participant medical history will be recorded including currently prescribed medications; anthropometric measurements will be taken (height, weight, and waist circumference in metric units) and blood pressure will be recorded (measured in triplicate and averaged). Subjects will be allowed to take their blood pressure medication on the morning of their screening visit, but not the mornings of any of the other study visits to limit the acute influence of these medications on endothelial function. If the potential participant qualifies for the study, he/she will be randomized either to receive sitagliptin 1st (100 mg/day) or matching placebo. Prior to receiving either of set of pills, subjects will return to the study center within approximately 1-2 weeks of the screening visit to undergo initial tests of endothelial function and receive their pills. Prior to all study visits except screening, subjects will also be asked to refrain from any vigorous physical activity (no weight lifting, jogging or any activity vigorous than walking) 24 hours to reduce the risk of fasting hypoglycemia during the study visits. Subjects will also be asked to fast for 6-8 hours prior to the visit to limit the acute dietary influences on vascular endothelial function. At Visit 2, endothelial function will determined by brachial artery reactivity testing prior to and following a single dose of 100 mg of sitagliptin or matching placebo depending on the arm to which the subject was randomized. Blood samples will also be taken at this visit for systemic measurements of endothelial cell activation/inflammation (VCAM-1 and ICAM-1) prior to and 2 hours following acute drug administration. These will be measured at the indicated time points using commercially available kits. Endothelial function, like the blood samples, will be measured just prior to medication administration and then 2 hours following medication administration by brachial artery reactivity testing as described in Section D.3. The 2 hour time from was chose in given the plasma levels of sitagliptin appear to peak 2 hours following dose administration.32 At the end of this visit, subjects will be given a 9 week supply of the study pills (sitagliptin or matching placebo) as dispensed by the Froedtert Hospital Investigational Pharmacy, and scheduled to return for Visit 3 approximately 8 weeks following Visit 2. Subjects will be asked to not take any study medication for the 24 hours prior to Visit 3. At Visit 3, subjects will undergo repeat testing of endothelial function. Following this study visit, subjects will remain off study pills until they return for Visit 4 approximately 4 weeks following Visit 3. Visit 4 repeats Visit 2 except subjects will receive the set of pills to which they had been randomized to receive second. Subjects will return to the study center for Visit 5 approximately 8 weeks after Visit 4. Visit 5 is identical to Visit 3. Subject adherence will be determined by pill counts performed by MCW Translational Research Unit nursing staff who will perform all pill accounting. All medication dispensation will be handled by the Froedtert Hospital Investigational Drug Pharmacy.
Interventions
DRUGsitagliptin
100 mg pill, administered once/day orally
DRUGPlacebo
Matching placebo in appearance given once/day orally
Sponsors
Merck Sharp & Dohme LLC
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Adult age 21-70 years of age. 2. Diagnosis of type 2 diabetes by a physician as defined by the American Diabetes Association standard criteria: 1) Fasting Plasma glucose at or above 126 mg/dL 2) a two-hour value in an oral glucose tolerance test at or above 200 mg/dL, or 3) a random plasma glucose concentration 200 mg/dL in the presence of symptoms, or 4) glycosylated hemoglobin greater than or equal to 6.5%. 3. On stable metformin therapy for at least 6 weeks prior to enrollment. 4. Glycosylated Hemoglobin ≥6.2% and ≤ 9.5%.
Exclusion criteria
1. History of stroke, peripheral arterial disease, or coronary artery disease (as defined by the presence of at least one coronary stenosis ≥ 50% on angiography or by confirmed history of myocardial infarction by standard criteria.) 2. Evidence of other evident major illness including chronic renal insufficiency (creatinine clearance less than 60 mL/min),chronic liver disease (AST or ALT greater than 2.5 x normal), or cancer currently undergoing systemic therapy or had systemic therapy for cancer within 1 year of enrollment. 3. Pregnancy as determined by urinary beta-HCG test 4. Illicit drug use (heroin, cocaine etc) in the past 1 year. 5. Alcohol abuse, defined as the equivalent of 14 beers/week for a man or 7 beers/week for a woman 6. History of allergy to DPP-4 inhibitors at the time of screening/enrollment 7. Prior history of pancreatitis 8. Patients currently on insulin or sulfonylurea therapy. 9. Patients currently on digoxin. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brachial Artery Flow Mediated Dilation | Change before and after a single dose (2 hours post) and 8 weeks after daily dosing | A measurement of endothelial function in humans |
Secondary
| Measure | Time frame |
|---|---|
| Circulating Inflammatory Marker ICAM-1 | Change before and after acute dose (2 hours) and 8 weeks after daily dosing of medication |
| Circulating Inflammatory Markers VCAM-1 | Change before and after acute dose (2 hours) and 8 weeks after daily dosing of medication |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Matching Placebo 1st Matching Placebo for Sitagliptin
Placebo: Matching placebo in appearance given once/day orally | 14 |
| Sitagliptin 1st 100mg pill, PO administered once daily.
sitagliptin: 100 mg pill, administered once/day orally | 16 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (8 Weeks) | Adverse Event | 1 | 0 |
| First Intervention (8 Weeks) | Protocol Violation | 2 | 0 |
| First Intervention (8 Weeks) | Withdrawal by Subject | 2 | 1 |
| Washout Period (4 Weeks) | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Matching Placebo 1st | Sitagliptin 1st | Total |
|---|---|---|---|
| ACE Inhibitor No | 4 participants | 8 participants | 12 participants |
| ACE Inhibitor Yes | 10 participants | 8 participants | 18 participants |
| Age, Continuous | 62 years STANDARD_DEVIATION 10 | 63 years STANDARD_DEVIATION 9 | 63 years STANDARD_DEVIATION 9 |
| Alanine Aminotransferase (ALT) | 30 mg/dL STANDARD_DEVIATION 30 | 28 mg/dL STANDARD_DEVIATION 23 | 29 mg/dL STANDARD_DEVIATION 26 |
| Alkaline Phosphatase | 73 mg/dL STANDARD_DEVIATION 10 | 78 mg/dL STANDARD_DEVIATION 20 | 78 mg/dL STANDARD_DEVIATION 16 |
| Aspartate Aminotransferase (AST) | 25 mg/dL STANDARD_DEVIATION 17 | 25 mg/dL STANDARD_DEVIATION 13 | 25 mg/dL STANDARD_DEVIATION 15 |
| Beta-Blocker No | 13 participants | 15 participants | 28 participants |
| Beta-Blocker Yes | 1 participants | 1 participants | 2 participants |
| Body Mass Index | 32.1 kg/m^2 STANDARD_DEVIATION 6.6 | 32.6 kg/m^2 STANDARD_DEVIATION 6.3 | 32.4 kg/m^2 STANDARD_DEVIATION 6.3 |
| Diastolic Blood Pressure | 73 mmHg STANDARD_DEVIATION 11 | 78 mmHg STANDARD_DEVIATION 20 | 75 mmHg STANDARD_DEVIATION 8 |
| Glucose | 117 mg/dL STANDARD_DEVIATION 26 | 134 mg/dL STANDARD_DEVIATION 31 | 126 mg/dL STANDARD_DEVIATION 30 |
| Heart Rate | 72 bpm STANDARD_DEVIATION 10 | 76 bpm STANDARD_DEVIATION 8 | 74 bpm STANDARD_DEVIATION 11 |
| HgA1C | 6.8 percent STANDARD_DEVIATION 0.2 | 6.9 percent STANDARD_DEVIATION 0.8 | 6.8 percent STANDARD_DEVIATION 0.6 |
| High Density Lipoprotein | 55 mg/dL STANDARD_DEVIATION 12 | 56 mg/dL STANDARD_DEVIATION 20 | 55 mg/dL STANDARD_DEVIATION 16 |
| History of High Cholesterol With Dyslipidemia | 8 participants | 13 participants | 21 participants |
| History of High Cholesterol Without Dyslipidemia | 6 participants | 3 participants | 9 participants |
| History of Hypertension With Hypertension | 10 participants | 10 participants | 20 participants |
| History of Hypertension Without Hypertension | 4 participants | 6 participants | 10 participants |
| HMG CoA-Reductase No | 5 participants | 3 participants | 8 participants |
| HMG CoA-Reductase Yes | 9 participants | 13 participants | 22 participants |
| Homeostatic Assessment of Insulin Resistance | 4.4 units on a scale STANDARD_DEVIATION 1.9 | 5.3 units on a scale STANDARD_DEVIATION 2.9 | 4.9 units on a scale STANDARD_DEVIATION 2.5 |
| Insulin | 15.1 microU/mL STANDARD_DEVIATION 5.6 | 16.0 microU/mL STANDARD_DEVIATION 8.9 | 15.6 microU/mL STANDARD_DEVIATION 7.4 |
| Low Density Lipoprotein | 85 mg/dL STANDARD_DEVIATION 29 | 84 mg/dL STANDARD_DEVIATION 26 | 84 mg/dL STANDARD_DEVIATION 27 |
| Race/Ethnicity, Customized Caucasian | 10 participants | 15 participants | 25 participants |
| Race/Ethnicity, Customized Non-Caucasian | 4 participants | 1 participants | 5 participants |
| Region of Enrollment United States | 14 participants | 16 participants | 30 participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 14 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 16 Participants |
| Smoking Status Never | 9 participants | 13 participants | 22 participants |
| Smoking Status Past or Current | 5 participants | 3 participants | 8 participants |
| Systolic Blood Pressure | 131 mmHg STANDARD_DEVIATION 13 | 136 mmHg STANDARD_DEVIATION 15 | 134 mmHg STANDARD_DEVIATION 14 |
| Total Bilirubin | 0.4 mg/dL STANDARD_DEVIATION 0.2 | 0.5 mg/dL STANDARD_DEVIATION 0.3 | 0.5 mg/dL STANDARD_DEVIATION 0.3 |
| Total Cholesterol | 165 mg/dL STANDARD_DEVIATION 31 | 169 mg/dL STANDARD_DEVIATION 29 | 167 mg/dL STANDARD_DEVIATION 30 |
| Triglycerides | 126 mg/dL STANDARD_DEVIATION 53 | 138 mg/dL STANDARD_DEVIATION 40 | 132 mg/dL STANDARD_DEVIATION 46 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 36 | 0 / 32 |
| serious Total, serious adverse events | 0 / 36 | 0 / 32 |
Outcome results
Primary
Brachial Artery Flow Mediated Dilation
A measurement of endothelial function in humans
Time frame: Change before and after a single dose (2 hours post) and 8 weeks after daily dosing
Population: All 30 subjects who completed both arms of the cross-over study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Matching Placebo | Brachial Artery Flow Mediated Dilation | Prior To Intervention | 5.2 %FMD | Standard Deviation 1.8 |
| Matching Placebo | Brachial Artery Flow Mediated Dilation | 2 hours post acute dose | 5.6 %FMD | Standard Deviation 2.1 |
| Matching Placebo | Brachial Artery Flow Mediated Dilation | Following 8 weeks of therapy | 6.0 %FMD | Standard Deviation 2.9 |
| Sitagliptin | Brachial Artery Flow Mediated Dilation | Prior To Intervention | 5.6 %FMD | Standard Deviation 2.3 |
| Sitagliptin | Brachial Artery Flow Mediated Dilation | 2 hours post acute dose | 6.3 %FMD | Standard Deviation 2.4 |
| Sitagliptin | Brachial Artery Flow Mediated Dilation | Following 8 weeks of therapy | 5.8 %FMD | Standard Deviation 2.3 |
Comparison: Primary and secondary outcome variables were compared across measurement periods by repeated measures ANOVA and post hoc analyses using Tukey's test were applied if significant differences were detected. A priori sample size calculation demonstrated our study design has 80% power to detect a 1.5% absolute increase in FMD% with 30 subjects completing the entire study protocol at α=0.05.p-value: <0.05ANOVA
Secondary
Circulating Inflammatory Marker ICAM-1
Time frame: Change before and after acute dose (2 hours) and 8 weeks after daily dosing of medication
Population: 29 of the 30 subjects who completed both arms of the study. One subject was missing the measurements post 8 weeks of each intervention arm and was excluded
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Matching Placebo | Circulating Inflammatory Marker ICAM-1 | Pre-Intervention | 226 mg/mL | Standard Deviation 72 |
| Matching Placebo | Circulating Inflammatory Marker ICAM-1 | 2 hours post acute dose | 216 mg/mL | Standard Deviation 73 |
| Matching Placebo | Circulating Inflammatory Marker ICAM-1 | post 8 weeks of therapy | 228 mg/mL | Standard Deviation 73 |
| Sitagliptin | Circulating Inflammatory Marker ICAM-1 | Pre-Intervention | 223 mg/mL | Standard Deviation 73 |
| Sitagliptin | Circulating Inflammatory Marker ICAM-1 | 2 hours post acute dose | 211 mg/mL | Standard Deviation 68 |
| Sitagliptin | Circulating Inflammatory Marker ICAM-1 | post 8 weeks of therapy | 232 mg/mL | Standard Deviation 74 |
Comparison: Outcome variables were compared across measurement periods by repeated measures ANOVA and post hoc analyses using Tukey's test were applied if significant differences were detectedp-value: <0.05ANOVA
Secondary
Circulating Inflammatory Markers VCAM-1
Time frame: Change before and after acute dose (2 hours) and 8 weeks after daily dosing of medication
Population: 29 of the 30 subject who completed the study. Once subject had missing data for the post-8 weeks of each intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Matching Placebo | Circulating Inflammatory Markers VCAM-1 | Pre-Intervention | 584 mg/mL | Standard Deviation 187 |
| Matching Placebo | Circulating Inflammatory Markers VCAM-1 | 2 hours post acute dose | 575 mg/mL | Standard Deviation 141 |
| Matching Placebo | Circulating Inflammatory Markers VCAM-1 | post 8 weeks of therapy | 620 mg/mL | Standard Deviation 196 |
| Sitagliptin | Circulating Inflammatory Markers VCAM-1 | Pre-Intervention | 608 mg/mL | Standard Deviation 164 |
| Sitagliptin | Circulating Inflammatory Markers VCAM-1 | 2 hours post acute dose | 574 mg/mL | Standard Deviation 157 |
| Sitagliptin | Circulating Inflammatory Markers VCAM-1 | post 8 weeks of therapy | 620 mg/mL | Standard Deviation 196 |
Comparison: Outcome variables were compared across measurement periods by repeated measures ANOVA and post hoc analyses using Tukey's test were applied if significant differences were detectedp-value: <0.05ANOVA