Hypertension, Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus, Hypertension, Angiotensin Converting Enzyme Inhibitors, Dipeptidyl Peptidase IV Inhibitors, Sitagliptin, Aprepitant, Ramipril
Brief summary
In this study the investigators will test the hypothesis that dipeptidyl peptidase IV (DPP4) inhibition attenuates the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibition but not angiotensin receptor blockade or calcium channel blockade. The investigators further hypothesize that this effect is mediated by substance P.
Detailed description
The use of dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes (T2DM) is growing rapidly. The majority of patients with T2DM are also taking ACE inhibitors or angiotensin receptor blockers (ARBs) in order to reduce cardiovascular and renal morbidity and mortality. DPP4 and ACE inhibitors share the common vasoactive substrate substance P. Substance P acts as a vasodilator but also activates the sympathetic nervous system. Understanding the interactive effects of DPP4 and ACE inhibitors on blood pressure and neurohumoral activation has important implications for the millions of patients with T2DM who take these drugs concurrently.
Interventions
DRUGPlacebo
Subjects will receive two capsules of placebo to preserve the blinding of the study. In a separate period, subjects will receive one capsule of placebo and one capsule of sitagliptin.
DRUGSitagliptin
Subjects will receive sitagliptin 100mg daily for 7 days. In addition, subjects will receive either aprepitant or a capsule of placebo to preserve the blinding of the study.
DRUGAprepitant
Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.
OTHERMixed Meal Test (MMT)
The first 18 subjects per arm/ group will undergo a mixed meal test on the 7th day of each medication intervention. This will take place after the first half of the study day at the clinical research center, following a 30 minute rest. Subjects will ingest a shake (combination of fixed carbohydrates/ fat/ protein) and have blood pressure, heart rate, and venous blood sample measurements collected for 4 hours after the meal.
Sponsors
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Age 18 to 80 years old For female subjects the following conditions must be met: Postmenopausal status for at least 1 year, or Status-post surgical sterilization, or If of childbearing potential, utilization of barrier methods of birth control and willingness to undergo urine β-HCG testing prior to drug treatment and on every study day T2DM, as defined by 1 or more of the following at the time of screening visit: * Hgb A1C ≥6.5%, or * Fasting plasma glucose ≥126mg/dL, or * 2-hour plasma glucose ≥200 mg/dL following 75gr oral glucose load Hypertension, as defined by: * Seated SBP ≥130 mm Hg on three occasions documented in medical record, or * Seated DBP ≥80 mm Hg on three occasions documented in medical record, or * Treatment with antihypertensive medications for a minimum of 6 months
Exclusion criteria
* Type 1 diabetes * Poorly controlled T2DM, defined as Hgb A1C\>8.7% * Use of anti-diabetic medications other than metformin for at least 12 months prior to initiation of the study * Secondary hypertension * Subjects who have participated in a weight-reduction program during the last 6 months and whose weight has increased or decreased more than 5 kg over the preceding 6 months * Pregnancy * Breast-feeding * Treatment with drugs primarily metabolized through CYP3A4 (e.g. cisapride, pimozide) * Clinically significant gastrointestinal impairment that could interfere with drug absorption * Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy and diastolic dysfunction acceptable), deep vein thrombosis, pulmonary embolism, second- or third-degree AV block, mitral valve stenosis, or hypertrophic cardiomyopathy * Impaired hepatic function (aspartate amino transaminase \[AST\] and/or alanine amino transaminase \[ALT\] \>3 x upper limit of normal range) * Impaired renal function (eGFR\< 50mL/min/1.73m2 as determined by the MDRD equation) * History or presence of immunological or hematological disorders. * History of pancreatitis or know pancreatic lesion * History of angioedema while taking an ACE inhibitor * Hematocrit \<35% * Treatment with anticoagulants * Diagnosis of asthma requiring use of inhaled β-2 agonist more than 1 time per week * Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult * Treatment with systemic glucocorticoids within the last 6 months * Treatment with lithium salts * Treatment with any investigational drug in the 1 month preceding the study * Mental conditions rendering the subject unable to understand the nature, scope, or possible consequences of the study * Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Arterial Blood Pressure | 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant) | The primary analyses will focus on mean arterial blood pressure, heart rate, and norepinephrine (NE) concentrations during ramipril versus ramipril+sitagliptin, and during ramipril+sitagliptin versus ramipril+sitagliptin+aprepitant. We will make similar comparisons within the valsartan- and placebo-treated groups. In addition, we will compare blood pressure and heart rate parameters among the ramipril-treated, valsartan-treated, and placebo-treated groups during comparable concurrent treatment. |
| Heart Rate | 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant) | The primary analyses will focus on blood pressure, heart rate, and norepinephrine (NE) concentrations during ramipril versus ramipril+sitagliptin, and during ramipril+sitagliptin versus ramipril+sitagliptin+aprepitant. We will make similar comparisons within the valsartan- and placebo-treated groups. In addition, we will compare blood pressure and heart rate parameters among the ramipril-treated, valsartan-treated, and placebo-treated groups during comparable concurrent treatment. |
| Norepinephrine (NE) Concentrations | 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant) | The primary analyses will focus on blood pressure, heart rate, and norepinephrine (NE) concentrations during ramipril versus ramipril+sitagliptin, and during ramipril+sitagliptin versus ramipril+sitagliptin+aprepitant. We will make similar comparisons within the valsartan- and placebo-treated groups. In addition, we will compare blood pressure and heart rate parameters among the ramipril-treated, valsartan-treated, and placebo-treated groups during comparable concurrent treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dipeptidyl Peptidase IV (DPP4) Activity | for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant) | Measure of DPP4 inhibitor administration. |
| Angiotensin Converting Enzyme (ACE) Activity | for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant) | This is a measure of activity of the angiotensin-converting enzyme (ACE). The assay is a kinetic assay (Labcore) that measures the rate of cleavage of an added ACE substrate over time and the results are reported in Units, which represent the rate of increase in fluorescent metabolite over 30 minutes under standard conditions at 37C. |
| Mean Arterial Blood Pressure | Value provided is the AVERAGE of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal. | Average of measurements made every five minutes beginning just prior to (time 0) and for four hours after the ingestion of a mixed meal |
| Heart Rate | Value provided is the average of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal. | The average of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal |
| Neuropeptide Y | Neuropeptide Y concentration prior to ingestion of the mixed meal. | Measurement of Neuropeptide Y (NPY) concentrations |
| 24hr Urinary Testing for Sodium | Urine was collected for sodium for 24 hrs prior to each of the study days listed below. Study days occurred after each 7-day treatment arm (placebo/placebo, sitagliptin/placebo, or sitagliptin/aprepitant) within 3 anti-hypertensive groups. | Subjects will collect 24hr urine sample and bring with to the study day for analysis |
| Low Frequency Variability of Blood Pressure Activity | for 5 minutes on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant) | Low frequency variability of systolic blood pressure will be measured using spectral analysis. |
| Glucose | fasting at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant) | measure of effectiveness of DPP4 inhibitor |
| Insulin | fasting insulin measured at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitatliptin+aprepitant) | Measure of insulin resistance. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Aldosterone, Angiotensin II, and Plasma Renin Activity (PRA) | for 4.5 hours on the 7th day of each intervention | renin-angiotensin system measurements were not done because there were not significant differences in blood pressure |
Countries
United States
Participant flow
Pre-assignment details
Participants were enrolled if they met inclusion and exclusion criteria. 174 were consented to enroll 106. In other words, 68 of 174 consented were excluded because they did not meet inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Amlodipine Subjects in this arm will receive calcium channel blocker therapy with amlodipine 5mg daily for 3 days then 10mg daily for 15 weeks. After 4 weeks of treatment, subjects will receive three different 1 week concurrent interventions, in a cross-over fashion, separated by a 4 week washout. The interventions will be: placebo + placebo, sitagliptin + placebo, sitagliptin + aprepitant.
Placebo: Subjects will receive two capsules of placebo to preserve the blinding of the study.
In a separate period, subjects will receive one capsule of placebo and one capsule of sitagliptin.
Sitagliptin: Subjects will receive sitagliptin 100mg daily for 7 days. In addition, subjects will receive either aprepitant or a capsule of placebo to preserve the blinding of the study.
Aprepitant: Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.
Mixed Meal Test (MMT): The first 18 subjects per arm/ group will undergo a mixed meal test on the 7th day of each medication intervention. This will take place after the first half of the study day at the clinical research center, following a 30 minute rest. Subjects will ingest a shake (combination of fixed carbohydrates/ fat/ protein) and have blood pressure, heart rate, and venous blood sample measurements collected for 4 hours after the meal. | 36 |
| Ramipril Subjects will receive ACE-inhibitor therapy with ramipril 5mg daily for 3 days, followed by 10mg daily for the remaining 15 weeks. After 4 weeks of treatment, subjects will receive three different 1 week concurrent interventions, in a cross-over fashion, separated by a 4 week washout. The interventions will be: placebo + placebo, sitagliptin + placebo, sitagliptin + aprepitant.
Placebo: Subjects will receive two capsules of placebo to preserve the blinding of the study.
In a separate period, subjects will receive one capsule of placebo and one capsule of sitagliptin.
Sitagliptin: Subjects will receive sitagliptin 100mg daily for 7 days. In addition, subjects will receive either aprepitant or a capsule of placebo to preserve the blinding of the study.
Aprepitant: Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.
Mixed Meal Test (MMT): The first 18 subjects per arm/ group will undergo a mixed meal test on the 7th day of each medication intervention. This will take place after the first half of the study day at the clinical research center, following a 30 minute rest. Subjects will ingest a shake (combination of fixed carbohydrates/ fat/ protein) and have blood pressure, heart rate, and venous blood sample measurements collected for 4 hours after the meal. | 35 |
| Valsartan Subjects will receive ARB therapy with valsartan 160mg daily for 3 days, followed by 320mg daily for the remaining 15 weeks. After 4 weeks of treatment, subjects will receive three different 1 week concurrent interventions, in a cross-over fashion, separated by a 4 week washout. The interventions will be: placebo + placebo, sitagliptin + placebo, sitagliptin + aprepitant.
Placebo: Subjects will receive two capsules of placebo to preserve the blinding of the study.
In a separate period, subjects will receive one capsule of placebo and one capsule of sitagliptin.
Sitagliptin: Subjects will receive sitagliptin 100mg daily for 7 days. In addition, subjects will receive either aprepitant or a capsule of placebo to preserve the blinding of the study.
Aprepitant: Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.
Mixed Meal Test (MMT): The first 18 subjects per arm/ group will undergo a mixed meal test on the 7th day of each medication intervention. This will take place after the first half of the study day at the clinical research center, following a 30 minute rest. Subjects will ingest a shake (combination of fixed carbohydrates/ fat/ protein) and have blood pressure, heart rate, and venous blood sample measurements collected for 4 hours after the meal. | 35 |
| Total | 106 |
Baseline characteristics
| Characteristic | Amlodipine | Total | Valsartan | Ramipril |
|---|---|---|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 10.9 | 56.3 years STANDARD_DEVIATION 10.6 | 57.9 years STANDARD_DEVIATION 10.4 | 52.9 years STANDARD_DEVIATION 9.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 26 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 76 Participants | 25 Participants | 27 Participants |
| Region of Enrollment United States | 36 participants | 106 participants | 35 participants | 35 participants |
| Sex: Female, Male Female | 18 Participants | 53 Participants | 17 Participants | 18 Participants |
| Sex: Female, Male Male | 18 Participants | 53 Participants | 18 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 36 | 0 / 33 | 0 / 33 | 0 / 33 | 0 / 35 | 0 / 33 | 0 / 27 | 0 / 25 | 0 / 28 | 0 / 35 | 0 / 31 | 0 / 28 | 0 / 29 | 0 / 29 |
| other Total, other adverse events | 4 / 36 | 1 / 36 | 7 / 33 | 4 / 33 | 9 / 33 | 3 / 35 | 3 / 33 | 3 / 27 | 1 / 25 | 4 / 28 | 5 / 35 | 0 / 31 | 4 / 28 | 5 / 29 | 3 / 29 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 | 0 / 33 | 0 / 33 | 0 / 33 | 0 / 35 | 0 / 33 | 0 / 27 | 0 / 25 | 0 / 28 | 1 / 35 | 1 / 31 | 0 / 28 | 0 / 29 | 0 / 29 |
Outcome results
Primary
Heart Rate
The primary analyses will focus on blood pressure, heart rate, and norepinephrine (NE) concentrations during ramipril versus ramipril+sitagliptin, and during ramipril+sitagliptin versus ramipril+sitagliptin+aprepitant. We will make similar comparisons within the valsartan- and placebo-treated groups. In addition, we will compare blood pressure and heart rate parameters among the ramipril-treated, valsartan-treated, and placebo-treated groups during comparable concurrent treatment.
Time frame: 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Heart Rate | 69.59 beats per minute | Standard Deviation 9.75 |
| Amlodipine Plus Sitagliptin/Placebo | Heart Rate | 70.43 beats per minute | Standard Deviation 9.79 |
| Amlodipine Plus Sitagliptin/Aprepitant | Heart Rate | 69.41 beats per minute | Standard Deviation 9.84 |
| Ramipril Plus Placebo/Placebo | Heart Rate | 66.58 beats per minute | Standard Deviation 7.71 |
| Ramipril Plus Sitagliptin/Placebo | Heart Rate | 66.30 beats per minute | Standard Deviation 8.16 |
| Ramipril Plus Sitagliptin/Aprepitant | Heart Rate | 66.15 beats per minute | Standard Deviation 8.06 |
| Valsartan Plus Placebo/Placebo | Heart Rate | 66.19 beats per minute | Standard Deviation 9.19 |
| Valsartan Plus Sitagliptin/Placebo | Heart Rate | 65.86 beats per minute | Standard Deviation 8.46 |
| Valsartan Plus Sitagliptin/Aprepitant | Heart Rate | 65.10 beats per minute | Standard Deviation 8.52 |
Primary
Mean Arterial Blood Pressure
The primary analyses will focus on mean arterial blood pressure, heart rate, and norepinephrine (NE) concentrations during ramipril versus ramipril+sitagliptin, and during ramipril+sitagliptin versus ramipril+sitagliptin+aprepitant. We will make similar comparisons within the valsartan- and placebo-treated groups. In addition, we will compare blood pressure and heart rate parameters among the ramipril-treated, valsartan-treated, and placebo-treated groups during comparable concurrent treatment.
Time frame: 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Mean Arterial Blood Pressure | 94.42 mmHg | Standard Deviation 7.53 |
| Amlodipine Plus Sitagliptin/Placebo | Mean Arterial Blood Pressure | 93.41 mmHg | Standard Deviation 8.75 |
| Amlodipine Plus Sitagliptin/Aprepitant | Mean Arterial Blood Pressure | 91.54 mmHg | Standard Deviation 7.8 |
| Ramipril Plus Placebo/Placebo | Mean Arterial Blood Pressure | 90.21 mmHg | Standard Deviation 12.46 |
| Ramipril Plus Sitagliptin/Placebo | Mean Arterial Blood Pressure | 89.88 mmHg | Standard Deviation 9.67 |
| Ramipril Plus Sitagliptin/Aprepitant | Mean Arterial Blood Pressure | 86.95 mmHg | Standard Deviation 10.16 |
| Valsartan Plus Placebo/Placebo | Mean Arterial Blood Pressure | 94.54 mmHg | Standard Deviation 9.96 |
| Valsartan Plus Sitagliptin/Placebo | Mean Arterial Blood Pressure | 93.71 mmHg | Standard Deviation 10.75 |
| Valsartan Plus Sitagliptin/Aprepitant | Mean Arterial Blood Pressure | 93.98 mmHg | Standard Deviation 10.75 |
Primary
Norepinephrine (NE) Concentrations
The primary analyses will focus on blood pressure, heart rate, and norepinephrine (NE) concentrations during ramipril versus ramipril+sitagliptin, and during ramipril+sitagliptin versus ramipril+sitagliptin+aprepitant. We will make similar comparisons within the valsartan- and placebo-treated groups. In addition, we will compare blood pressure and heart rate parameters among the ramipril-treated, valsartan-treated, and placebo-treated groups during comparable concurrent treatment.
Time frame: 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Norepinephrine (NE) Concentrations | 741.65 pg/mL | Standard Deviation 660.82 |
| Amlodipine Plus Sitagliptin/Placebo | Norepinephrine (NE) Concentrations | 730.88 pg/mL | Standard Deviation 613.69 |
| Amlodipine Plus Sitagliptin/Aprepitant | Norepinephrine (NE) Concentrations | 610.65 pg/mL | Standard Deviation 587.19 |
| Ramipril Plus Placebo/Placebo | Norepinephrine (NE) Concentrations | 470.69 pg/mL | Standard Deviation 474.88 |
| Ramipril Plus Sitagliptin/Placebo | Norepinephrine (NE) Concentrations | 627.55 pg/mL | Standard Deviation 593.92 |
| Ramipril Plus Sitagliptin/Aprepitant | Norepinephrine (NE) Concentrations | 649.39 pg/mL | Standard Deviation 624.67 |
| Valsartan Plus Placebo/Placebo | Norepinephrine (NE) Concentrations | 874.22 pg/mL | Standard Deviation 863.75 |
| Valsartan Plus Sitagliptin/Placebo | Norepinephrine (NE) Concentrations | 986.31 pg/mL | Standard Deviation 1114.67 |
| Valsartan Plus Sitagliptin/Aprepitant | Norepinephrine (NE) Concentrations | 1013.54 pg/mL | Standard Deviation 1073.91 |
Secondary
24hr Urinary Testing for Sodium
Subjects will collect 24hr urine sample and bring with to the study day for analysis
Time frame: Urine was collected for sodium for 24 hrs prior to each of the study days listed below. Study days occurred after each 7-day treatment arm (placebo/placebo, sitagliptin/placebo, or sitagliptin/aprepitant) within 3 anti-hypertensive groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | 24hr Urinary Testing for Sodium | 147.66 mEq | Standard Deviation 69.46 |
| Amlodipine Plus Sitagliptin/Placebo | 24hr Urinary Testing for Sodium | 146.90 mEq | Standard Deviation 74.29 |
| Amlodipine Plus Sitagliptin/Aprepitant | 24hr Urinary Testing for Sodium | 154.42 mEq | Standard Deviation 61.01 |
| Ramipril Plus Placebo/Placebo | 24hr Urinary Testing for Sodium | 177.70 mEq | Standard Deviation 74.48 |
| Ramipril Plus Sitagliptin/Placebo | 24hr Urinary Testing for Sodium | 162.05 mEq | Standard Deviation 68.55 |
| Ramipril Plus Sitagliptin/Aprepitant | 24hr Urinary Testing for Sodium | 142.95 mEq | Standard Deviation 94.62 |
| Valsartan Plus Placebo/Placebo | 24hr Urinary Testing for Sodium | 158.77 mEq | Standard Deviation 60.19 |
| Valsartan Plus Sitagliptin/Placebo | 24hr Urinary Testing for Sodium | 138.65 mEq | Standard Deviation 44.48 |
| Valsartan Plus Sitagliptin/Aprepitant | 24hr Urinary Testing for Sodium | 160.92 mEq | Standard Deviation 80.86 |
Secondary
Angiotensin Converting Enzyme (ACE) Activity
This is a measure of activity of the angiotensin-converting enzyme (ACE). The assay is a kinetic assay (Labcore) that measures the rate of cleavage of an added ACE substrate over time and the results are reported in Units, which represent the rate of increase in fluorescent metabolite over 30 minutes under standard conditions at 37C.
Time frame: for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Angiotensin Converting Enzyme (ACE) Activity | 37.00 Units | Standard Deviation 14.56 |
| Amlodipine Plus Sitagliptin/Placebo | Angiotensin Converting Enzyme (ACE) Activity | 40.15 Units | Standard Deviation 14.87 |
| Amlodipine Plus Sitagliptin/Aprepitant | Angiotensin Converting Enzyme (ACE) Activity | 35.78 Units | Standard Deviation 13.73 |
| Ramipril Plus Placebo/Placebo | Angiotensin Converting Enzyme (ACE) Activity | 15.44 Units | Standard Deviation 9.2 |
| Ramipril Plus Sitagliptin/Placebo | Angiotensin Converting Enzyme (ACE) Activity | 14.69 Units | Standard Deviation 9.37 |
| Ramipril Plus Sitagliptin/Aprepitant | Angiotensin Converting Enzyme (ACE) Activity | 13.46 Units | Standard Deviation 5.38 |
| Valsartan Plus Placebo/Placebo | Angiotensin Converting Enzyme (ACE) Activity | 37.21 Units | Standard Deviation 14.75 |
| Valsartan Plus Sitagliptin/Placebo | Angiotensin Converting Enzyme (ACE) Activity | 36.68 Units | Standard Deviation 13.08 |
| Valsartan Plus Sitagliptin/Aprepitant | Angiotensin Converting Enzyme (ACE) Activity | 36.89 Units | Standard Deviation 13.2 |
Secondary
Dipeptidyl Peptidase IV (DPP4) Activity
Measure of DPP4 inhibitor administration.
Time frame: for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Dipeptidyl Peptidase IV (DPP4) Activity | 20.27 nmol/mL/min | Standard Deviation 6.8 |
| Amlodipine Plus Sitagliptin/Placebo | Dipeptidyl Peptidase IV (DPP4) Activity | 7.34 nmol/mL/min | Standard Deviation 2.98 |
| Amlodipine Plus Sitagliptin/Aprepitant | Dipeptidyl Peptidase IV (DPP4) Activity | 6.96 nmol/mL/min | Standard Deviation 4.33 |
| Ramipril Plus Placebo/Placebo | Dipeptidyl Peptidase IV (DPP4) Activity | 20.61 nmol/mL/min | Standard Deviation 6.24 |
| Ramipril Plus Sitagliptin/Placebo | Dipeptidyl Peptidase IV (DPP4) Activity | 8.78 nmol/mL/min | Standard Deviation 6.5 |
| Ramipril Plus Sitagliptin/Aprepitant | Dipeptidyl Peptidase IV (DPP4) Activity | 7.71 nmol/mL/min | Standard Deviation 3.4 |
| Valsartan Plus Placebo/Placebo | Dipeptidyl Peptidase IV (DPP4) Activity | 19.4 nmol/mL/min | Standard Deviation 7.14 |
| Valsartan Plus Sitagliptin/Placebo | Dipeptidyl Peptidase IV (DPP4) Activity | 7.83 nmol/mL/min | Standard Deviation 4.07 |
| Valsartan Plus Sitagliptin/Aprepitant | Dipeptidyl Peptidase IV (DPP4) Activity | 6.70 nmol/mL/min | Standard Deviation 3.53 |
Secondary
Glucose
measure of effectiveness of DPP4 inhibitor
Time frame: fasting at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Glucose | 123.78 mg/dL | Standard Deviation 34.28 |
| Amlodipine Plus Sitagliptin/Placebo | Glucose | 112.51 mg/dL | Standard Deviation 29.96 |
| Amlodipine Plus Sitagliptin/Aprepitant | Glucose | 109.08 mg/dL | Standard Deviation 21.35 |
| Ramipril Plus Placebo/Placebo | Glucose | 118.04 mg/dL | Standard Deviation 21.79 |
| Ramipril Plus Sitagliptin/Placebo | Glucose | 107.55 mg/dL | Standard Deviation 18.41 |
| Ramipril Plus Sitagliptin/Aprepitant | Glucose | 107.66 mg/dL | Standard Deviation 17.47 |
| Valsartan Plus Placebo/Placebo | Glucose | 112.01 mg/dL | Standard Deviation 21.6 |
| Valsartan Plus Sitagliptin/Placebo | Glucose | 103.69 mg/dL | Standard Deviation 18.13 |
| Valsartan Plus Sitagliptin/Aprepitant | Glucose | 99.75 mg/dL | Standard Deviation 15.59 |
Secondary
Heart Rate
The average of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal
Time frame: Value provided is the average of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Heart Rate | 71.8 bpm | Standard Deviation 13.1 |
| Amlodipine Plus Sitagliptin/Placebo | Heart Rate | 70.3 bpm | Standard Deviation 11.6 |
| Amlodipine Plus Sitagliptin/Aprepitant | Heart Rate | 71.7 bpm | Standard Deviation 13 |
| Ramipril Plus Placebo/Placebo | Heart Rate | 69.9 bpm | Standard Deviation 10.7 |
| Ramipril Plus Sitagliptin/Placebo | Heart Rate | 73.3 bpm | Standard Deviation 9.2 |
| Ramipril Plus Sitagliptin/Aprepitant | Heart Rate | 72.0 bpm | Standard Deviation 10.4 |
| Valsartan Plus Placebo/Placebo | Heart Rate | 70.3 bpm | Standard Deviation 11.9 |
| Valsartan Plus Sitagliptin/Placebo | Heart Rate | 71.9 bpm | Standard Deviation 11.3 |
| Valsartan Plus Sitagliptin/Aprepitant | Heart Rate | 71.9 bpm | Standard Deviation 11.3 |
Secondary
Insulin
Measure of insulin resistance.
Time frame: fasting insulin measured at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitatliptin+aprepitant)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Insulin | 20.7 microU/mL | Standard Deviation 10.36 |
| Amlodipine Plus Sitagliptin/Placebo | Insulin | 20.72 microU/mL | Standard Deviation 11.95 |
| Amlodipine Plus Sitagliptin/Aprepitant | Insulin | 20.22 microU/mL | Standard Deviation 16.32 |
| Ramipril Plus Placebo/Placebo | Insulin | 26.15 microU/mL | Standard Deviation 13.82 |
| Ramipril Plus Sitagliptin/Placebo | Insulin | 22.59 microU/mL | Standard Deviation 13.01 |
| Ramipril Plus Sitagliptin/Aprepitant | Insulin | 26.02 microU/mL | Standard Deviation 18.48 |
| Valsartan Plus Placebo/Placebo | Insulin | 21.39 microU/mL | Standard Deviation 16.22 |
| Valsartan Plus Sitagliptin/Placebo | Insulin | 19.92 microU/mL | Standard Deviation 14.46 |
| Valsartan Plus Sitagliptin/Aprepitant | Insulin | 16.83 microU/mL | Standard Deviation 10.58 |
Secondary
Low Frequency Variability of Blood Pressure Activity
Low frequency variability of systolic blood pressure will be measured using spectral analysis.
Time frame: for 5 minutes on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Low Frequency Variability of Blood Pressure Activity | 5.14 mmHg2 | Standard Deviation 2.65 |
| Amlodipine Plus Sitagliptin/Placebo | Low Frequency Variability of Blood Pressure Activity | 7.32 mmHg2 | Standard Deviation 7.72 |
| Amlodipine Plus Sitagliptin/Aprepitant | Low Frequency Variability of Blood Pressure Activity | 7.07 mmHg2 | Standard Deviation 6.57 |
| Ramipril Plus Placebo/Placebo | Low Frequency Variability of Blood Pressure Activity | 8.78 mmHg2 | Standard Deviation 8.1 |
| Ramipril Plus Sitagliptin/Placebo | Low Frequency Variability of Blood Pressure Activity | 7.27 mmHg2 | Standard Deviation 5.91 |
| Ramipril Plus Sitagliptin/Aprepitant | Low Frequency Variability of Blood Pressure Activity | 12.18 mmHg2 | Standard Deviation 11.16 |
| Valsartan Plus Placebo/Placebo | Low Frequency Variability of Blood Pressure Activity | 8.51 mmHg2 | Standard Deviation 5.43 |
| Valsartan Plus Sitagliptin/Placebo | Low Frequency Variability of Blood Pressure Activity | 7.81 mmHg2 | Standard Deviation 3.65 |
| Valsartan Plus Sitagliptin/Aprepitant | Low Frequency Variability of Blood Pressure Activity | 8.58 mmHg2 | Standard Deviation 6.57 |
Secondary
Mean Arterial Blood Pressure
Average of measurements made every five minutes beginning just prior to (time 0) and for four hours after the ingestion of a mixed meal
Time frame: Value provided is the AVERAGE of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Mean Arterial Blood Pressure | 96.0 mmHg | Standard Deviation 10 |
| Amlodipine Plus Sitagliptin/Placebo | Mean Arterial Blood Pressure | 93.6 mmHg | Standard Deviation 8.9 |
| Amlodipine Plus Sitagliptin/Aprepitant | Mean Arterial Blood Pressure | 92.9 mmHg | Standard Deviation 8.7 |
| Ramipril Plus Placebo/Placebo | Mean Arterial Blood Pressure | 94.2 mmHg | Standard Deviation 11.3 |
| Ramipril Plus Sitagliptin/Placebo | Mean Arterial Blood Pressure | 92.6 mmHg | Standard Deviation 10.7 |
| Ramipril Plus Sitagliptin/Aprepitant | Mean Arterial Blood Pressure | 91.0 mmHg | Standard Deviation 9.6 |
| Valsartan Plus Placebo/Placebo | Mean Arterial Blood Pressure | 94.2 mmHg | Standard Deviation 11.6 |
| Valsartan Plus Sitagliptin/Placebo | Mean Arterial Blood Pressure | 96.1 mmHg | Standard Deviation 8.8 |
| Valsartan Plus Sitagliptin/Aprepitant | Mean Arterial Blood Pressure | 94.5 mmHg | Standard Deviation 8.6 |
Secondary
Neuropeptide Y
Measurement of Neuropeptide Y (NPY) concentrations
Time frame: Neuropeptide Y concentration prior to ingestion of the mixed meal.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Amlodipine Plus Placebo/Placebo | Neuropeptide Y | 0.35 pM | Standard Error 0.28 |
| Amlodipine Plus Sitagliptin/Placebo | Neuropeptide Y | 0.52 pM | Standard Error 0.34 |
| Amlodipine Plus Sitagliptin/Aprepitant | Neuropeptide Y | 0.51 pM | Standard Error 0.33 |
| Ramipril Plus Placebo/Placebo | Neuropeptide Y | 0.32 pM | Standard Error 0.32 |
| Ramipril Plus Sitagliptin/Placebo | Neuropeptide Y | 0.54 pM | Standard Error 0.26 |
| Ramipril Plus Sitagliptin/Aprepitant | Neuropeptide Y | 0.52 pM | Standard Error 0.29 |
| Valsartan Plus Placebo/Placebo | Neuropeptide Y | 0.27 pM | Standard Error 0.15 |
| Valsartan Plus Sitagliptin/Placebo | Neuropeptide Y | 0.50 pM | Standard Error 0.26 |
| Valsartan Plus Sitagliptin/Aprepitant | Neuropeptide Y | 0.47 pM | Standard Error 0.28 |
Other Pre-specified
Aldosterone, Angiotensin II, and Plasma Renin Activity (PRA)
renin-angiotensin system measurements were not done because there were not significant differences in blood pressure
Time frame: for 4.5 hours on the 7th day of each intervention