Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02130687
• Collaborator: (none)
• Enrollment: 106
• Location: 1
• Arms: 3
• Duration (Months): 74
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus; Hypertension	Drug: Placebo; Drug: Sitagliptin; Drug: Aprepitant; Other: Mixed Meal Test (MMT)	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Contribution of Substance P to Blood Pressure Regulation in the Setting of Dipeptidyl Peptidase IV (DPP4) and Angiotensin-Converting Enzyme (ACE) Inhibition
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: May 1, 2020
• Actual Study Completion Date: Aug 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: 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.; Other Names: Microcrystalline cellulose ; Drug: 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.; Other Names: Januvia ; Drug: Aprepitant; Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.; Other Names: Emend ; Other: 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.
Experimental: 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.	Drug: 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.; Other Names: Microcrystalline cellulose ; Drug: 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.; Other Names: Januvia ; Drug: Aprepitant; Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.; Other Names: Emend ; Other: 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.
Active Comparator: 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.	Drug: 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.; Other Names: Microcrystalline cellulose ; Drug: 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.; Other Names: Januvia ; Drug: Aprepitant; Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.; Other Names: Emend ; Other: 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.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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.

2. Glucose [fasting at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)]

   measure of effectiveness of DPP4 inhibitor

3. Insulin [fasting insulin measured at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitatliptin+aprepitant)]

   Measure of insulin resistance.

4. 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.

5. 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.

6. 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

7. 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

8. Neuropeptide Y [Neuropeptide Y concentration prior to ingestion of the mixed meal.]

   Measurement of Neuropeptide Y (NPY) concentrations

9. 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

Other Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University

Investigators

• Principal Investigator: Nancy J Brown, M.D., Vanderbilt University

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Feb 19, 2019

More Information

Publications

None provided.

• Responsible Party: Nancy J. Brown, MD, Hugh Jackson Morgan Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT02130687
• Other Study ID Numbers: 121253
• First Posted: May 5, 2014
• Last Update Posted: Mar 2, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by Nancy J. Brown, MD, Hugh Jackson Morgan Professor, Vanderbilt University: Type 2 Diabetes Mellitus; Hypertension; Angiotensin Converting Enzyme Inhibitors; Dipeptidyl Peptidase IV Inhibitors; Sitagliptin; Aprepitant; Ramipril
• Additional relevant MeSH terms: Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2; Sitagliptin Phosphate; Aprepitant

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Amlodipine	Ramipril	Valsartan
Arm/Group Description	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.	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.	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.
Period Title: Washout
STARTED	36	35	35
COMPLETED	36	33	31
NOT COMPLETED	0	2	4
Period Title: Washout
STARTED	36	33	31
COMPLETED	33	30	30
NOT COMPLETED	3	3	1
Period Title: Washout
STARTED	33	30	30
COMPLETED	33	30	30
NOT COMPLETED	0	0	0
Period Title: Washout
STARTED	33	30	30
COMPLETED	33	26	29
NOT COMPLETED	0	4	1
Period Title: Washout
STARTED	33	26	29
COMPLETED	33	26	29
NOT COMPLETED	0	0	0
Period Title: Washout
STARTED	33	26	29
COMPLETED	33	25	27
NOT COMPLETED	0	1	2
Period Title: Washout
STARTED	33	25	27
COMPLETED	33	25	27
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Amlodipine	Ramipril	Valsartan	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	36	35	35	106
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.1 (10.9)	52.9 (9.9)	57.9 (10.4)	56.3 (10.6)
Sex: Female, Male (Count of Participants)
Female	18 50%	18 51.4%	17 48.6%	53 50%
Male	18 50%	17 48.6%	18 51.4%	53 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 2.8%	1 2.9%	0 0%	2 1.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	11 30.6%	6 17.1%	9 25.7%	26 24.5%
White	24 66.7%	27 77.1%	25 71.4%	76 71.7%
More than one race	0 0%	1 2.9%	1 2.9%	2 1.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	36 100%	35 100%	35 100%	106 100%

Outcome Measures

1. Primary Outcome

Title	Mean Arterial Blood Pressure
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	33	33	33	27	25	28	28	29	29
Mean (Standard Deviation) [mmHg]	94.42 (7.53)	93.41 (8.75)	91.54 (7.80)	90.21 (12.46)	89.88 (9.67)	86.95 (10.16)	94.54 (9.96)	93.71 (10.75)	93.98 (10.75)

2. Primary Outcome

Title	Heart Rate
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	33	33	33	27	25	28	28	29	29
Mean (Standard Deviation) [beats per minute]	69.59 (9.75)	70.43 (9.79)	69.41 (9.84)	66.58 (7.71)	66.30 (8.16)	66.15 (8.06)	66.19 (9.19)	65.86 (8.46)	65.10 (8.52)

3. Primary Outcome

Title	Norepinephrine (NE) Concentrations
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	32	32	32	27	25	27	28	28	28
Mean (Standard Deviation) [pg/mL]	741.65 (660.82)	730.88 (613.69)	610.65 (587.19)	470.69 (474.88)	627.55 (593.92)	649.39 (624.67)	874.22 (863.75)	986.31 (1114.67)	1013.54 (1073.91)

4. Secondary Outcome

Title	Low Frequency Variability of Blood Pressure Activity
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	19	20	20	13	14	13	16	16	16
Mean (Standard Deviation) [mmHg2]	5.14 (2.65)	7.32 (7.72)	7.07 (6.57)	8.78 (8.10)	7.27 (5.91)	12.18 (11.16)	8.51 (5.43)	7.81 (3.65)	8.58 (6.57)

5. Secondary Outcome

Title	Glucose
Description	measure of effectiveness of DPP4 inhibitor
Time Frame	fasting at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	32	33	32	27	25	27	28	29	29
Mean (Standard Deviation) [mg/dL]	123.78 (34.28)	112.51 (29.96)	109.08 (21.35)	118.04 (21.79)	107.55 (18.41)	107.66 (17.47)	112.01 (21.6)	103.69 (18.13)	99.75 (15.59)

6. Secondary Outcome

Title	Insulin
Description	Measure of insulin resistance.
Time Frame	fasting insulin measured at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitatliptin+aprepitant)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	26	22	21	21	21	22	20	21	20
Mean (Standard Deviation) [microU/mL]	20.7 (10.36)	20.72 (11.95)	20.22 (16.32)	26.15 (13.82)	22.59 (13.01)	26.02 (18.48)	21.39 (16.22)	19.92 (14.46)	16.83 (10.58)

7. Secondary Outcome

Title	Dipeptidyl Peptidase IV (DPP4) Activity
Description	Measure of DPP4 inhibitor administration.
Time Frame	for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	33	33	31	25	23	26	26	27	27
Mean (Standard Deviation) [nmol/mL/min]	20.27 (6.80)	7.34 (2.98)	6.96 (4.33)	20.61 (6.24)	8.78 (6.5)	7.71 (3.4)	19.4 (7.14)	7.83 (4.07)	6.70 (3.53)

8. Secondary Outcome

Title	Angiotensin Converting Enzyme (ACE) Activity
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	33	33	32	26	24	25	28	28	28
Mean (Standard Deviation) [Units]	37.00 (14.56)	40.15 (14.87)	35.78 (13.73)	15.44 (9.20)	14.69 (9.37)	13.46 (5.38)	37.21 (14.75)	36.68 (13.08)	36.89 (13.20)

9. Secondary Outcome

Title	Mean Arterial Blood Pressure
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	20	20	20	15	15	15	16	16	16
Mean (Standard Deviation) [mmHg]	96.0 (10.0)	93.6 (8.9)	92.9 (8.7)	94.2 (11.3)	92.6 (10.7)	91.0 (9.6)	94.2 (11.6)	96.1 (8.8)	94.5 (8.6)

10. Secondary Outcome

Title	Heart Rate
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	20	20	20	15	15	15	16	16	16
Mean (Standard Deviation) [bpm]	71.8 (13.1)	70.3 (11.6)	71.7 (13.0)	69.9 (10.7)	73.3 (9.2)	72.0 (10.4)	70.3 (11.9)	71.9 (11.3)	71.9 (11.3)

11. Secondary Outcome

Title	Neuropeptide Y
Description	Measurement of Neuropeptide Y (NPY) concentrations
Time Frame	Neuropeptide Y concentration prior to ingestion of the mixed meal.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	20	20	20	15	15	15	16	16	16
Mean (Standard Error) [pM]	0.35 (0.28)	0.52 (0.34)	0.51 (0.33)	0.32 (0.32)	0.54 (0.26)	0.52 (0.29)	0.27 (0.15)	0.50 (0.26)	0.47 (0.28)

12. Secondary Outcome

Title	24hr Urinary Testing for Sodium
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Amlodipine Plus Placebo/Placebo	Amlodipine Plus Sitagliptin/Placebo	Amlodipine Plus Sitagliptin/Aprepitant	Ramipril Plus Placebo/Placebo	Ramipril Plus Sitagliptin/Placebo	Ramipril Plus Sitagliptin/Aprepitant	Valsartan Plus Placebo/Placebo	Valsartan Plus Sitagliptin/Placebo	Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for one week for 7 days.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule.	Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and a placebo capsule for 7 days.	Participants in this group received valsartan 320mg/d for 15 weeks. During this intervention period they also received sitagliptin 100mg/day and aprepitant 125mg/d for one day followed by 80 mg/d for a total of 7 days.
Measure Participants	29	29	29	20	20	22	26	26	25
Mean (Standard Deviation) [mEq]	147.66 (69.46)	146.90 (74.29)	154.42 (61.01)	177.70 (74.48)	162.05 (68.55)	142.95 (94.62)	158.77 (60.19)	138.65 (44.48)	160.92 (80.86)

13. Other Pre-specified Outcome

Title	Aldosterone, Angiotensin II, and Plasma Renin Activity (PRA)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse event data were collected through study completion or for approximately 15 weeks.
Adverse Event Reporting Description	Information for adverse events are provided for each anti-hypertensive group. Most events occurred during periods before or between crossover treatment periods and these are listed as such.
Arm/Group Title	Washout Prior to Amlodipine		Amlodipine Alone		Amlodipine Plus Sitagliptin/Placebo		Amlodipine Plus Placebo/Placebo		Amlodipine Plus Sitagliptin/Aprepitant		Washout Prior to Ramipril		Ramipril Alone		Ramipril Plus Placebo/Placebo		Ramipril Plus Sitagliptin/Placebo		Ramipril Plus Sitagliptin/Aprepitant		Washout Prior to Valsartan		Valsartan Alone		Valsartan Plus Placebo/Placebo		Valsartan Plus Sitagliptin/Placebo		Valsartan Plus Sitagliptin/Aprepitant
Arm/Group Description	Subjects in this arm received calcium channel blocker therapy with amlodipine 5mg daily for 3 days then 10mg daily for 15 weeks. Subjects underwent washout prior to starting amlodipine.		Subjects in this arm received calcium channel blocker therapy with amlodipine 5mg daily for 3 days then 10mg daily for 15 weeks. After 4 weeks of treatment, subjects received three different 1 week concurrent interventions, in a cross-over fashion, separated by a 4 week washout. The interventions were: placebo + placebo, sitagliptin + placebo, sitagliptin + aprepitant. During the first four weeks and between crossover therapies, participants received amlodipine alone.		Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.		Participants received amlodipine 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100 mg/day and a placebo capsule for 7 days.		Participants received amlodipine 10mg/day for 15 weeks. During this intervention period they also received sitagliptin 100 mg/day and aprepitant 125 mg/d for one day followed by 80 mg/d for a total of 7 days.		Subjects received ACE-inhibitor therapy with ramipril 5mg daily for 3 days, followed by 10mg daily for the remaining 15 weeks. Subjects underwent washout prior to starting ramipril.		Subjects received 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 received three different 1 week concurrent interventions, in a cross-over fashion, separated by a 4 week washout. The interventions were: placebo + placebo, sitagliptin + placebo, sitagliptin + aprepitant. During the first four weeks and between crossover therapies, participants received ramipril alone.		Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.		Participants in this group received ramipril 10mg/d for 15 weeks. During this intervention period they also received sitagliptin 100 mg/day and a placebo capsule for 7 days.		Participants in this group received ramipril 10mg/d for 15 days. During this intervention period they also received sitagliptin 100 mg/day and aprepitant 125 mg/d for one day followed by 80 mg/d for a total of 7 days.		Subjects received ARB therapy with valsartan 160mg daily for 3 days, followed by 320mg daily for the remaining 15 weeks. Subjects underwent washout prior to starting valsartan.		Subjects received ARB therapy with valsartan 160mg daily for 3 days, followed by 320mg daily for the remaining 15 weeks. After 4 weeks of treatment, subjects received 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. During the first four weeks and between crossover therapies, participants received valsartan alone.		Participants in this group received valsartan 320 mg/d for 15 weeks. During this intervention period they also received two placebo capsules for 7 days.		Participants in this group received valsartan 320 mg/d for 15 weeks. During this intervention period they also received sitagliptin 100 mg/day and a placebo capsule for 7 days.		Participants in this group received valsartan 320 mg/d for 15 weeks. During this intervention period they also received sitagliptin 100 mg/day and aprepitant 125 mg/d for one day followed by 80 mg/d for a total of 7 days.
All Cause Mortality
	Washout Prior to Amlodipine		Amlodipine Alone		Amlodipine Plus Sitagliptin/Placebo		Amlodipine Plus Placebo/Placebo		Amlodipine Plus Sitagliptin/Aprepitant		Washout Prior to Ramipril		Ramipril Alone		Ramipril Plus Placebo/Placebo		Ramipril Plus Sitagliptin/Placebo		Ramipril Plus Sitagliptin/Aprepitant		Washout Prior to Valsartan		Valsartan Alone		Valsartan Plus Placebo/Placebo		Valsartan Plus Sitagliptin/Placebo		Valsartan Plus Sitagliptin/Aprepitant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/36 (0%)		0/33 (0%)		0/33 (0%)		0/33 (0%)		0/35 (0%)		0/33 (0%)		0/27 (0%)		0/25 (0%)		0/28 (0%)		0/35 (0%)		0/31 (0%)		0/28 (0%)		0/29 (0%)		0/29 (0%)
Serious Adverse Events
	Washout Prior to Amlodipine		Amlodipine Alone		Amlodipine Plus Sitagliptin/Placebo		Amlodipine Plus Placebo/Placebo		Amlodipine Plus Sitagliptin/Aprepitant		Washout Prior to Ramipril		Ramipril Alone		Ramipril Plus Placebo/Placebo		Ramipril Plus Sitagliptin/Placebo		Ramipril Plus Sitagliptin/Aprepitant		Washout Prior to Valsartan		Valsartan Alone		Valsartan Plus Placebo/Placebo		Valsartan Plus Sitagliptin/Placebo		Valsartan Plus Sitagliptin/Aprepitant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/36 (0%)		0/33 (0%)		0/33 (0%)		0/33 (0%)		0/35 (0%)		0/33 (0%)		0/27 (0%)		0/25 (0%)		0/28 (0%)		1/35 (2.9%)		1/31 (3.2%)		0/28 (0%)		0/29 (0%)		0/29 (0%)
Cardiac disorders
atrial fibrillation	0/36 (0%)	0	0/36 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/35 (0%)	0	0/33 (0%)	0	0/27 (0%)	0	0/25 (0%)	0	0/28 (0%)	0	1/35 (2.9%)	1	0/31 (0%)	0	0/28 (0%)	0	0/29 (0%)	0	0/29 (0%)	0
unstable angina	0/36 (0%)	0	0/36 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/35 (0%)	0	0/33 (0%)	0	0/27 (0%)	0	0/25 (0%)	0	0/28 (0%)	0	0/35 (0%)	0	1/31 (3.2%)	1	0/28 (0%)	0	0/29 (0%)	0	0/29 (0%)	0
Other (Not Including Serious) Adverse Events
	Washout Prior to Amlodipine		Amlodipine Alone		Amlodipine Plus Sitagliptin/Placebo		Amlodipine Plus Placebo/Placebo		Amlodipine Plus Sitagliptin/Aprepitant		Washout Prior to Ramipril		Ramipril Alone		Ramipril Plus Placebo/Placebo		Ramipril Plus Sitagliptin/Placebo		Ramipril Plus Sitagliptin/Aprepitant		Washout Prior to Valsartan		Valsartan Alone		Valsartan Plus Placebo/Placebo		Valsartan Plus Sitagliptin/Placebo		Valsartan Plus Sitagliptin/Aprepitant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/36 (11.1%)		1/36 (2.8%)		7/33 (21.2%)		4/33 (12.1%)		9/33 (27.3%)		3/35 (8.6%)		3/33 (9.1%)		3/27 (11.1%)		1/25 (4%)		4/28 (14.3%)		5/35 (14.3%)		0/31 (0%)		4/28 (14.3%)		5/29 (17.2%)		3/29 (10.3%)
Cardiac disorders
elevated blood pressure	4/36 (11.1%)	4	0/35 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	1/33 (3%)	1	3/35 (8.6%)	3	0/31 (0%)	0	0/27 (0%)	0	0/25 (0%)	0	0/28 (0%)	0	2/35 (5.7%)	2	0/31 (0%)	0	1/28 (3.6%)	1	1/29 (3.4%)	1	0/29 (0%)	0
orthostasis	0/36 (0%)	0	0/35 (0%)	0	3/33 (9.1%)	3	3/33 (9.1%)	3	1/33 (3%)	1	0/35 (0%)	0	1/31 (3.2%)	1	0/27 (0%)	0	0/25 (0%)	0	0/28 (0%)	0	0/35 (0%)	0	0/31 (0%)	0	1/28 (3.6%)	1	1/29 (3.4%)	1	1/29 (3.4%)	1
Gastrointestinal disorders
diarrhea	0/36 (0%)	0	0/35 (0%)	0	1/33 (3%)	1	1/33 (3%)	1	2/33 (6.1%)	2	0/35 (0%)	0	0/31 (0%)	0	1/27 (3.7%)	1	0/25 (0%)	0	0/28 (0%)	0	0/35 (0%)	0	0/31 (0%)	0	1/28 (3.6%)	1	1/29 (3.4%)	1	1/29 (3.4%)	1
Nervous system disorders
headache	0/36 (0%)	0	0/35 (0%)	0	1/33 (3%)	1	0/33 (0%)	0	1/33 (3%)	1	0/35 (0%)	0	0/31 (0%)	0	0/27 (0%)	0	0/25 (0%)	0	2/28 (7.1%)	2	2/35 (5.7%)	2	0/31 (0%)	0	1/28 (3.6%)	1	2/29 (6.9%)	2	1/29 (3.4%)	1
Renal and urinary disorders
hypokalemia	0/36 (0%)	0	0/35 (0%)	0	1/33 (3%)	1	0/33 (0%)	0	2/33 (6.1%)	2	0/35 (0%)	0	0/31 (0%)	0	0/27 (0%)	0	0/25 (0%)	0	1/28 (3.6%)	1	0/35 (0%)	0	0/31 (0%)	0	0/28 (0%)	0	0/29 (0%)	0	0/29 (0%)	0
Respiratory, thoracic and mediastinal disorders
cough	0/36 (0%)	0	1/35 (2.9%)	1	0/33 (0%)	0	0/33 (0%)	0	0/33 (0%)	0	0/35 (0%)	0	2/31 (6.5%)	2	1/27 (3.7%)	1	1/25 (4%)	1	1/28 (3.6%)	1	0/35 (0%)	0	0/31 (0%)	0	0/28 (0%)	0	0/29 (0%)	0	0/29 (0%)	0
Vascular disorders
edema	0/36 (0%)	0	0/35 (0%)	0	1/33 (3%)	1	0/33 (0%)	0	2/33 (6.1%)	3	0/35 (0%)	0	0/31 (0%)	0	1/27 (3.7%)	1	0/25 (0%)	0	0/28 (0%)	0	1/35 (2.9%)	1	0/31 (0%)	0	0/28 (0%)	0	0/29 (0%)	0	0/29 (0%)	0

Limitations/Caveats

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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.