Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure

Study Overview
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Brief Summary
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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
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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.

Official Title
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Contribution of Substance P to Blood Pressure Regulation in the Setting of Dipeptidyl Peptidase IV (DPP4) and Angiotensin-Converting Enzyme (ACE) Inhibition

Conditions
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Type 2 Diabetes Mellitus, Hypertension

Intervention / Treatment
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* Drug: Placebo
* Drug: Sitagliptin
* Drug: Aprepitant
* Other: Mixed Meal Test (MMT)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Amlodipine<br>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<br>* 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.<br>* Other names: Microcrystalline cellulose;Drug: Sitagliptin<br>* 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.<br>* Other names: Januvia;Drug: Aprepitant<br>* Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.<br>* Other names: Emend;Other: Mixed Meal Test (MMT)<br>* 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.<br>|
| Experimental: Ramipril<br>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<br>* 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.<br>* Other names: Microcrystalline cellulose;Drug: Sitagliptin<br>* 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.<br>* Other names: Januvia;Drug: Aprepitant<br>* Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.<br>* Other names: Emend;Other: Mixed Meal Test (MMT)<br>* 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.<br>|
| Active Comparator: Valsartan<br>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<br>* 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.<br>* Other names: Microcrystalline cellulose;Drug: Sitagliptin<br>* 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.<br>* Other names: Januvia;Drug: Aprepitant<br>* Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.<br>* Other names: Emend;Other: Mixed Meal Test (MMT)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant) | 
| 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. | 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant) | 
| 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. | 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Low Frequency Variability of Blood Pressure Activity | Low frequency variability of systolic blood pressure will be measured using spectral analysis. | for 5 minutes on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant) | 
| Glucose | measure of effectiveness of DPP4 inhibitor | fasting at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant) | 
| Insulin | Measure of insulin resistance. | fasting insulin measured at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitatliptin+aprepitant) | 
| Dipeptidyl Peptidase IV (DPP4) Activity | Measure of DPP4 inhibitor administration. | for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant) | 
| 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. | for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant) | 
| 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 | 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. | 
| 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 | 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. | 
| Neuropeptide Y | Measurement of Neuropeptide Y (NPY) concentrations | Neuropeptide Y concentration prior to ingestion of the mixed meal. | 
| 24hr Urinary Testing for Sodium | Subjects will collect 24hr urine sample and bring with to the study day for analysis | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Hypertension, Angiotensin Converting Enzyme Inhibitors, Dipeptidyl Peptidase IV Inhibitors, Sitagliptin, Aprepitant, Ramipril