Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure

Not Applicable

Completed

Conditions: Hypertension
Type 2 Diabetes Mellitus

Interventions: Drug: Placebo
Drug: Sitagliptin
Drug: Aprepitant
Other: Mixed Meal Test (MMT)

Registration Number: NCT02130687

Lead Sponsor: Vanderbilt University

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 106

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Amlodipine	Mixed Meal Test (MMT)	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.
Ramipril	Placebo	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.
Ramipril	Aprepitant	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.
Amlodipine	Placebo	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.
Amlodipine	Aprepitant	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.
Valsartan	Placebo	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.
Ramipril	Mixed Meal Test (MMT)	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.
Valsartan	Mixed Meal Test (MMT)	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.
Amlodipine	Sitagliptin	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.
Ramipril	Sitagliptin	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.
Valsartan	Sitagliptin	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.
Valsartan	Aprepitant	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.

Primary Outcome Measures

Name	Time	Method
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.
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.
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.

Secondary Outcome Measures

Name	Time	Method
Insulin	fasting insulin measured at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitatliptin+aprepitant)	Measure of insulin resistance.
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.
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.
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
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
Glucose	fasting at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)	measure of effectiveness of DPP4 inhibitor
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
Neuropeptide Y	Neuropeptide Y concentration prior to ingestion of the mixed meal.	Measurement of Neuropeptide Y (NPY) concentrations