Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure

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

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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Sitagliptin; Drug: Aprepitant; Other: Mixed Meal Test (MMT)

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 Type: Interventional
• Enrollment (Actual): 106
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aldosterone, Angiotensin II, and Plasma Renin Activity (PRA)	renin-angiotensin system measurements were not done because there were not significant differences in blood pressure	for 4.5 hours on the 7th day of each intervention

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Mashayekhi M, Wilson JR, Jafarian-Kerman S, Nian H, Yu C, Shuey MM, Luther JM, Brown NJ. Association of a glucagon-like peptide-1 receptor gene variant with glucose response to a mixed meal. Diabetes Obes Metab. 2021 Jan;23(1):281-286. doi: 10.1111/dom.14216. Epub 2020 Oct 22.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): May 1, 2020
• Study Completion (Actual): August 1, 2020

Study Registration Dates

• First Submitted: April 30, 2014
• First Submitted That Met QC Criteria: May 2, 2014
• First Posted (Estimate): May 5, 2014

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: February 8, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Hypertension; Sitagliptin; Type 2 Diabetes Mellitus; Aprepitant; Ramipril; Angiotensin Converting Enzyme Inhibitors; Dipeptidyl Peptidase IV Inhibitors
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antiemetics; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Neurokinin-1 Receptor Antagonists; Sitagliptin Phosphate; Aprepitant
• Other Study ID Numbers: 121253