Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure

• ClinicalTrials.gov Identifier: NCT02130687
• Recruitment Status: Recruiting
• First Posted: May 5, 2014
• Last Update Posted: September 26, 2018
• Sponsor: Vanderbilt University
• Information provided by (Responsible Party): Nancy J. Brown, MD, Vanderbilt University

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)	Not Applicable

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 (Clinical Trial)
• Estimated Enrollment: 150 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: June 2014
• Estimated Primary Completion Date: March 2020
• Estimated Study Completion Date: June 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 Name: 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 Name: Januvia; Drug: Aprepitant; Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.; Other Name: 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 Name: 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 Name: Januvia; Drug: Aprepitant; Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.; Other Name: 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 Name: 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 Name: Januvia; Drug: Aprepitant; Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.; Other Name: 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. Blood pressure [ Time Frame: 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.
2. heart rate [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: for 5 minutes on the 7th day of each intervention ]
   Low frequency variability of blood pressure will be measured using spectral analysis.
2. glucose [ Time Frame: for 9 hours for the first 18 subjects per group and 4.5 hours for subsequent subjects, on the 7th day of each intervention ]
   measure of effectiveness of DPP4 inhibitor
3. insulin [ Time Frame: for 9 hours for the first 18 subjects per group and 4.5 hours for subsequent subjects, on the 7th day of each intervention ]
   Measure of insulin resistance.
4. Dipeptidyl Peptidase IV (DPP4) activity [ Time Frame: for 4.5 hours on the 7th day of each intervention ]
   Measure of DPP4 inhibitor administration
5. Angiotensin converting enzyme (ACE) [ Time Frame: for 4.5 hours on the 7th day of each intervention ]
   Measure of ACE inhibition
6. Aldosterone, Angiotensin II, and plasma renin activity (PRA) [ Time Frame: for 4.5 hours on the 7th day of each intervention ]
   renin-angiotensin system measurements
7. blood pressure [ Time Frame: during mixed meal test, for the first 18 subjects per group, on the 7th day of each intervention, 4 hours total (time points 5 to 9 hours on study day) ]
   measurement before and after ingestion of a mixed meal
8. heart rate [ Time Frame: during mixed meal test, for the first 18 subjects per group, on the 7th day of each intervention, 4 hours total (time points 5 to 9 hours on study day) ]
   measurement before and after ingestion of a mixed meal
9. Neurohormonal and vasoactive peptide measurements [ Time Frame: during mixed meal test, for the first 18 subjects per group, on the 7th day of each intervention, 4 hours total (time points 5 to 9 hours on study day) ]
   Measurement of Neuropeptide Y (NPY), Peptide YY (PYY), Glucagon-like peptide-1 (GLP-1), Free Fatty Acids (FFA), and Norepinephrine (NE) before and after ingestion of a mixed meal
10. 24hr urinary testing for catecholamines, sodium, potassium, creatinine [ Time Frame: 24hrs prior to each study day ]
    Subjects will collect 24hr urine sample and bring with to the study day for analysis

Eligibility Criteria

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

Criteria

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

Contacts

Contact: Nancy J Brown, M.D.; 6153438701; nancy.j.brown@vanderbilt.edu

Locations

United States, Tennessee

Vanderbilt University; Recruiting

Nashville, Tennessee, United States, 37232

Contact: Jessica R Wilson, M.D. jessica.r.wilson@vanderbilt.edu

Contact: Scott Hubers, M.D. scott.hubers@vanderbilt.edu

Principal Investigator: Nancy J Brown, M.D.

Sub-Investigator: Jessica Devin, M.D.

Sub-Investigator: Jessica R Wilson, M.D.

Sub-Investigator: Claudia E Ramirez, M.D.

Sub-Investigator: Scott Hubers, M.D.

Sponsors and Collaborators

Vanderbilt University

Investigators

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

More Information

• Responsible Party: Nancy J. Brown, MD, Hugh Jackson Morgan Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT02130687 History of Changes
• Other Study ID Numbers: 121253
• First Posted: May 5, 2014
• Last Update Posted: September 26, 2018
• Last Verified: September 2018

Keywords provided by Nancy J. Brown, MD, 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; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Sitagliptin Phosphate; Ramipril; Aprepitant; Fosaprepitant; Antihypertensive Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Hypoglycemic Agents; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Dipeptidyl-Peptidase IV Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Neurokinin-1 Receptor Antagonists; Neurotransmitter Agents; Angiotensin-Converting Enzyme Inhibitors