Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure

NCT02130687 | Completed Results DMC

• 1 other identifier: 121253
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes Mellitus; Hypertension

Keywords

Type 2 Diabetes Mellitus; Hypertension; Angiotensin Converting Enzyme Inhibitors; Dipeptidyl Peptidase IV Inhibitors; Sitagliptin; Aprepitant; Ramipril

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (9)

• Low Frequency Variability of Blood Pressure Activity

  for 5 minutes on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)

• Glucose

  fasting at 3 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)

• Insulin

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

• Dipeptidyl Peptidase IV (DPP4) Activity

  for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)

• Angiotensin Converting Enzyme (ACE) Activity

  for 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant)

Other Outcomes (1)

• Aldosterone, Angiotensin II, and Plasma Renin Activity (PRA)

  for 4.5 hours on the 7th day of each intervention

Study Arms (3)

Amlodipine

ACTIVE COMPARATOR

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; Drug: Sitagliptin; Drug: Aprepitant; Other: Mixed Meal Test (MMT)

Ramipril

EXPERIMENTAL

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; Drug: Sitagliptin; Drug: Aprepitant; Other: Mixed Meal Test (MMT)

Valsartan

ACTIVE COMPARATOR

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; Drug: Sitagliptin; Drug: Aprepitant; Other: Mixed Meal Test (MMT)

Interventions

Placebo DRUG

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.

Also known as: Microcrystalline cellulose

Amlodipine; Ramipril; Valsartan

Sitagliptin DRUG

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.

Also known as: Januvia

Amlodipine; Ramipril; Valsartan

Aprepitant DRUG

Subjects will receive aprepitant (125 mg on the first day followed by 80mg/d) for 7 days along with sitagliptin.

Also known as: Emend

Amlodipine; Ramipril; Valsartan

Mixed Meal Test (MMT) OTHER

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.

Amlodipine; Ramipril; Valsartan

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

Related Publications (1)

• 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.

  PMID: 33001556 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Hypertension

Interventions

microcrystalline cellulose; Sitagliptin Phosphate; Aprepitant

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Morpholines; Oxazines

Results Point of Contact

• Title: Nancy J. Brown, M.D.
• Organization: Yale University

nancy.j.brown@yale.edu

16153644022

Study Officials

• Nancy J Brown, M.D.

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hugh Jackson Morgan Professor

Study Record Dates

• First Submitted: April 30, 2014
• First Posted: May 5, 2014
• Study Start: June 1, 2014
• Primary Completion: May 1, 2020
• Study Completion: August 1, 2020
• Last Updated: March 2, 2022
• Results First Posted: July 26, 2021

Record last verified: 2022-02

Locations

US (1)