Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure

NCT ID: NCT02130687

Last Updated: 2022-03-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 106 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-06-30
• Study Completion Date: 2020-08-31

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.

Conditions

Type 2 Diabetes Mellitus; Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: 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.

Sitagliptin

Intervention Type: 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.

Aprepitant

Intervention Type: DRUG

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

Mixed Meal Test (MMT)

Intervention Type: 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.

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.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: 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.

Sitagliptin

Intervention Type: 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.

Aprepitant

Intervention Type: DRUG

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

Mixed Meal Test (MMT)

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: 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.

Sitagliptin

Intervention Type: 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.

Aprepitant

Intervention Type: DRUG

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

Mixed Meal Test (MMT)

Intervention Type: 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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Aprepitant

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

Intervention Type: DRUG

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.

Intervention Type: OTHER

Other Intervention Names

Microcrystalline cellulose; Januvia; Emend

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Nancy J. Brown, MD

Hugh Jackson Morgan Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nancy J Brown, M.D.

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

Locations

Vanderbilt University

Nashville, Tennessee, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33001556 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

121253

Identifier Type: -

Identifier Source: org_study_id