Purpose

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

Eligibility

Eligible Ages
Between 18 Years and 80 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Phase
N/A
Study Type
Interventional
Allocation
Randomized
Intervention Model
Crossover Assignment
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
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.

Recruiting Locations

Vanderbilt University
Nashville, Tennessee 37232
Contact:
Jessica R Wilson, M.D.
jessica.r.wilson@vanderbilt.edu

More Details

NCT ID
NCT02130687
Status
Recruiting
Sponsor
Vanderbilt University

Study Contact

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

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.