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Type 2 Diabetes Mellitus | Effect of Chronic ACE and DPP4 Inhibition on Blood Pressure

Type 2 Diabetes Mellitus research study

What is the primary objective of this study?

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.

Who is eligible to participate?

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

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

Type 2 Diabetes Mellitus

Hypertension

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Drug:PlaceboSubjects 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.

Drug:SitagliptinSubjects 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.

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

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.

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

AmlodipineSubjects 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.

RamiprilSubjects 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.

ValsartanSubjects 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.

Study Status

Recruiting

Start Date: June 2014

Completed Date: June 2020

Phase: N/A

Type: Interventional

Design:

Primary Outcome: Blood pressure

Secondary Outcome: Low frequency variability of blood pressure activity

Study sponsors, principal investigator, and references

Principal Investigator: Nancy J Brown, M.D.

Lead Sponsor: Vanderbilt University

Collaborator:

More information:https://clinicaltrials.gov/show/NCT02130687

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