Contribution of Substance P to Blood Pressure Regulation in the Setting of Dipeptidyl Peptidase IV (DPP4) and Angiotensin-Converting Enzyme (ACE) Inhibition
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 106
- 试验地点
- 1
- 主要终点
- Norepinephrine (NE) Concentrations
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Placebo (Drug)
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.
干预措施: Sitagliptin (Drug)
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.
干预措施: Aprepitant (Drug)
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.
干预措施: Mixed Meal Test (MMT) (Other)
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.
干预措施: Placebo (Drug)
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.
干预措施: Sitagliptin (Drug)
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.
干预措施: Aprepitant (Drug)
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.
干预措施: Mixed Meal Test (MMT) (Other)
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.
干预措施: Placebo (Drug)
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.
干预措施: Sitagliptin (Drug)
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.
干预措施: Aprepitant (Drug)
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.
干预措施: Mixed Meal Test (MMT) (Other)
结局指标
主要结局
Norepinephrine (NE) Concentrations
时间窗: 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.
Heart Rate
时间窗: 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.
Mean Arterial Blood Pressure
时间窗: 4.5 hours on the 7th day of each intervention (placebo, sitagliptin, or sitagliptin+aprepitant)
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.
次要结局
- 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))
- Low Frequency Variability of Blood Pressure Activity(for 5 minutes on the 7th day of each intervention (placebo, sitagliptin, sitagliptin+aprepitant))
- Heart Rate(Value provided is the average of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal.)
- 24hr Urinary Testing for Sodium(Urine was collected for sodium for 24 hrs prior to each of the study days listed below. Study days occurred after each 7-day treatment arm (placebo/placebo, sitagliptin/placebo, or sitagliptin/aprepitant) within 3 anti-hypertensive groups.)
- Glucose(fasting at 3 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))
- Mean Arterial Blood Pressure(Value provided is the AVERAGE of measurements made every five minutes prior to (time 0) and for four four hours after ingestion of a mixed meal.)
- Neuropeptide Y(Neuropeptide Y concentration prior to ingestion of the mixed meal.)
研究者
Nancy J. Brown, MD
Hugh Jackson Morgan Professor
Vanderbilt University