Contribution of Neuropeptide Y (NPY) to Vasoconstriction and Sympathetic Activation in the Setting of Dipeptidyl Peptidase IV (DPP4) Inhibition
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Forearm Blood Flow
研究概览
简要总结
The purpose of this study is to understand how dipeptidyl peptidase IV (DPP4) inhibition in diabetics affects hemodynamic parameters and sympathetic activation in the setting of increasing concentrations of neuropeptide Y, an endogenous peptide. The central hypothesis is that DPP4 inhibition decreases degradation of neuropeptide Y, resulting in increased vasoconstriction and sympathetic activation.
详细描述
Dipeptidyl peptidase IV (DPP4) inhibitors are routinely used for the treatment of type II diabetes mellitus (T2DM). Since the prevalence of hypertension is 1.5-3 times greater in diabetics compared to sex-aged matched controls, the use of antihypertensives such as ACE inhibitors is also common in diabetics. DPP4 is involved in the degradation of multiple vasoactive peptides, one of which is neuropeptide Y. This peptide is thought to play a role in blood pressure regulation and sympathetic nervous system activation. The aim of this study is to investigate how DPP4 inhibition affects vasoconstriction in response to increasing neuropeptide Y concentrations. Additionally, the investigators want to understand how the combination of DPP4 inhibition and ACE inhibition affects vasoconstriction and sympathetic activation. Understanding the hemodynamic and neurohumoral changes associated with DPP4 and ACE inhibitors 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
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Type 2 Diabetes Mellitus, as defined by one or more of the following,
- •Hgb A1C ≥6.5%, or
- •Fasting plasma glucose ≥126mg/dL, or
- •Two hour plasma glucose ≥200 mg/dL following 75gr oral glucose load
- •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 some form of birth control and willingness to undergo β-HCG testing prior to drug treatment and on every study day
排除标准
- •Type 1 diabetes.
- •Poorly controlled T2DM, defined as Hgb A1C>8.7%.
- •Use of anti-diabetic medications other than metformin.
- •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 any of the following drugs: cisapride, pimozide, terfenadine, astemizol
- •Clinically significant gastrointestinal impairment that could interfere with drug absorption
- •Cardiovascular disease that would pose risk for the subject to participate in the study, such as: myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy 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] >2 x upper limit of normal range)
- •Impaired renal function (eGFR< 60mL/min/1.73m2 as determined by the MDRD equation).
- •History or presence of immunological or hematological disorders.
- •History of pancreatitis or known pancreatic lesions.
- •History of angioedema or cough while taking an ACE inhibitor.
- •Hematocrit <35%.
- •Treatment with anticoagulants.
- •Growth hormone deficiency.
- •Diagnosis of asthma requiring use of an 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
- •Ongoing tobacco use or recreational drug use.
- •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
Sitagliptin then Placebo
Subjects in this arm will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive placebo for one week followed by study day #2.
干预措施: Sitagliptin (Drug)
Sitagliptin then Placebo
Subjects in this arm will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive placebo for one week followed by study day #2.
干预措施: Placebo (Drug)
Sitagliptin then Placebo
Subjects in this arm will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive placebo for one week followed by study day #2.
干预措施: Neuropeptide Y (Drug)
Sitagliptin then Placebo
Subjects in this arm will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive placebo for one week followed by study day #2.
干预措施: Enalaprilat (Drug)
Placebo then Sitagliptin
Subjects in this arm will receive placebo for one week. After this, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive 100 mg of sitagliptin daily for one week followed by study day #2.
干预措施: Sitagliptin (Drug)
Placebo then Sitagliptin
Subjects in this arm will receive placebo for one week. After this, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive 100 mg of sitagliptin daily for one week followed by study day #2.
干预措施: Placebo (Drug)
Placebo then Sitagliptin
Subjects in this arm will receive placebo for one week. After this, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive 100 mg of sitagliptin daily for one week followed by study day #2.
干预措施: Neuropeptide Y (Drug)
Placebo then Sitagliptin
Subjects in this arm will receive placebo for one week. After this, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive 100 mg of sitagliptin daily for one week followed by study day #2.
干预措施: Enalaprilat (Drug)
Sitagliptin then Placebo: Valsartan
Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive placebo/d and valsartan 160 mg/d for one week followed by study day #2.
干预措施: Sitagliptin (Drug)
Sitagliptin then Placebo: Valsartan
Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive placebo/d and valsartan 160 mg/d for one week followed by study day #2.
干预措施: Placebo (Drug)
Sitagliptin then Placebo: Valsartan
Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive placebo/d and valsartan 160 mg/d for one week followed by study day #2.
干预措施: Valsartan 160mg (Drug)
Placebo then Sitagliptin: Valsartan
Subjects in this arm will receive placebo/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive sitagliptin 100mg/d and valsartan 160 mg/d for one week followed by study day #2.
干预措施: Sitagliptin (Drug)
Placebo then Sitagliptin: Valsartan
Subjects in this arm will receive placebo/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive sitagliptin 100mg/d and valsartan 160 mg/d for one week followed by study day #2.
干预措施: Placebo (Drug)
Placebo then Sitagliptin: Valsartan
Subjects in this arm will receive placebo/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive sitagliptin 100mg/d and valsartan 160 mg/d for one week followed by study day #2.
干预措施: Valsartan 160mg (Drug)
结局指标
主要结局
Forearm Blood Flow
时间窗: FBF measured after 5 min of the 1 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and two were separated by five weeks.
Forearm blood flow measured by strain gauge plethysmography in response to 1.0 nmol/min neuropeptide Y, the highest dose that all received.
次要结局
- Insulin(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days 1 and 2 were separated by five weeks, a four-week washout and one-week treatment period.)
- GLP-1(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- Glucose(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- ACE Activity(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- DPP4 Activity(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- Low Frequency Variability of Blood Pressure Activity(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- Arterial tPA(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- Venous tPA(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- Mean Arterial Pressure(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- Heart Rate(Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.)
- Arterial Norepinephrine(Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks.)
- Venous Norepinephrine(Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks.)
- NPY Metabolites(Measured after 5 min infusion of the 1.0 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and 2 were separated by five weeks.)
研究者
Nancy J. Brown, MD
Professor
Vanderbilt University