Effect of DPP4 Inhibition on Vasoconstriction
2018年7月27日 更新者：Nancy J. Brown, MD、Vanderbilt University
Contribution of Neuropeptide Y (NPY) to Vasoconstriction and Sympathetic Activation in the Setting of Dipeptidyl Peptidase IV (DPP4) Inhibition
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.
調査の概要
詳細な説明
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.
研究の種類
介入
入学 (実際)
18
段階
- フェーズ 4
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究場所
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Tennessee
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Nashville、Tennessee、アメリカ、37232
- Vanderbilt University Medical Center
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参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
18年～55年 (大人)
健康ボランティアの受け入れ
いいえ
受講資格のある性別
全て
説明
Inclusion Criteria:
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
Exclusion Criteria:
- 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
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：基礎科学
- 割り当て：ランダム化
- 介入モデル：クロスオーバー割り当て
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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他の：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.
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Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
他の名前：
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
他の名前：
During the study days, neuropeptide Y will be infused through an intra-arterial line.
There will be four doses of neuropeptide Y used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
他の名前：
Ninety minutes after the last dose of neuropeptide Y, enalaprilat will be infused through the intra-arterial line at 0.33 µg/min/100mL of forearm volume.
After 30 minutes, a second infusion of neuropeptide Y will begin.
Similar to the previous neuropeptide infusion, four doses of neuropeptide Y will be used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
他の名前：
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他の：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.
|
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
他の名前：
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
他の名前：
During the study days, neuropeptide Y will be infused through an intra-arterial line.
There will be four doses of neuropeptide Y used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
他の名前：
Ninety minutes after the last dose of neuropeptide Y, enalaprilat will be infused through the intra-arterial line at 0.33 µg/min/100mL of forearm volume.
After 30 minutes, a second infusion of neuropeptide Y will begin.
Similar to the previous neuropeptide infusion, four doses of neuropeptide Y will be used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
他の名前：
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プラセボコンパレーター：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.
|
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
他の名前：
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
他の名前：
Valsartan 160 mg/d for 7 days prior to one of the study days.
他の名前：
|
|
プラセボコンパレーター：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.
|
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
他の名前：
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
他の名前：
Valsartan 160 mg/d for 7 days prior to one of the study days.
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Forearm Blood Flow
時間枠：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.
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Forearm blood flow measured by strain gauge plethysmography in response to 1.0 nmol/min neuropeptide Y, the highest dose that all received.
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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.
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Arterial Norepinephrine
時間枠：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.
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Arterial norepinephrine concentration measured by high-performance liquid chromatography.
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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.
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Venous Norepinephrine
時間枠：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.
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Venous norepinephrine concentration measured by high-performance liquid chromatography
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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.
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NPY Metabolites
時間枠：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.
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NPY (3-36) concentration measured by micro ultra-hgih pressure liquid chromatography tandem mass spectrometry. NPY (3-36) is the degradation product of NPY by dipeptidyl peptidase 4. It was measured only in the diabetics studied. |
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.
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Insulin
時間枠：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.
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Plasma insulin measured by radioimmunoassay.
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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.
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GLP-1
時間枠：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.
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GLP--1 was not analyzed as subjects were studied in the fasting state.
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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.
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Glucose
時間枠：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.
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Glucose was measured by the glucose oxidase method using a YSI glucose analyzer
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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.
|
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ACE Activity
時間枠：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.
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ACE activity was measured using a commercially available assay (Olympus AU400/AU600, Alpco Diagnotics, Salem, NH.)
The lower level of detection was 15 U/L and values below the level of detection were reported at half the level of detection.
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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.
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DPP4 Activity
時間枠：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 was measured by detection of cleavage of a colorimetric substrate.
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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.
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Low Frequency Variability of Blood Pressure Activity
時間枠：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.
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Measured using the VITAL-GARD 450c monitor Ivy Biomedical Systems, Branford, CT, USA)
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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.
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Arterial tPA
時間枠：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.
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Measured using an ELISA.
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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.
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Venous tPA
時間枠：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.
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Measured using an ELISA.
This was measured in a few subjects.
After it was determined that there was no change in net t-PA release it was not measured in the remainder.
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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.
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Mean Arterial Pressure
時間枠：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.
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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.
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Heart Rate
時間枠：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.
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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.
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協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
スポンサー
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始
2015年12月1日
一次修了 (実際)
2017年6月1日
研究の完了 (実際)
2017年9月1日
試験登録日
最初に提出
2015年12月16日
QC基準を満たした最初の提出物
2015年12月20日
最初の投稿 (見積もり)
2015年12月24日
学習記録の更新
投稿された最後の更新 (実際)
2018年8月27日
QC基準を満たした最後の更新が送信されました
2018年7月27日
最終確認日
2018年7月1日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- 151133
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