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Effect of DPP4 Inhibition on Vasoconstriction

27. července 2018 aktualizováno: 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.

Přehled studie

Postavení

Dokončeno

Podmínky

Intervence / Léčba

Detailní popis

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.

Typ studie

Intervenční

Zápis (Aktuální)

18

Fáze

  • Fáze 4

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní místa

  • Spojené státy
    • Tennessee
      • Nashville, Tennessee, Spojené státy, 37232
        • Vanderbilt University Medical Center

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

18 let až 55 let (Dospělý)

Přijímá zdravé dobrovolníky

Ne

Pohlaví způsobilá ke studiu

Všechno

Popis

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

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Základní věda
  • Přidělení: Randomizované
  • Intervenční model: Crossover Assignment
  • Maskování: Čtyřnásobek

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Jiný: 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.
Lék: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Ostatní jména:
  • Januvia
Lék: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Ostatní jména:
  • Mikrokrystalická celulóza
Lék: Neuropeptide Y
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.
Ostatní jména:
  • NPY
Lék: Enalaprilat
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.
Ostatní jména:
  • Vasotec I.V.
Jiný: 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.
Lék: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Ostatní jména:
  • Januvia
Lék: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Ostatní jména:
  • Mikrokrystalická celulóza
Lék: Neuropeptide Y
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.
Ostatní jména:
  • NPY
Lék: Enalaprilat
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.
Ostatní jména:
  • Vasotec I.V.
Komparátor placeba: 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.
Lék: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Ostatní jména:
  • Januvia
Lék: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Ostatní jména:
  • Mikrokrystalická celulóza
Lék: Valsartan 160mg
Valsartan 160 mg/d for 7 days prior to one of the study days.
Ostatní jména:
  • valsartan p.o.
Komparátor placeba: 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.
Lék: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Ostatní jména:
  • Januvia
Lék: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Ostatní jména:
  • Mikrokrystalická celulóza
Lék: Valsartan 160mg
Valsartan 160 mg/d for 7 days prior to one of the study days.
Ostatní jména:
  • valsartan p.o.

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Forearm Blood Flow
Časové okno: 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.
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.

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Arterial Norepinephrine
Časové okno: 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.
Arterial norepinephrine concentration measured by high-performance liquid chromatography.
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
Časové okno: 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 concentration measured by high-performance liquid chromatography
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
Časové okno: 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.

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.
Insulin
Časové okno: 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.
Plasma insulin measured by radioimmunoassay.
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
Časové okno: 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.
GLP--1 was not analyzed as subjects were studied in the fasting state.
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
Časové okno: 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 was measured by the glucose oxidase method using a YSI glucose analyzer
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
Časové okno: 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 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.
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
Časové okno: 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.
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
Časové okno: 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.
Measured using the VITAL-GARD 450c monitor Ivy Biomedical Systems, Branford, CT, USA)
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
Časové okno: 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.
Measured using an ELISA.
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
Časové okno: 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.
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.
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
Časové okno: 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.
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
Časové okno: 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.
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.

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

Vanderbilt University

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia

1. prosince 2015

Primární dokončení (Aktuální)

1. června 2017

Dokončení studie (Aktuální)

1. září 2017

Termíny zápisu do studia

První předloženo

16. prosince 2015

První předloženo, které splnilo kritéria kontroly kvality

20. prosince 2015

První zveřejněno (Odhad)

24. prosince 2015

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Aktuální)

27. srpna 2018

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

27. července 2018

Naposledy ověřeno

1. července 2018

Více informací

Termíny související s touto studií

Klíčová slova

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