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Effect of DPP4 Inhibition on Vasoconstriction

27 de julho de 2018 atualizado por: 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.

Visão geral do estudo

Status

Concluído

Condições

Intervenção / Tratamento

Descrição detalhada

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.

Tipo de estudo

Intervencional

Inscrição (Real)

18

Estágio

  • Fase 4

Contactos e Locais

Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.

Locais de estudo

  • Estados Unidos
    • Tennessee
      • Nashville, Tennessee, Estados Unidos, 37232
        • Vanderbilt University Medical Center

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

18 anos a 55 anos (Adulto)

Aceita Voluntários Saudáveis

Não

Gêneros Elegíveis para o Estudo

Tudo

Descrição

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

Plano de estudo

Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.

Como o estudo é projetado?

Detalhes do projeto

  • Finalidade Principal: Ciência básica
  • Alocação: Randomizado
  • Modelo Intervencional: Atribuição cruzada
  • Mascaramento: Quadruplicar

Armas e Intervenções

Grupo de Participantes / Braço
Intervenção / Tratamento
Outro: 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.
Medicamento: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Outros nomes:
  • Januvia
Medicamento: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Outros nomes:
  • Celulose microcristalina
Medicamento: 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.
Outros nomes:
  • NPY
Medicamento: 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.
Outros nomes:
  • Vasotec I.V.
Outro: 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.
Medicamento: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Outros nomes:
  • Januvia
Medicamento: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Outros nomes:
  • Celulose microcristalina
Medicamento: 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.
Outros nomes:
  • NPY
Medicamento: 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.
Outros nomes:
  • Vasotec I.V.
Comparador de Placebo: 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.
Medicamento: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Outros nomes:
  • Januvia
Medicamento: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Outros nomes:
  • Celulose microcristalina
Medicamento: Valsartan 160mg
Valsartan 160 mg/d for 7 days prior to one of the study days.
Outros nomes:
  • valsartan p.o.
Comparador de Placebo: 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.
Medicamento: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Outros nomes:
  • Januvia
Medicamento: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Outros nomes:
  • Celulose microcristalina
Medicamento: Valsartan 160mg
Valsartan 160 mg/d for 7 days prior to one of the study days.
Outros nomes:
  • valsartan p.o.

O que o estudo está medindo?

Medidas de resultados primários

Medida de resultado
Descrição da medida
Prazo
Forearm Blood Flow
Prazo: 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.

Medidas de resultados secundários

Medida de resultado
Descrição da medida
Prazo
Arterial Norepinephrine
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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.

Colaboradores e Investigadores

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

Patrocinador

Vanderbilt University

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados ​​pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Início do estudo

1 de dezembro de 2015

Conclusão Primária (Real)

1 de junho de 2017

Conclusão do estudo (Real)

1 de setembro de 2017

Datas de inscrição no estudo

Enviado pela primeira vez

16 de dezembro de 2015

Enviado pela primeira vez que atendeu aos critérios de CQ

20 de dezembro de 2015

Primeira postagem (Estimativa)

24 de dezembro de 2015

Atualizações de registro de estudo

Última Atualização Postada (Real)

27 de agosto de 2018

Última atualização enviada que atendeu aos critérios de controle de qualidade

27 de julho de 2018

Última verificação

1 de julho de 2018

Mais Informações

Termos relacionados a este estudo

Palavras-chave

Termos MeSH relevantes adicionais

Outros números de identificação do estudo

  • 151133

Essas informações foram obtidas diretamente do site clinicaltrials.gov sem nenhuma alteração. Se você tiver alguma solicitação para alterar, remover ou atualizar os detalhes do seu estudo, entre em contato com register@clinicaltrials.gov. Assim que uma alteração for implementada em clinicaltrials.gov, ela também será atualizada automaticamente em nosso site .

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