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Effect of DPP4 Inhibition on Vasoconstriction

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ClinicalTrials.gov Identifier: NCT02639637
Recruitment Status : Completed
First Posted : December 24, 2015
Results First Posted : August 27, 2018
Last Update Posted : August 27, 2018
Sponsor:
Information provided by (Responsible Party):
Nancy J. Brown, MD, Vanderbilt University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Sitagliptin Drug: Placebo Drug: Neuropeptide Y Drug: Enalaprilat Drug: Valsartan 160mg Phase 4

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Crossover Arms 1 and 2, Crossover Arms 3 and 4
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Contribution of Neuropeptide Y (NPY) to Vasoconstriction and Sympathetic Activation in the Setting of Dipeptidyl Peptidase IV (DPP4) Inhibition
Study Start Date : December 2015
Actual Primary Completion Date : June 2017
Actual Study Completion Date : September 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Sitagliptin

Arm Intervention/treatment
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.
Drug: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Other Name: Januvia

Drug: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Other Name: Microcrystalline cellulose

Drug: 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.
Other Name: NPY

Drug: 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.
Other Name: Vasotec I.V.

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.
Drug: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Other Name: Januvia

Drug: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Other Name: Microcrystalline cellulose

Drug: 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.
Other Name: NPY

Drug: 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.
Other Name: Vasotec I.V.

Placebo Comparator: 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.
Drug: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Other Name: Januvia

Drug: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Other Name: Microcrystalline cellulose

Drug: Valsartan 160mg
Valsartan 160 mg/d for 7 days prior to one of the study days.
Other Name: valsartan p.o.

Placebo Comparator: 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.
Drug: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Other Name: Januvia

Drug: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Other Name: Microcrystalline cellulose

Drug: Valsartan 160mg
Valsartan 160 mg/d for 7 days prior to one of the study days.
Other Name: valsartan p.o.




Primary Outcome Measures :
  1. Forearm Blood Flow [ Time Frame: 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.


Secondary Outcome Measures :
  1. Arterial Norepinephrine [ Time Frame: 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.

  2. Venous Norepinephrine [ Time Frame: 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

  3. NPY Metabolites [ Time Frame: 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.


  4. Insulin [ Time Frame: 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.

  5. GLP-1 [ Time Frame: 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.

  6. Glucose [ Time Frame: 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

  7. ACE Activity [ Time Frame: 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.

  8. DPP4 Activity [ Time Frame: 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.

  9. Low Frequency Variability of Blood Pressure Activity [ Time Frame: 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)

  10. Arterial tPA [ Time Frame: 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.

  11. Venous tPA [ Time Frame: 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.

  12. Mean Arterial Pressure [ Time Frame: 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. ]
  13. Heart Rate [ Time Frame: 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. ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02639637


Locations
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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Investigators
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Principal Investigator: Nancy J Brown, MD Vanderbilt University Medical Center
  Study Documents (Full-Text)

Documents provided by Nancy J. Brown, MD, Vanderbilt University:
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Responsible Party: Nancy J. Brown, MD, Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02639637    
Other Study ID Numbers: 151133
First Posted: December 24, 2015    Key Record Dates
Results First Posted: August 27, 2018
Last Update Posted: August 27, 2018
Last Verified: July 2018
Keywords provided by Nancy J. Brown, MD, Vanderbilt University:
Type 2 Diabetes Mellitus
Sitagliptin
Dipeptidyl Peptidase IV Inhibitors
Angiotensin Converting Enzyme Inhibitors
Enalaprilat
Neuropeptide Y
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin Phosphate
Valsartan
Enalaprilat
Enalapril
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors