Back to resultsEffect of DPP4 Inhibition on Vasoconstriction
Primary Purpose
Type 2 Diabetes Mellitus
Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Sitagliptin
Placebo
Neuropeptide Y
Enalaprilat
Valsartan 160mg
Sponsored by
About this trial
This is an interventional basic science trial for Type 2 Diabetes Mellitus focused on measuring Type 2 Diabetes Mellitus, Sitagliptin, Dipeptidyl Peptidase IV Inhibitors, Angiotensin Converting Enzyme Inhibitors, Enalaprilat, Neuropeptide Y
Eligibility 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
Sites / Locations
- Vanderbilt University Medical Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Other
Other
Placebo Comparator
Placebo Comparator
Arm Label
Sitagliptin then Placebo
Placebo then Sitagliptin
Sitagliptin then Placebo: Valsartan
Placebo then Sitagliptin: Valsartan
Arm Description
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.
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 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 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.
Outcomes
Primary Outcome Measures
Forearm Blood Flow
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
Arterial Norepinephrine
Arterial norepinephrine concentration measured by high-performance liquid chromatography.
Venous Norepinephrine
Venous norepinephrine concentration measured by high-performance liquid chromatography
NPY Metabolites
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.
Insulin
Plasma insulin measured by radioimmunoassay.
GLP-1
GLP--1 was not analyzed as subjects were studied in the fasting state.
Glucose
Glucose was measured by the glucose oxidase method using a YSI glucose analyzer
ACE Activity
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.
DPP4 Activity
DPP4 activity was measured by detection of cleavage of a colorimetric substrate.
Low Frequency Variability of Blood Pressure Activity
Measured using the VITAL-GARD 450c monitor Ivy Biomedical Systems, Branford, CT, USA)
Arterial tPA
Measured using an ELISA.
Venous tPA
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.
Mean Arterial Pressure
Heart Rate
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02639637
Brief Title
Effect of DPP4 Inhibition on Vasoconstriction
Official Title
Contribution of Neuropeptide Y (NPY) to Vasoconstriction and Sympathetic Activation in the Setting of Dipeptidyl Peptidase IV (DPP4) Inhibition
Study Type
Interventional
2. Study Status
Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
December 2015 (undefined)
Primary Completion Date
June 2017 (Actual)
Study Completion Date
September 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus
Keywords
Type 2 Diabetes Mellitus, Sitagliptin, Dipeptidyl Peptidase IV Inhibitors, Angiotensin Converting Enzyme Inhibitors, Enalaprilat, Neuropeptide Y
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
Crossover Arms 1 and 2, Crossover Arms 3 and 4
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sitagliptin then Placebo
Arm Type
Other
Arm Description
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.
Arm Title
Placebo then Sitagliptin
Arm Type
Other
Arm Description
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.
Arm Title
Sitagliptin then Placebo: Valsartan
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Placebo then Sitagliptin: Valsartan
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Sitagliptin
Other Intervention Name(s)
Januvia
Intervention Description
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Microcrystalline cellulose
Intervention Description
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Intervention Type
Drug
Intervention Name(s)
Neuropeptide Y
Other Intervention Name(s)
NPY
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Enalaprilat
Other Intervention Name(s)
Vasotec I.V.
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Valsartan 160mg
Other Intervention Name(s)
valsartan p.o.
Intervention Description
Valsartan 160 mg/d for 7 days prior to one of the study days.
Primary Outcome Measure Information:
Title
Forearm Blood Flow
Description
Forearm blood flow measured by strain gauge plethysmography in response to 1.0 nmol/min neuropeptide Y, the highest dose that all received.
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.
Secondary Outcome Measure Information:
Title
Arterial Norepinephrine
Description
Arterial norepinephrine concentration measured by high-performance liquid chromatography.
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.
Title
Venous Norepinephrine
Description
Venous norepinephrine concentration measured by high-performance liquid chromatography
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.
Title
NPY Metabolites
Description
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.
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.
Title
Insulin
Description
Plasma insulin measured by radioimmunoassay.
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.
Title
GLP-1
Description
GLP--1 was not analyzed as subjects were studied in the fasting state.
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.
Title
Glucose
Description
Glucose was measured by the glucose oxidase method using a YSI glucose analyzer
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.
Title
ACE Activity
Description
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.
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.
Title
DPP4 Activity
Description
DPP4 activity was measured by detection of cleavage of a colorimetric substrate.
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.
Title
Low Frequency Variability of Blood Pressure Activity
Description
Measured using the VITAL-GARD 450c monitor Ivy Biomedical Systems, Branford, CT, USA)
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.
Title
Arterial tPA
Description
Measured using an ELISA.
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.
Title
Venous tPA
Description
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.
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.
Title
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.
Title
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy J Brown, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
12. IPD Sharing Statement
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Effect of DPP4 Inhibition on Vasoconstriction
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