Effect of DPP4 Inhibition on Vasoconstriction

NCT ID: NCT02639637

Last Updated: 2018-08-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-31
• Study Completion Date: 2017-09-30

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.

Conditions

Type 2 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: OTHER

Sitagliptin

Intervention Type: DRUG

Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.

Placebo

Intervention Type: DRUG

Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.

Neuropeptide Y

Intervention Type: DRUG

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.

Enalaprilat

Intervention Type: DRUG

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.

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.

Group Type: OTHER

Sitagliptin

Intervention Type: DRUG

Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.

Placebo

Intervention Type: DRUG

Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.

Neuropeptide Y

Intervention Type: DRUG

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.

Enalaprilat

Intervention Type: DRUG

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.

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.

Group Type: PLACEBO_COMPARATOR

Sitagliptin

Intervention Type: DRUG

Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.

Placebo

Intervention Type: DRUG

Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.

Valsartan 160mg

Intervention Type: DRUG

Valsartan 160 mg/d for 7 days prior to one of the study days.

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.

Group Type: PLACEBO_COMPARATOR

Sitagliptin

Intervention Type: DRUG

Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.

Placebo

Intervention Type: DRUG

Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.

Valsartan 160mg

Intervention Type: DRUG

Valsartan 160 mg/d for 7 days prior to one of the study days.

Interventions

Sitagliptin

Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.

Intervention Type: DRUG

Placebo

Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Valsartan 160mg

Valsartan 160 mg/d for 7 days prior to one of the study days.

Intervention Type: DRUG

Other Intervention Names

Januvia; Microcrystalline cellulose; NPY; Vasotec I.V.; valsartan p.o.

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Nancy J. Brown, MD

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nancy J Brown, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

151133

Identifier Type: -

Identifier Source: org_study_id