Effect of DPP4 Inhibition on Vasoconstriction

NCT02639637 | Completed Phase 4 Results DMC

• 1 other identifier: 151133
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes Mellitus

Keywords

Type 2 Diabetes Mellitus; Sitagliptin; Dipeptidyl Peptidase IV Inhibitors; Angiotensin Converting Enzyme Inhibitors; Enalaprilat; Neuropeptide Y

Outcome Measures

Primary Outcomes (1)

• 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.

  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 Outcomes (13)

• Arterial Norepinephrine

  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

  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

  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

  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

  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.

Study Arms (4)

Sitagliptin then Placebo

OTHER

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; Drug: Placebo; Drug: Neuropeptide Y; Drug: Enalaprilat

Placebo then Sitagliptin

OTHER

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; Drug: Placebo; Drug: Neuropeptide Y; Drug: Enalaprilat

Sitagliptin then Placebo: Valsartan

PLACEBO COMPARATOR

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; Drug: Placebo; Drug: Valsartan 160mg

Placebo then Sitagliptin: Valsartan

PLACEBO COMPARATOR

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; Drug: Placebo; Drug: Valsartan 160mg

Interventions

Sitagliptin DRUG

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

Also known as: Januvia

Placebo then Sitagliptin; Placebo then Sitagliptin: Valsartan; Sitagliptin then Placebo; Sitagliptin then Placebo: Valsartan

Placebo DRUG

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

Also known as: Microcrystalline cellulose

Placebo then Sitagliptin; Placebo then Sitagliptin: Valsartan; Sitagliptin then Placebo; Sitagliptin then Placebo: Valsartan

Neuropeptide Y 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.

Also known as: NPY

Placebo then Sitagliptin; Sitagliptin then Placebo

Enalaprilat 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.

Also known as: Vasotec I.V.

Placebo then Sitagliptin; Sitagliptin then Placebo

Valsartan 160mg DRUG

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

Also known as: valsartan p.o.

Placebo then Sitagliptin: Valsartan; Sitagliptin then Placebo: Valsartan

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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%.

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Sitagliptin Phosphate; microcrystalline cellulose; Neuropeptide Y; Enalaprilat; Valsartan

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Nerve Tissue Proteins; Proteins; Enalapril; Dipeptides; Oligopeptides; Tetrazoles; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Essential

Results Point of Contact

• Title: Nancy J. Brown, M.D., Principal Investigator
• Organization: Vanderbilt University Medical Center

nancy.j.brown@vanderbilt.edu

6153644022

Study Officials

• Nancy J Brown, MD

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Crossover Arms 1 and 2, Crossover Arms 3 and 4

Study Record Dates

• First Submitted: December 16, 2015
• First Posted: December 24, 2015
• Study Start: December 1, 2015
• Primary Completion: June 1, 2017
• Study Completion: September 1, 2017
• Last Updated: August 27, 2018
• Results First Posted: August 27, 2018

Record last verified: 2018-07

Locations

US (1)