Pharmacogenetics of Ace Inhibitor-Associated Angioedema

NCT01413542 | Completed Results DMC

• 1 other identifier: HL079184
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators would like to find out if sitagliptin (dipeptidyl peptidase-4 or DPP4 inhibition), a drug to treat diabetes, affects blood vessel relaxation in healthy people receiving enalapril (angiotensin converting enzyme or ACE inhibition), a blood pressure medicine. Understanding how these drugs interact in healthy people will help us learn their potential effects in people who have diabetes.

Conditions

Hypertension; Diabetes Type 2

Keywords

DPPIV inhibitors; ACE inhibitors; Bradykinin; glucagon-like peptide (GLP-1); BNP; diabetes; hypertension

Outcome Measures

Primary Outcomes (1)

• The Effect of Enalaprilat (ACE Inhibition), Sitagliptin (DPP4 Inhibition), or the Combination on the Vasodilator Response (Forearm Blood Flow) to Substance P (SP) and Bradykinin (Group 1) or Glucagon Like Peptide-1 and Brain Naturetic Peptide (Group 2).

  Forearm blood flow (FBF) was measured by strain gauge plethysmography at the completion of each dose of intra-arterial peptide. A dose response curve was therefore constructed for each vasoactive peptide substrate. The effect of sitagliptin (DPP4 inhibition) vs. placebo and enalaprilat (ACE inhibition) vs. vehicle on the forearm blood flow response to each peptide could then be determined.

  60 minutes post-placebo or sitagliptin (DPP4 inhibition) and over last 2 minutes of each 5 min infusion per peptide dose (30 min washout between peptides); sequence repeated with enalaprilat (ACE inhibition) or vehicle

Secondary Outcomes (4)

• Assess Tissue Type Plasminogen Activator (tPA) Release

  Blood for analysis of tPA release was obtained 60 minutes after sitagliptin (DPP4 inhibition) vs. placebo and after each assessment of FBF (see primary outcome measure)

• Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP)

  Heart rate was measured every 5 minutes throughout the study day (and thus during each dose of peptide infusion)

• Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP)

  Blood for analysis of norepinephrine (NE) release was obtained 60 minutes after sitagliptin (DPP4 inhibition) vs. placebo and after each assessment of FBF (see primary outcome measure)

• Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion

  Blood for analysis of GLP-1 levels was obtained one hour after sitagliptin (DPP4 inhibition) vs. placebo administration and after each dose of GLP-1

Study Arms (4)

Placebo then sitagliptin (DPP4 inhibition) group 1

PLACEBO COMPARATOR

The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to bradykinin and substance P are studied after administration of placebo or sitagliptin (DPP4 inhibition).

Drug: Sitagliptin (DPP4 inhibitor); Drug: Substance P,; Drug: bradykinin; Drug: enalaprilat (ACE inhibitor)

Sitagliptin (DPP4 inhibition) then placebo group 1

PLACEBO COMPARATOR

The effect of vehicle and enalaprilat (ACE inhibition) on the forearm blood flow and t-PA responses to substance P and bradykinin are studied after administration of sitagliptin (DPP4 inhibition) or placebo

Drug: Sitagliptin (DPP4 inhibitor); Drug: Substance P,; Drug: bradykinin; Drug: enalaprilat (ACE inhibitor)

Placebo then sitagliptin group 2

PLACEBO COMPARATOR

The effect of vehicle and enalaprilat (ACE inhibition) on the forearm blood flow and t-PA responses to glucagon-like peptide-1 and brain natriuretic pepdie are studied after administration of placebo or sitagliptin (DPP4 inhibition).

Drug: Sitagliptin (DPP4 inhibitor); Drug: Glucagon-like peptide 1; Drug: brain natriuretic peptide

Sitagliptin (DPP4 inhibition) then comparator group 2

PLACEBO COMPARATOR

The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to glucagon-like peptide and brain natriuretic peptide are studied after administration of placebo or sitagliptin (DPP4 inhibition).

Drug: Sitagliptin (DPP4 inhibitor); Drug: Glucagon-like peptide 1; Drug: brain natriuretic peptide

Interventions

Sitagliptin (DPP4 inhibitor) DRUG

Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions

Also known as: Januvia

Placebo then sitagliptin (DPP4 inhibition) group 1; Placebo then sitagliptin group 2; Sitagliptin (DPP4 inhibition) then comparator group 2; Sitagliptin (DPP4 inhibition) then placebo group 1

Substance P, DRUG

Substance P intra-brachial artery (2,4,8 pmol/min)

Placebo then sitagliptin (DPP4 inhibition) group 1; Sitagliptin (DPP4 inhibition) then placebo group 1

bradykinin DRUG

bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min)

Placebo then sitagliptin (DPP4 inhibition) group 1; Sitagliptin (DPP4 inhibition) then placebo group 1

enalaprilat (ACE inhibitor) DRUG

intra-brachial artery(0.33 µg/min per 100 mL forearm volume)

Also known as: vasotec

Placebo then sitagliptin (DPP4 inhibition) group 1; Sitagliptin (DPP4 inhibition) then placebo group 1

Glucagon-like peptide 1 DRUG

intra-brachial artery (0.45-3.60 pmol/min)

Also known as: GLP-1

Placebo then sitagliptin group 2; Sitagliptin (DPP4 inhibition) then comparator group 2

brain natriuretic peptide DRUG

Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min)

Also known as: nesiritide

Placebo then sitagliptin group 2; Sitagliptin (DPP4 inhibition) then comparator group 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 65 inclusive
• Men and women
• Black and White Americans
• BMI \<25
• For female subjects:
• Postmenopausal status for at least 1 year
• Status post surgical sterilization
• If childbearing potential, utilization of a barrier method of birth control and willingness to undergo blood B-hcg testing prior to drug treatment and on every study day

You may not qualify if:

• Smoking
• Diabetes type 1 or 2, as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication
• Hypertension as defined by an untreated seated SBP greater than 140 mmHg an untreated DBP greater than 90 mmHg or the use of antihypertensives
• History of reported or recorded hypoglycemia (plasma glucose less than 70 mg/dl)
• Pregnancy
• Breast-feeding
• Use of hormone replacement therapy
• The use of contraceptive therapy
• Use of any medication other than multivitamin
• Hematocrit \<35%
• Cardiovascular disease such as history of myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure(LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
• Asthma
• History of angioedema
• History of cough or other side effect during ACE inhibitor use
• Impaired renal function, as defined by an eGFR\<60ml/min/1.73M2

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University- General Clinic Research Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (2)

• Devin JK, Pretorius M, Nian H, Yu C, Billings FT 4th, Brown NJ. Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm. J Am Heart Assoc. 2014 Aug 26;3(4):e001075. doi: 10.1161/JAHA.114.001075.

  PMID: 25158865 DERIVED

• Devin JK, Pretorius M, Nian H, Yu C, Billings FT 4th, Brown NJ. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. Hypertension. 2014 May;63(5):951-7. doi: 10.1161/HYPERTENSIONAHA.113.02767. Epub 2014 Feb 10.

  PMID: 24516103 DERIVED

MeSH Terms

Conditions

Hypertension; Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Sitagliptin Phosphate; Dipeptidyl-Peptidase IV Inhibitors; Substance P; Bradykinin; Enalaprilat; Angiotensin-Converting Enzyme Inhibitors; Glucagon-Like Peptide 1; Natriuretic Peptide, Brain

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs; Tachykinins; Kinins; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Neuropeptides; Oligopeptides; Proteins; Nerve Tissue Proteins; Autacoids; Inflammation Mediators; Biological Factors; Enalapril; Dipeptides; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Peptides; Peptide Hormones

Results Point of Contact

• Title: Dr. Nancy J. Brown
• Organization: Department of Medicine Vanderbilt University Medical Center

nancy.j.brown@vanderbilt.edu

615-343-8701

Study Officials

• Nancy J Brown, MD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chair of Dept of Medicine

Study Record Dates

• First Submitted: August 8, 2011
• First Posted: August 10, 2011
• Study Start: November 1, 2011
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2014
• Last Updated: November 4, 2015
• Results First Posted: November 4, 2015

Record last verified: 2015-10

Locations

US (1)