Pharmacogenetics of Ace Inhibitor-Associated Angioedema

Pharmacogenetics of Ace Inhibitor-Associated Angioedema:Aim 1

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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Diabetes Type 2
• Intervention / Treatment: Drug: Sitagliptin (DPP4 inhibitor); Drug: Substance P,; Drug: bradykinin; Drug: enalaprilat (ACE inhibitor); Drug: Glucagon-like peptide 1; Drug: brain natriuretic peptide

Detailed Description

To test the hypothesis that DPPIV inhibition with sitagliptin potentiates the vasodilator response to substance P in the presence of ACE inhibition with enalaprilat and to BNP and GLP-1 even in the presence of ACE inhibition. The aim promises to provide important new data regarding the mechanism of action of DPPIV inhibitors and interactive effects of these two drug classes used in a growing population of diabetic patients.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University- General Clinic Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• Clinically significant gastrointestinal impairment that could interfere with drug absorption
• Impaired hepatic function (aspartate amino transaminase[AST] and/or alanine amino transferase [ALT]>2 x upper limit of normal range
• History of alcohol or drug abuse
• Treatment with any investigational drug in the 1 month preceding the study
• Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
• Inability to comply with the protocol, e.g., uncooperative attitude, inability to return to follow-up visits, and the unlikelihood of completing the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo then sitagliptin (DPP4 inhibition) group 1; 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); Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions; Other Names: Januvia; Drug: Substance P,; Substance P intra-brachial artery (2,4,8 pmol/min); Drug: bradykinin; bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min); Drug: enalaprilat (ACE inhibitor); intra-brachial artery(0.33 µg/min per 100 mL forearm volume); Other Names: vasotec
Placebo Comparator: Sitagliptin (DPP4 inhibition) then placebo group 1; 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); Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions; Other Names: Januvia; Drug: Substance P,; Substance P intra-brachial artery (2,4,8 pmol/min); Drug: bradykinin; bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min); Drug: enalaprilat (ACE inhibitor); intra-brachial artery(0.33 µg/min per 100 mL forearm volume); Other Names: vasotec
Placebo Comparator: Placebo then sitagliptin group 2; 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); Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions; Other Names: Januvia; Drug: Glucagon-like peptide 1; intra-brachial artery (0.45-3.60 pmol/min); Other Names: GLP-1; Drug: brain natriuretic peptide; Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min); Other Names: nesiritide
Placebo Comparator: Sitagliptin (DPP4 inhibition) then comparator group 2; 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); Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions; Other Names: Januvia; Drug: Glucagon-like peptide 1; intra-brachial artery (0.45-3.60 pmol/min); Other Names: GLP-1; Drug: brain natriuretic peptide; Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min); Other Names: nesiritide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess Tissue Type Plasminogen Activator (tPA) Release	Following measurement of FBF, samples will be obtained to determine the effect of ACE inhibition and/or DPP4 inhibition on tPA release in response to bradykinin and substance P (SP) (group 1)	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

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Investigators: Principal Investigator: Nancy J Brown, MD, Vanderbilt University

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: August 8, 2011
• First Submitted That Met QC Criteria: August 9, 2011
• First Posted (Estimate): August 10, 2011

Study Record Updates

• Last Update Posted (Estimate): November 4, 2015
• Last Update Submitted That Met QC Criteria: October 5, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: diabetes; hypertension; Bradykinin; BNP; ACE inhibitors; DPPIV inhibitors; glucagon-like peptide (GLP-1)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Endocrine System Diseases; Diabetes Mellitus; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hypertension; Diabetes Mellitus, Type 2; Angioedema; Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Natriuretic Agents; Incretins; Glucagon; Enalaprilat; Sitagliptin Phosphate; Natriuretic Peptide, Brain; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Angiotensin-Converting Enzyme Inhibitors; Substance P; Neurokinin A; Bradykinin
• Other Study ID Numbers: HL079184