Pharmacogenetics of Ace Inhibitor-Associated Angioedema

Vanderbilt University

Status: Completed

Conditions: Hypertension; Diabetes Type 2

Treatments: Drug: brain natriuretic peptide; Drug: Glucagon-like peptide 1; Drug: Sitagliptin (DPP4 inhibitor); Drug: Substance P,; Drug: enalaprilat (ACE inhibitor); Drug: bradykinin

Study type: Interventional

Funder types: Other

Identifiers

NCT01413542

HL079184

Details and patient eligibility

About

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.

Full 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.

Enrollment: 44 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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44 participants in 4 patient groups, including a placebo group

Placebo then sitagliptin (DPP4 inhibition) group 1

Placebo Comparator group

Description:

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).

Treatment:

Drug: enalaprilat (ACE inhibitor)

Drug: Sitagliptin (DPP4 inhibitor)

Drug: bradykinin

Drug: Substance P,

Sitagliptin (DPP4 inhibition) then placebo group 1

Placebo Comparator group

Description:

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

Treatment:

Drug: enalaprilat (ACE inhibitor)

Drug: Sitagliptin (DPP4 inhibitor)

Drug: bradykinin

Drug: Substance P,

Placebo then sitagliptin group 2

Placebo Comparator group

Description:

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).

Treatment:

Drug: Sitagliptin (DPP4 inhibitor)

Drug: Glucagon-like peptide 1

Drug: brain natriuretic peptide

Sitagliptin (DPP4 inhibition) then comparator group 2

Placebo Comparator group

Description:

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).

Treatment:

Drug: Sitagliptin (DPP4 inhibitor)

Drug: Glucagon-like peptide 1

Drug: brain natriuretic peptide