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.

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.

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