Pharmacogenetics of Ace Inhibitor-Associated Angioedema

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