Pharmacogenetics of Ace Inhibitor-Associated Angioedema

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Pharmacogenetics of Ace Inhibitor-Associated Angioedema:Aim 1

Conditions
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Hypertension, Diabetes Type 2

Intervention / Treatment
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* Drug: Sitagliptin (DPP4 inhibitor)
* Drug: Substance P,
* Drug: bradykinin
* Drug: enalaprilat (ACE inhibitor)
* Drug: Glucagon-like peptide 1
* Drug: brain natriuretic peptide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bradykinin, DPPIV inhibitors, ACE inhibitors, glucagon-like peptide (GLP-1), BNP, diabetes, hypertension