Pharmacogenetics of Ace Inhibitor-Associated Angioedema

Not Applicable

Completed

Conditions: Diabetes Type 2
Hypertension

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

Registration Number: NCT01413542

Lead Sponsor: Vanderbilt University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 44

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sitagliptin (DPP4 inhibition) then placebo group 1	enalaprilat (ACE inhibitor)	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
Placebo then sitagliptin (DPP4 inhibition) group 1	Substance P,	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).
Sitagliptin (DPP4 inhibition) then placebo group 1	Sitagliptin (DPP4 inhibitor)	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
Placebo then sitagliptin (DPP4 inhibition) group 1	enalaprilat (ACE inhibitor)	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).
Placebo then sitagliptin group 2	Sitagliptin (DPP4 inhibitor)	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).
Placebo then sitagliptin group 2	brain natriuretic peptide	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).
Sitagliptin (DPP4 inhibition) then comparator group 2	Sitagliptin (DPP4 inhibitor)	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).
Placebo then sitagliptin (DPP4 inhibition) group 1	Sitagliptin (DPP4 inhibitor)	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).
Sitagliptin (DPP4 inhibition) then placebo group 1	Substance P,	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
Placebo then sitagliptin group 2	Glucagon-like peptide 1	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).
Sitagliptin (DPP4 inhibition) then comparator group 2	Glucagon-like peptide 1	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).
Sitagliptin (DPP4 inhibition) then comparator group 2	brain natriuretic peptide	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).
Placebo then sitagliptin (DPP4 inhibition) group 1	bradykinin	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).
Sitagliptin (DPP4 inhibition) then placebo group 1	bradykinin	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

Primary Outcome Measures

Name	Time	Method
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).	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	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.

Secondary Outcome Measures

Name	Time	Method
Assess Tissue Type Plasminogen Activator (tPA) Release	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)	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)
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