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.

• Sitagliptin (DPP4 inhibitor) (Drug), also known as Januvia: Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions
• Substance P, (Drug): Substance P intra-brachial artery (2,4,8 pmol/min)
• bradykinin (Drug): bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min)
• enalaprilat (ACE inhibitor) (Drug), also known as vasotec: intra-brachial artery(0.33 µg/min per 100 mL forearm volume)
• Glucagon-like peptide 1 (Drug), also known as GLP-1: intra-brachial artery (0.45-3.60 pmol/min)
• brain natriuretic peptide (Drug), also known as nesiritide: Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min)

Primary outcomes

• 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 outcomes

• 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]

Sex: All, ages: 18 Years to 65 Years, 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

Participant flow

Outcome results

• 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). (Primary), Mean, estimate of difference(ml/min/100ml FBF): Group 1 6.5 (4.0 to 9.0); Group 2 NA (NA to NA) (p <0.001)
• Assess Tissue Type Plasminogen Activator (tPA) Release (Secondary), Number, estimate of difference (ng/min/100mL): Group 1 (Males) 118.6 (78.9 to 158.4); Group 1 (Females) 145.5 (107.0 to 184.1) (p 0.02)
• Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP) (Secondary), Mean, beats per minute: Group 1 -1.8 +/- 1.76 (p 0.011)
• Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP) (Secondary), Mean, pg/mL: Group 1 -43.18 +/- 8.95 (p 0.05)
• Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion (Secondary), Mean, pmol/L: Group 2 5.13 +/- 1.05 (p 0.01)

Adverse events

Serious adverse events by term

Other adverse events by term

• Results publication: Devin JK, Pretorius M, Nian H, Yu C, Billings FT 4th, Brown NJ. Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm. J Am Heart Assoc. 2014 Aug 26;3(4):e001075. doi: 10.1161/JAHA.114.001075. PMID 25158865
• Results publication: Devin JK, Pretorius M, Nian H, Yu C, Billings FT 4th, Brown NJ. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. Hypertension. 2014 May;63(5):951-7. doi: 10.1161/HYPERTENSIONAHA.113.02767. Epub 2014 Feb 10. PMID 24516103

• Nancy J Brown, MD, Principal investigator, Vanderbilt University