Hypertension, Diabetes Type 2
Conditions
Keywords
DPPIV inhibitors, ACE inhibitors, Bradykinin, glucagon-like peptide (GLP-1), BNP, diabetes, hypertension
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.
Interventions
Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions
DRUGSubstance P,
Substance P intra-brachial artery (2,4,8 pmol/min)
DRUGbradykinin
bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min)
DRUGenalaprilat (ACE inhibitor)
intra-brachial artery(0.33 µg/min per 100 mL forearm volume)
intra-brachial artery (0.45-3.60 pmol/min)
Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min)
Sponsors
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
Countries
United States
Participant flow
Pre-assignment details
44 participants were enrolled in this study (23 in Group 1 and 21 in Group 2) and completed screening procedures. Twelve of 23 participants met inclusion and exclusion criteria and completed all study-related procedures in Group 1. Seventeen of 21 participants met inclusion/exclusion criteria and completed all study-related procedures in Group 2.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Participants were randomized to sitagliptin 200 mg vs. placebo on each of two study days. On each study day, the effects of vehicle and enalaprilat on forearm blood flow and tPA responses to bradykinin and substance P were studied. | 12 |
| Group 2 Participants were randomized to sitagliptin 200 mg vs. placebo on each of two study days. On each study day, the effect of brain natriuretic peptide and glucagon like receptor-1 (GLP-1) on forearm blood flow and tPA release was studied. | 17 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Group 1 | Total | Group 2 |
|---|---|---|---|
| Age, Continuous | 38.1 years STANDARD_DEVIATION 12 | 36.5 years STANDARD_DEVIATION 10.7 | 35.4 years STANDARD_DEVIATION 10 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 21 Participants | 12 Participants |
| Region of Enrollment United States | 12 participants | 29 participants | 17 participants |
| Sex: Female, Male Female | 7 Participants | 15 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 14 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 12 | 2 / 11 | 3 / 16 | 1 / 14 |
| serious Total, serious adverse events | 0 / 12 | 0 / 11 | 0 / 16 | 1 / 14 |
Outcome results
Primary
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.
Time frame: 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
Population: In Group 1: Peptide 1=Max dose Bradykinin; Peptide 2=Substance P (SP) In Group 2: Peptide 1=GLP-1; Peptide 2=BNP (FBF expressed as percent change for both peptides) ACE inhibition=enalaprilat DPP4 inhibition=sitagliptin
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group 1 | 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). | Effect DPP4/ACEinhib vs. ACEinhib (FBF to Pep2) | -0.3 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect DPP4 inhibition on FBF Response to Peptide1 | 0.2 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect ACE/DPP4 inhibition on Peptide 2 FBF | 0.6 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect ACE/DPP4 inhibit on FBF response Peptide 1 | 5.9 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect DPP4/ACEinhib vs. DPP4inhib (FBF to Pep2) | 0.4 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect DPP4/ACEinhib vs. ACEinhib (FBF to Pep1) | -0.6 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect DPP4 inhibition on FBF response to Peptide2 | 0.1 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect DPP4/ACEinhib vs. DPP4inhib (FBF to Pep1) | 5.7 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect ACE inhibition on FBF response to Peptide 1 | 6.5 estimate of difference(ml/min/100ml FBF) |
| Group 1 | 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). | Effect ACE inhibition on FBF response to Peptide 2 | 0.8 estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect ACE inhibition on FBF response to Peptide 1 | NA estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect DPP4 inhibition on FBF response to Peptide2 | -3.2 estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect ACE/DPP4 inhibition on Peptide 2 FBF | NA estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect DPP4/ACEinhib vs. ACEinhib (FBF to Pep2) | NA estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect DPP4/ACEinhib vs. DPP4inhib (FBF to Pep2) | NA estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect ACE inhibition on FBF response to Peptide 2 | NA estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect DPP4 inhibition on FBF Response to Peptide1 | -5.0 estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect ACE/DPP4 inhibit on FBF response Peptide 1 | NA estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect DPP4/ACEinhib vs. ACEinhib (FBF to Pep1) | NA estimate of difference(ml/min/100ml FBF) |
| Group 2 | 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). | Effect DPP4/ACEinhib vs. DPP4inhib (FBF to Pep1) | NA estimate of difference(ml/min/100ml FBF) |
Comparison: Group 1: The effect of treatment (placebo, ACE or DPP4 inhibitor, or the combination) on vasodilator response to peptide, measured as forearm blood flow was determined.~Group 2: The effect of treatment (placebo, DPP4 inhibitor) on vasodilator response to peptide, measured as percent change in forearm blood flow was determined.p-value: <0.001Mixed Models Analysis
Secondary
Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP)
Time frame: Heart rate was measured every 5 minutes throughout the study day (and thus during each dose of peptide infusion)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 | Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP) | Change in Pulse after SP during Placebo | -1.8 beats per minute | Standard Error 1.76 |
| Group 1 | Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP) | Change in Pulse after SP w/ACE inhibition | 2.55 beats per minute | Standard Error 1.04 |
| Group 1 | Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP) | Change in Pulse after SP w/DPP4inhibition | 0.45 beats per minute | Standard Error 1.74 |
| Group 1 | Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP) | Pulse change after SP w/ACE+DPP4inhibition | 4.55 beats per minute | Standard Error 1.87 |
p-value: 0.011Wilcoxon signed rank
Secondary
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)
Time frame: 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)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | effect ace/dpp4 vs. dpp4inhib on bradykinin tpa | 89.3 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | effect ace/dpp4 vs. dpp4inhibi on SP tpa | 26.6 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of ACE/DPP4 inhibitio on bradykinin tPA | 90.9 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of ACE inhibition on SP tPA release | -15.3 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of DPP4 inhibition on SP tPA | -25.8 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of ACE+DPP4 inhibition on SP tPA | 0.8 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | effect ace/dpp4 vs. aceinhibi on SP tpa | 16.1 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect ACE inhibition on bradykinin tPA release | 118.6 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of DPP4 inhibition on bradykinintPA release | 1.6 estimate of difference (ng/min/100mL) |
| Group 1 | Assess Tissue Type Plasminogen Activator (tPA) Release | effect ace/dpp4 vs. aceinhibi on bradykinin tpa | -27.8 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of ACE/DPP4 inhibitio on bradykinin tPA | 132.1 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | effect ace/dpp4 vs. aceinhibi on SP tpa | -40.1 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | effect ace/dpp4 vs. dpp4inhibi on SP tpa | 32.8 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of DPP4 inhibition on SP tPA | -29.0 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | effect ace/dpp4 vs. dpp4inhib on bradykinin tpa | 119.3 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect ACE inhibition on bradykinin tPA release | 145.5 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of ACE inhibition on SP tPA release | 43.9 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | effect ace/dpp4 vs. aceinhibi on bradykinin tpa | -13.4 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of DPP4 inhibition on bradykinintPA release | 12.9 estimate of difference (ng/min/100mL) |
| Group 2 | Assess Tissue Type Plasminogen Activator (tPA) Release | Effect of ACE+DPP4 inhibition on SP tPA | 3.8 estimate of difference (ng/min/100mL) |
p-value: 0.02Mixed Models Analysis
Secondary
Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP)
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 | Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP) | Change NE AV Gradient with SP after placebo | -43.18 pg/mL | Standard Error 8.95 |
| Group 1 | Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP) | Change NE AV Gradient with SP after ACEinhibition | -52.18 pg/mL | Standard Error 18.34 |
| Group 1 | Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP) | Change NE AV Gradient with SP after DPP4inhibition | -37.27 pg/mL | Standard Error 12.21 |
| Group 1 | Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP) | Change NE AV with SP after ACE+DPPinhibition | 23.45 pg/mL | Standard Error 31.47 |
p-value: 0.05Wilcoxon signed rank
p-value: 0.007Wilcoxon signed rank
Secondary
Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 | Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion | Venous GLP-1 levels 1 hour after placebo | 5.13 pmol/L | Standard Error 1.05 |
| Group 1 | Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion | Venous GLP-1 Levels after Max Dose GLP-1 (Placebo) | 15.44 pmol/L | Standard Error 2.94 |
| Group 1 | Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion | Venous GLP-1 levels 1 hour after DPP4 inhibition | 5.39 pmol/L | Standard Error 0.99 |
| Group 1 | Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion | Venous GLP-1 levels Max Dose GLP-1 (DPP4inhibiton) | 30.63 pmol/L | Standard Error 3.4 |
p-value: 0.01wilxocon signed rank test
p-value: 0.01Wilcoxon signed rank
p-value: 0.04Wilcoxon signed rank