Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus, Sitagliptin, Dipeptidyl Peptidase IV Inhibitors, Angiotensin Converting Enzyme Inhibitors, Enalaprilat, Neuropeptide Y
Brief summary
The purpose of this study is to understand how dipeptidyl peptidase IV (DPP4) inhibition in diabetics affects hemodynamic parameters and sympathetic activation in the setting of increasing concentrations of neuropeptide Y, an endogenous peptide. The central hypothesis is that DPP4 inhibition decreases degradation of neuropeptide Y, resulting in increased vasoconstriction and sympathetic activation.
Detailed description
Dipeptidyl peptidase IV (DPP4) inhibitors are routinely used for the treatment of type II diabetes mellitus (T2DM). Since the prevalence of hypertension is 1.5-3 times greater in diabetics compared to sex-aged matched controls, the use of antihypertensives such as ACE inhibitors is also common in diabetics. DPP4 is involved in the degradation of multiple vasoactive peptides, one of which is neuropeptide Y. This peptide is thought to play a role in blood pressure regulation and sympathetic nervous system activation. The aim of this study is to investigate how DPP4 inhibition affects vasoconstriction in response to increasing neuropeptide Y concentrations. Additionally, the investigators want to understand how the combination of DPP4 inhibition and ACE inhibition affects vasoconstriction and sympathetic activation. Understanding the hemodynamic and neurohumoral changes associated with DPP4 and ACE inhibitors has important implications for the millions of patients with T2DM who take these drugs concurrently.
Interventions
DRUGSitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
DRUGPlacebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
DRUGNeuropeptide Y
During the study days, neuropeptide Y will be infused through an intra-arterial line. There will be four doses of neuropeptide Y used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
DRUGEnalaprilat
Ninety minutes after the last dose of neuropeptide Y, enalaprilat will be infused through the intra-arterial line at 0.33 µg/min/100mL of forearm volume. After 30 minutes, a second infusion of neuropeptide Y will begin. Similar to the previous neuropeptide infusion, four doses of neuropeptide Y will be used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
DRUGValsartan 160mg
Valsartan 160 mg/d for 7 days prior to one of the study days.
Sponsors
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Crossover Arms 1 and 2, Crossover Arms 3 and 4
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Type 2 Diabetes Mellitus, as defined by one or more of the following, * Hgb A1C ≥6.5%, or * Fasting plasma glucose ≥126mg/dL, or * Two hour plasma glucose ≥200 mg/dL following 75gr oral glucose load For female subjects the following conditions must be met: * Postmenopausal status for at least 1 year, or * Status post-surgical sterilization, or * If of childbearing potential, utilization of some form of birth control and willingness to undergo β-HCG testing prior to drug treatment and on every study day
Exclusion criteria
* Type 1 diabetes. * Poorly controlled T2DM, defined as Hgb A1C\>8.7%. * Use of anti-diabetic medications other than metformin. * Hypertension. * Subjects who have participated in a weight-reduction program during the last 6 months and whose weight has increased or decreased more than 5 kg over the preceding 6 months. * Pregnancy. Breast-feeding. * Treatment with any of the following drugs: cisapride, pimozide, terfenadine, astemizol * Clinically significant gastrointestinal impairment that could interfere with drug absorption * Cardiovascular disease that would pose risk for the subject to participate in the study, such as: myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second- or third-degree AV block, mitral valve stenosis, or hypertrophic cardiomyopathy. * Impaired hepatic function (aspartate amino transaminase \[AST\] and/or alanine amino transaminase \[ALT\] \>2 x upper limit of normal range) * Impaired renal function (eGFR\< 60mL/min/1.73m2 as determined by the MDRD equation). * History or presence of immunological or hematological disorders. * History of pancreatitis or known pancreatic lesions. * History of angioedema or cough while taking an ACE inhibitor. * Hematocrit \<35%. * Treatment with anticoagulants. * Growth hormone deficiency. * Diagnosis of asthma requiring use of an inhaled β-2 agonist more than 1 time per week. * Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult * Treatment with systemic glucocorticoids within the last 6 months. * Treatment with lithium salts * Ongoing tobacco use or recreational drug use. * Treatment with any investigational drug in the 1 month preceding the study * Mental conditions rendering the subject unable to understand the nature, scope, or possible consequences of the study * Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forearm Blood Flow | FBF measured after 5 min of the 1 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and two were separated by five weeks. | Forearm blood flow measured by strain gauge plethysmography in response to 1.0 nmol/min neuropeptide Y, the highest dose that all received. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Venous Norepinephrine | Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks. | Venous norepinephrine concentration measured by high-performance liquid chromatography |
| NPY Metabolites | Measured after 5 min infusion of the 1.0 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and 2 were separated by five weeks. | NPY (3-36) concentration measured by micro ultra-hgih pressure liquid chromatography tandem mass spectrometry. NPY (3-36) is the degradation product of NPY by dipeptidyl peptidase 4. It was measured only in the diabetics studied. |
| Insulin | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days 1 and 2 were separated by five weeks, a four-week washout and one-week treatment period. | Plasma insulin measured by radioimmunoassay. |
| GLP-1 | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | GLP--1 was not analyzed as subjects were studied in the fasting state. |
| Glucose | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | Glucose was measured by the glucose oxidase method using a YSI glucose analyzer |
| ACE Activity | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | ACE activity was measured using a commercially available assay (Olympus AU400/AU600, Alpco Diagnotics, Salem, NH.) The lower level of detection was 15 U/L and values below the level of detection were reported at half the level of detection. |
| Arterial Norepinephrine | Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks. | Arterial norepinephrine concentration measured by high-performance liquid chromatography. |
| Low Frequency Variability of Blood Pressure Activity | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | Measured using the VITAL-GARD 450c monitor Ivy Biomedical Systems, Branford, CT, USA) |
| Arterial tPA | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | Measured using an ELISA. |
| Venous tPA | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | Measured using an ELISA. This was measured in a few subjects. After it was determined that there was no change in net t-PA release it was not measured in the remainder. |
| Mean Arterial Pressure | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | — |
| Heart Rate | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | — |
| DPP4 Activity | Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period. | DPP4 activity was measured by detection of cleavage of a colorimetric substrate. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Controls Who Completed Crossover Arm 1 or 2 Healthy non-smokers Crossover arm 1 is sitagliptin then placebo Crossover arm 2 is placebo then sitagliptin | 7 |
| Patients With Diabetes Who Completed Crossover Arm 1 or 2 Non-smokers with diabetes who were taking no medication or metformin only Crossover arm 1 is sitagliptin then placebo Crossover arm 2 is placebo then sitagliptin | 6 |
| Controls Who Completed Crossover Arm 3 or 4 Healthy non-smokers Crossover arm 3 is sitagliptin and valsartan, then placebo and valsartan Crossover arm 4 is placebo and valsartan, then sitagliptin and valsartan | 5 |
| Total | 18 |
Baseline characteristics
| Characteristic | Total | Controls Who Completed Crossover Arm 1 or 2 | Controls Who Completed Crossover Arm 3 or 4 | Patients With Diabetes Who Completed Crossover Arm 1 or 2 |
|---|---|---|---|---|
| Age, Continuous | 36.2 years STANDARD_DEVIATION 9.7 | 33.2 years STANDARD_DEVIATION 10 | 31.4 years STANDARD_DEVIATION 9 | 43.6 years STANDARD_DEVIATION 6 |
| Body mass index | 28.4 kg/m^2 STANDARD_DEVIATION 6.3 | 25.9 kg/m^2 STANDARD_DEVIATION 2.7 | 25.7 kg/m^2 STANDARD_DEVIATION 2 | 33.6 kg/m^2 STANDARD_DEVIATION 8.7 |
| Fasting glucose | 88.0 mg/dL STANDARD_DEVIATION 15.3 | 78.3 mg/dL STANDARD_DEVIATION 12.7 | 80.4 mg/dL STANDARD_DEVIATION 4.4 | 105.7 mg/dL STANDARD_DEVIATION 12.7 |
| Hemoglobin A1c | 5.6 percentage of hemoglobin STANDARD_DEVIATION 0.8 | 5.2 percentage of hemoglobin STANDARD_DEVIATION 0.6 | 5.0 percentage of hemoglobin STANDARD_DEVIATION 0.2 | 6.6 percentage of hemoglobin STANDARD_DEVIATION 0.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 6 Participants | 5 Participants | 4 Participants |
| Region of Enrollment United States | 18 Participants | 7 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Female | 9 Participants | 4 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 9 Participants | 3 Participants | 3 Participants | 3 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 | 0 / 13 | 0 / 13 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 2 / 13 | 2 / 13 | 0 / 5 | 1 / 5 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 | 0 / 5 | 0 / 5 |
Outcome results
Primary
Forearm Blood Flow
Forearm blood flow measured by strain gauge plethysmography in response to 1.0 nmol/min neuropeptide Y, the highest dose that all received.
Time frame: FBF measured after 5 min of the 1 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and two were separated by five weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Forearm Blood Flow | 1.72 mL/min/100 mL | Standard Deviation 0.93 |
| Placebo and Enalaprilat (Diabetics and Controls) | Forearm Blood Flow | 2.29 mL/min/100 mL | Standard Deviation 0.93 |
| Sitagliptin and Valsartan (Controls Only) | Forearm Blood Flow | 1.17 mL/min/100 mL | Standard Deviation 0.21 |
| Placebo and Valsartan (Controls Only) | Forearm Blood Flow | 1.63 mL/min/100 mL | Standard Deviation 0.85 |
Secondary
ACE Activity
ACE activity was measured using a commercially available assay (Olympus AU400/AU600, Alpco Diagnotics, Salem, NH.) The lower level of detection was 15 U/L and values below the level of detection were reported at half the level of detection.
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
Population: Was not measured during the valsartan study days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | ACE Activity | 7.5 U/L | Standard Deviation 0 |
| Placebo and Enalaprilat (Diabetics and Controls) | ACE Activity | 7.5 U/L | Standard Deviation 0 |
Secondary
Arterial Norepinephrine
Arterial norepinephrine concentration measured by high-performance liquid chromatography.
Time frame: Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Arterial Norepinephrine | 211.8 pg/mL | Standard Deviation 81.8 |
| Placebo and Enalaprilat (Diabetics and Controls) | Arterial Norepinephrine | 174.7 pg/mL | Standard Deviation 80.2 |
| Sitagliptin and Valsartan (Controls Only) | Arterial Norepinephrine | 151.8 pg/mL | Standard Deviation 31.3 |
| Placebo and Valsartan (Controls Only) | Arterial Norepinephrine | 125.5 pg/mL | Standard Deviation 35.1 |
Secondary
Arterial tPA
Measured using an ELISA.
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
Population: This was measured in a few subjects. After it was determined that there was no change in net t-PA release it was not measured in the remainder.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Arterial tPA | 0.047 ng/mL | Standard Deviation 0.057 |
| Placebo and Enalaprilat (Diabetics and Controls) | Arterial tPA | 0.115 ng/mL | Standard Deviation 0.07 |
Secondary
DPP4 Activity
DPP4 activity was measured by detection of cleavage of a colorimetric substrate.
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | DPP4 Activity | 10.97 nmol/ml/min | Standard Deviation 4.47 |
| Placebo and Enalaprilat (Diabetics and Controls) | DPP4 Activity | 21.22 nmol/ml/min | Standard Deviation 5.36 |
| Sitagliptin and Valsartan (Controls Only) | DPP4 Activity | 17.46 nmol/ml/min | Standard Deviation 7.35 |
| Placebo and Valsartan (Controls Only) | DPP4 Activity | 32.55 nmol/ml/min | Standard Deviation 5.58 |
Secondary
GLP-1
GLP--1 was not analyzed as subjects were studied in the fasting state.
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
Population: GLP--1 was not analyzed as subjects were studied in the fasting state.
Secondary
Glucose
Glucose was measured by the glucose oxidase method using a YSI glucose analyzer
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Glucose | 94.3 mg/dL | Standard Deviation 16.1 |
| Placebo and Enalaprilat (Diabetics and Controls) | Glucose | 100.3 mg/dL | Standard Deviation 19.6 |
| Sitagliptin and Valsartan (Controls Only) | Glucose | 85.7 mg/dL | Standard Deviation 3.4 |
| Placebo and Valsartan (Controls Only) | Glucose | 88.3 mg/dL | Standard Deviation 1.9 |
Secondary
Heart Rate
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Heart Rate | 67.4 beats per minute | Standard Deviation 11.7 |
| Placebo and Enalaprilat (Diabetics and Controls) | Heart Rate | 66.0 beats per minute | Standard Deviation 9.4 |
| Sitagliptin and Valsartan (Controls Only) | Heart Rate | 59.8 beats per minute | Standard Deviation 14.3 |
| Placebo and Valsartan (Controls Only) | Heart Rate | 60.2 beats per minute | Standard Deviation 14.2 |
Secondary
Insulin
Plasma insulin measured by radioimmunoassay.
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days 1 and 2 were separated by five weeks, a four-week washout and one-week treatment period.
Population: The comparison of sitagliptin and placebo were original to the study. Because the purpose of the sitagliptin and valsartan versus placebo and valsartan comparison was to further understand the mechanism for forearm blood flow effects it was not necessary to measure insulin in that added part of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Insulin | 16.2 microU/mL | Standard Deviation 10.6 |
| Placebo and Enalaprilat (Diabetics and Controls) | Insulin | 19.6 microU/mL | Standard Deviation 14.1 |
Secondary
Low Frequency Variability of Blood Pressure Activity
Measured using the VITAL-GARD 450c monitor Ivy Biomedical Systems, Branford, CT, USA)
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Low Frequency Variability of Blood Pressure Activity | 5.16 mm Hg2 | Standard Deviation 2.54 |
| Placebo and Enalaprilat (Diabetics and Controls) | Low Frequency Variability of Blood Pressure Activity | 5.60 mm Hg2 | Standard Deviation 2.45 |
| Sitagliptin and Valsartan (Controls Only) | Low Frequency Variability of Blood Pressure Activity | 6.05 mm Hg2 | Standard Deviation 4.3 |
| Placebo and Valsartan (Controls Only) | Low Frequency Variability of Blood Pressure Activity | 4.27 mm Hg2 | Standard Deviation 2.21 |
Secondary
Mean Arterial Pressure
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Mean Arterial Pressure | 79.3 mm Hg | Standard Deviation 8 |
| Placebo and Enalaprilat (Diabetics and Controls) | Mean Arterial Pressure | 81.4 mm Hg | Standard Deviation 6.5 |
| Sitagliptin and Valsartan (Controls Only) | Mean Arterial Pressure | 75.4 mm Hg | Standard Deviation 4.2 |
| Placebo and Valsartan (Controls Only) | Mean Arterial Pressure | 74.0 mm Hg | Standard Deviation 5.7 |
Secondary
NPY Metabolites
NPY (3-36) concentration measured by micro ultra-hgih pressure liquid chromatography tandem mass spectrometry. NPY (3-36) is the degradation product of NPY by dipeptidyl peptidase 4. It was measured only in the diabetics studied.
Time frame: Measured after 5 min infusion of the 1.0 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and 2 were separated by five weeks.
Population: Because the purpose of measuring NPY metabolites was to assess whether sitagliptin blocks the formation of the metabolites, and because the analysis is laborious and costly, measurements were only completed in the diabetics studied.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | NPY Metabolites | 749 pmol/L | Standard Deviation 562 |
| Placebo and Enalaprilat (Diabetics and Controls) | NPY Metabolites | 1206 pmol/L | Standard Deviation 1559 |
Secondary
Venous Norepinephrine
Venous norepinephrine concentration measured by high-performance liquid chromatography
Time frame: Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Venous Norepinephrine | 250.6 pg/mL | Standard Deviation 192.9 |
| Placebo and Enalaprilat (Diabetics and Controls) | Venous Norepinephrine | 178.3 pg/mL | Standard Deviation 85.1 |
| Sitagliptin and Valsartan (Controls Only) | Venous Norepinephrine | 192.6 pg/mL | Standard Deviation 88.6 |
| Placebo and Valsartan (Controls Only) | Venous Norepinephrine | 173.1 pg/mL | Standard Deviation 65.5 |
Secondary
Venous tPA
Measured using an ELISA. This was measured in a few subjects. After it was determined that there was no change in net t-PA release it was not measured in the remainder.
Time frame: Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.
Population: This was measured in a few subjects. After it was determined that there was no change in net t-PA release it was not measured in the remainder.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin and Enalaprilat (Diabetics and Controls) | Venous tPA | 0.030 ng/mL | Standard Deviation 0.06 |
| Placebo and Enalaprilat (Diabetics and Controls) | Venous tPA | 0.110 ng/mL | Standard Deviation 0.096 |