Hypertension
Conditions
Keywords
Hypertension, Phenotyping, High Salt intake, frequently sampled IV glucose tolerance test(FSIVGTT), fenofibrate, epoxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, dihydroxyeicosatrienoic acid, PPAR Alpha Agonist, CYP Monooxygenase Activity
Brief summary
The hypothesis is to test to see if the drug fenofibrate will increase important chemicals in the body and specifically in the kidney, help to rid the body of salt by the kidneys, decrease blood pressure and improve insulin sensitivity during high-salt intake in individuals with hypertension.
Detailed description
Hypertension affects 73 million people in the United States and a billion people worldwide and contributes to death due to stroke, myocardial infarction, end-stage kidney disease and congestive heart failure. Fifty to 60% of individuals with hypertension have salt-sensitive hypertension, characterized by an exaggerated blood pressure response to increased salt intake. Salt-sensitive hypertension is associated with increased mortality due to cardiovascular disease. This study will test the hypothesis that administration of a PPARa agonist, an intervention increases renal tubular Cyp2c and 4a expression in rodents, will increase urinary excretion of 20-hydroxyeicosatetraenoic acid(HETE) and epoxyeicosatrienoic acids(EET)s, induce natriuresis, decrease blood pressure, and improve insulin sensitivity during high-salt intake in individuals with hypertension. Metabolites of the P450 arachidonic acid monooxygenases play an important role in the regulation of blood pressure in rodent models. Targeted disruption of murine Cyp4a genes provides insight into the roles of renal monooxygenases and epoxygenases in the regulation of salt excretion and blood pressure. PPARa agonists induce the expression of renal tubular monoxygenases and epoxygenases and decrease blood pressure in both Ang II- dependent and salt-sensitive rodent models of hypertension. PPARa agonists have been reported to reduce blood pressure in clinical trials in humans. The effect of PPARa agonist on renal vasodilation, sodium excretion and excretion of urinary epoxygenase or monooxygenase products in response to salt loading is not known. The regulation of urinary 20-HETE excretion may be impaired in human hypertension.
Interventions
DRUGfenofibrate
Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth.
DRUGPlacebo
Subjects will be randomized to receive placebo or fenofibrate for five days by mouth
Sponsors
National Institutes of Health (NIH)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Ambulatory subjects, 18-70 years of age, inclusive * 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 adequate birth control and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day
Exclusion criteria
* Secondary causes of hypertension * Diabetes type 1 or type 2 as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication * Use of hormone replacement therapy * Statin or fibrate therapy * A seated systolic blood pressure(SBP) greater than 179 mmHg or a seated diastolic blood pressure(DBP) greater than 110 mmHg * Pregnancy * Breast-feeding * 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 * Treatment with anticoagulants * History of serious neurologic diseases such as cerebral hemorrhage,stroke, or transient ischemic attack * History or presence of immunological or hematological disorders * Diagnosis of asthma * Clinically significant gastrointestinal impairment that could interfere with drug absorption * Impaired hepatic function (aspartate aminotransferase \[AST\] and or alanine aminotransferase \[ALT\] \> 2.0 x upper range) * Known preexisting gallbladder disease * Impaired renal function (eGFR \< 60 ml/min/1.73M2) * Hematocrit \< 35% * 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 a glucocorticoid therapy * Treatment with lithium salts * History of 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 for follow-up visits, and unlikelihood of completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment | pressure measured on day 6 of high salt fenofibrate minus pressure measured on day 6 of high salt placebo | Difference in blood pressure (mean arterial pressure) measured on the last day of high salt intake and fenofibrate treatment minus blood pressure (mean arterial pressure) measured during high salt intake and placebo treatment in participants classified as being salt-sensitive versus salt-resistant. Participants were classified as salt-sensitive if the average study day mean arterial pressure (MAP) was at least 5 mmHg higher during the high salt placebo arm than during low salt intake. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension | Measured on day 6 of high salt intake and fenofibrate treatment | HDL-cholesterol concentration measured on the last day of fenofibrate treatment in salt-resistant and salt-sensitive hypertensive patients |
Countries
United States
Participant flow
Recruitment details
After providing informed consent, subjects underwent a history and physical examination, screening electrocardiogram and laboratory assessment. Subjects were excluded if they did not meet inclusion and exclusion criteria.
Pre-assignment details
All anti-hypertensive medications were discontinued for 3 weeks. Participants who met blood pressure safety criteria were discontinued. Remaining participants underwent a 6-day low salt diet period and study day prior to randomization. Thirty-three of 75 enrolled met inclusion criteria, and were not withdrawn for high blood pressure during washout.
Participants by arm
| Arm | Count |
|---|---|
| Study Group | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Second Washout Period | Adverse Event | 1 | 1 |
Baseline characteristics
| Characteristic | Study Group |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants |
| Age Continuous | 43.4 years STANDARD_DEVIATION 11.6 |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 33 | 2 / 33 |
| serious Total, serious adverse events | 0 / 33 | 0 / 33 |
Outcome results
Primary
Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment
Difference in blood pressure (mean arterial pressure) measured on the last day of high salt intake and fenofibrate treatment minus blood pressure (mean arterial pressure) measured during high salt intake and placebo treatment in participants classified as being salt-sensitive versus salt-resistant. Participants were classified as salt-sensitive if the average study day mean arterial pressure (MAP) was at least 5 mmHg higher during the high salt placebo arm than during low salt intake.
Time frame: pressure measured on day 6 of high salt fenofibrate minus pressure measured on day 6 of high salt placebo
Population: All subjects who completed entire protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Salt-resistant Hypertension | Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment | 2.0 mm Hg | Standard Deviation 7.1 |
| Salt-sensitive Hypertension | Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment | -3.4 mm Hg | Standard Deviation 6.5 |
Secondary
HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension
HDL-cholesterol concentration measured on the last day of fenofibrate treatment in salt-resistant and salt-sensitive hypertensive patients
Time frame: Measured on day 6 of high salt intake and fenofibrate treatment
Population: All subjects who completed the protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Salt-resistant Hypertension | HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension | 54.1 mg/dL | Standard Deviation 20 |
| Salt-sensitive Hypertension | HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension | 52.1 mg/dL | Standard Deviation 15.8 |