Aortic Compliance, Diastolic Function, Insulin Sensitivity
Conditions
Brief summary
This study is an investigation of the effect of commonly prescribed anti-hypertensive agents on insulin sensitivity, diastolic function and aortic compliance. The aims of the study are as follows: Specific Aim 1: To determine in insulin resistant, hypertensive subjects if renin inhibition for 12 weeks modifies glucose homeostasis and insulin sensitivity. To accomplish this specific aim, we will use three approaches: a fasting HOMA Index; and a three hour glucose tolerance test. Only hypertensive subjects with insulin resistance, as assessed by HOMA index will be enrolled in the study. Insulin resistance will be assessed basally and after twelve weeks of treatment with either a calcium channel blocker with placebo, or calcium channel blocker with a renin inhibitor, or a calcium channel blocker with a renin inhibitor and an angiotensin receptor antagonist. Specific Aim 2: To determine in insulin resistant, hypertensive subjects if renin inhibition for 12 weeks modifies diastolic function and aortic compliance response to dietary sodium intake. The same protocol and subjects will be used as defined in Specific Aim 1. Myocardial relaxation velocity (tissue Doppler imaging at the mitral annulus) and aortic compliance (characteristic aortic impedance) will be measured at baseline and then after acute and chronic renin inhibition: 1. Acute effect of renin inhibition: Hemodynamic measurements will be obtained on both high and low dietary sodium intake conditions (\ 1 week each) before and after a single dose of a renin inhibitor. 2. Chronic effect of renin inhibition: Hemodynamic measurements will be obtained at baseline and after 12 weeks of each of the three drug treatment arms above. The study lasts 12 weeks and plans to study 45 hypertensive adults over the next two years.
Interventions
DRUGAliskiren
Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks.
DRUGValsartan and Aliskiren
Subject taking combination of valsartan and aliskiren.
DRUGAmlodipine
Taking Amlodipine as prescribed by MD for management of high blood pressure.
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Men and women, 18-70 years old * BMI =/\< 35 * BP: BP \> 145/95 on no BP medication or on 3 or less BP medications * HOMA =\>2.5 * Any race
Exclusion criteria
* 4 or more BP medications * Intolerance or known prior adverse history from taking the medications amlodipine, aliskiren or valsartan * BP \>170/110 on screening exam * Alcohol intake \>12 oz per week * Current smoking * Recreational drug use * Known or suspected secondary hypertension * Known history of coronary artery disease, cerebrovascular disease or congestive heart failure * History or known kidney disease (eGFR \<50cc/min) * Diabetes or current metformin use, or HbA1c \>=6.5% on screen * Steroid use (oral or inhaled, chronic or within the past 6 months) * Clinically significant screening lab abnormalities (See attached Screening Labs Acceptable Ranges) * Evidence of ischemia or heart block on screening electrocardiogram (greater than type I-second degree heart block, left bundle branch block, or ST-T wave changes in 2 or more contiguous leads). * Acute hospitalizations including surgery in the past 6 months * Chronic use of non-steroidal anti-inflammatory or narcotic medications * Women who are pregnant or nursing, or wish to become pregnant and/or who can not agree or tolerate two forms of birth control during the study period: Acceptable birth control methods for use in this study are: * hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants * barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm) * intrauterine device (IUD) * abstinence (no sex) * Significant concomitant medical illnesses (cancer, chronic active immunological conditions, etc.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin Sensitivity by HOMA at 12 Weeks | 12 weeks | The difference (change) in HOMA calculated as Baseline HOMA minus 12-week HOMA value |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aortic Compliance | 12 weeks | Characteristic aortic imedeance, dynes x s/cm5 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pulse Wave Velocity | 12 weeks | Measure of pulsewave velocity cm/s |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred from 8/2009 thru 12/2011 at Brigham and Women's Hospital, Boston, MA.
Pre-assignment details
All subjects washed out blood pressure medication for two weeks and ran in for two weeks on amlodipine 2.5-10mg titrated to BP \<160/90 every other day. All subjects consumed a very low salt calculated diet for one week followed by calculated high salt diet for 2 weeks prior to randomization
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren Aliskiren : Aliskiren 150 mg daily for 10 weeks, force titrated after initial 2 weeks. | 8 |
| Placebo Group Only taking Amlodipine
Amlodipine : Taking Amlodipine as prescribed by MD for management of high blood pressure. | 8 |
| Valsartan and Aliskiren Valsartan 150 mg and Aliskiren (150 mg followed by force titration to 300 mg)
Valsartan and Aliskiren : Subject taking combination of valsartan and aliskiren. | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Sponsor terminated study | 4 | 4 | 4 |
Baseline characteristics
| Characteristic | Placebo Group | Valsartan and Aliskiren | Aliskiren | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 7 Participants | 22 Participants |
| Age, Continuous | 51 years STANDARD_DEVIATION 6 | 47 years STANDARD_DEVIATION 5 | 47 years STANDARD_DEVIATION 12 | 48 years STANDARD_DEVIATION 7 |
| Region of Enrollment United States | 8 participants | 8 participants | 8 participants | 24 participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Change in Insulin Sensitivity by HOMA at 12 Weeks
The difference (change) in HOMA calculated as Baseline HOMA minus 12-week HOMA value
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren | Change in Insulin Sensitivity by HOMA at 12 Weeks | -0.7 HOMA Scale | Standard Deviation 1.3 |
| Placebo Group | Change in Insulin Sensitivity by HOMA at 12 Weeks | -0.4 HOMA Scale | Standard Deviation 1.4 |
| Valsartan and Aliskiren | Change in Insulin Sensitivity by HOMA at 12 Weeks | -0.5 HOMA Scale | Standard Deviation 1.5 |
Secondary
Aortic Compliance
Characteristic aortic imedeance, dynes x s/cm5
Time frame: 12 weeks
Population: Comparison of Baseline vs. study drug at 12 week2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren | Aortic Compliance | baseline | 212 dyne x sec/cm5 | Standard Error 88 |
| Aliskiren | Aortic Compliance | 12 weeks | 174 dyne x sec/cm5 | Standard Error 57 |
| Placebo Group | Aortic Compliance | baseline | 241 dyne x sec/cm5 | Standard Error 63 |
| Placebo Group | Aortic Compliance | 12 weeks | 127 dyne x sec/cm5 | Standard Error 0 |
| Valsartan and Aliskiren | Aortic Compliance | baseline | 111 dyne x sec/cm5 | Standard Error 7 |
| Valsartan and Aliskiren | Aortic Compliance | 12 weeks | 519 dyne x sec/cm5 | Standard Error 499 |
Other Pre-specified
Pulse Wave Velocity
Measure of pulsewave velocity cm/s
Time frame: 12 weeks
Population: Comparison of baseline vs at 12 weeks on study drug
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren | Pulse Wave Velocity | baseline | 991 cm/s | Standard Error 338 |
| Aliskiren | Pulse Wave Velocity | 12 weeks | 824 cm/s | Standard Error 183 |
| Placebo Group | Pulse Wave Velocity | baseline | 824 cm/s | Standard Error 106 |
| Placebo Group | Pulse Wave Velocity | 12 weeks | 696 cm/s | Standard Error 0 |
| Valsartan and Aliskiren | Pulse Wave Velocity | baseline | 1021 cm/s | Standard Error 5.6 |
| Valsartan and Aliskiren | Pulse Wave Velocity | 12 weeks | 574 cm/s | Standard Error 584 |