Endothelial Dysfunction, High Blood Pressure, Insulin Resistance, Metabolic Syndrome
Conditions
Keywords
High Blood pressure, Hypertension, metabolic syndrome, insulin resistance, endothelial dysfunction, pre-diabetic, amlodipine,, aliskiren,, IGT,, IFG,, MBF
Brief summary
The purpose of this study was to determine the effects of Aliskiren on insulin resistance (IR) and endothelial dysfunction (ED) in patients with high blood pressure and metabolic syndrome. The efficacy of Aliskiren was compared to Amlodipine.
Interventions
DRUGAliskiren
Aliskiren 300 mg tablets taken orally once daily
DRUGAmlodipine
Amlodipine 5 mg capsule taken orally once daily
DRUGPlacebo Aliskiren
Placebo Aliskiren taken orally once daily.
DRUGPlacebo Amlodipine
Placebo Amlodipine taken orally once daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female adults aged 18 to 55 years, inclusive. * Sitting diastolic blood pressure ≥80 mm Hg and/or sitting systolic blood pressure ≥ 130 at screening. * Metabolic Syndrome as defined by the Adult Treatment Panel (ATP) III criteria. * Hypertension (defined above) and impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) plus one or more out of the remaining 3 criteria to satisfy entry into the study. IGT and IFG will be classified according to American Diabetes Association (ADA) guidelines: * IFG: Fasting plasma glucose of 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) * IGT: Two-hour plasma glucose of 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) * Abnormal Positron Emission Tomography (PET) results at baseline. (Myocardial Blood Flow (MBF) of less than or equal to 35%.) * Abnormal euglycemic clamp results at baseline. (Glucose infusion rate (GINF) of less than or equal to 4.2 mg/kg/min.) * Body mass index (BMI) of less than 40.
Exclusion criteria
* Smokers (use of tobacco products in the recent past) * Cardiovascular abnormalities including myocardial infarction, angina pectoris, hypertensive encephalopathy, stroke, transient ischemic attack, valvular heart disease, ventricular arrhythmia, A-V block, atrial fibrillation or cardiac revascularization/angioplasty in the past 12 months. * Symptoms or clinical evidence of congestive heart failure or known left ventricular ejection fraction \< 40%. * Supine Blood pressure ≥ 160 mmHg systolic or ≥110 mmHg diastolic. * Clinically significant echocardiogram (ECG) abnormalities, including history of a prolonged QT-interval syndrome. * Significant autonomic dysfunction. * Severe bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated). * Clinically significant drug allergy, atopic allergy (asthma, urticaria, eczematous dermatitis). * Pregnant or breastfeeding females. Pre-menopausal females who are not practicing a non-hormonal method of birth control. * African Americans will not be eligible for this study. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Endothelial Function as Measured by Myocardial Blood Flow (MBF) From Baseline and After 12 Weeks of Treatment | At baseline and after 12 weeks of treatment | MBF is measured by Positron Emission Tomography (PET) first at rest, then 45 minutes later, during cold pressor testing (CPT). The patient is placed in the PET scanner and injected with N-13 ammonia as a tracer. PET images are taken to assess myocardial blood flow at rest. After 40 minutes, the patient immerses one hand in ice water and PET images are taken to assess myocardial blood flow at sympathetic activation. Change from baseline data is analyzed by an analysis of variance (ANOVA) model including treatment and week as fixed factors and subject (nested in treatment) as a random factor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Insulin Sensitivity as Measured by Glucose Infusion Rate (Last 30 Minutes) From Baseline and After 12 Weeks of Treatment. | At baseline and after 12 weeks of treatment | Insulin sensitivity is measured by the hyperglycemic euglycemic clamp procedure where a supine patient has 2 IV lines inserted for sampling blood. Regular human insulin (60mU/m\^2 surface area/min) is infused for 120 minutes. Dextrose (20% w/v) is infused to maintain glycemia at \< 100 mg/dL and is adjusted based on plasma glucose levels obtained every 5 minutes. Blood for glucose and insulin is taken at specified time intervals. Change from baseline data is analyzed by analysis of variance model including treatment and week as fixed factors, and subject (nested in treatment) as a random factor. |
| Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | At baseline and after 12 weeks of treatment | Insulin Concentration is determined by the Oral Glucose Tolerance Test (OGTT) which begins after a 10 hour overnight fast. Blood samples are taken at baseline and after an oral 75 gram dose of glucose. Additional samples of blood are taken to measure glucose and insulin levels at 30, 60, 120 and 180 minutes post glucose intake. Changes from pre-glucose intake values are analyzed by an analysis of variance (ANOVA) model including treatment, visit and post-dose time points ( 30, 60, 120 and 180 minutes) as fixed factors and subject (nested in treatment) as a random factor. |
| Mean Change From Baseline in Inflammatory Marker ( C-peptide) as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment [Time Frame: At Baseline and After 12 Weeks of Treatment | Baseline and after 12 weeks of treatment | C-peptide level is determined by the Oral Glucose Tolerance Test (OGTT) which begins after a 10 hour overnight fast. Blood samples are taken at baseline and after an oral 75 gram dose of glucose. Additional samples of blood are taken to measure glucose and insulin levels at 30, 60, 120 and 180 minutes post glucose intake. Changes from pre-glucose intake values are analyzed by an analysis of variance (ANOVA) model including treatment, visit and post-dose time points ( 30, 60, 120 and 180 minutes) as fixed factors and subject (nested in treatment) as a random factor. |
| Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | At baseline and after 12 weeks of treatment | Arterial Compliance is determined by Pulse Wave Analysis measured by a detector placed at the carotid artery while taking ECG and tonometry at the same time. Procedure is repeated for the femoral artery. Pulse Wave data are calculated by dividing distance between 2 arteries by the difference between the rise delay of the distal pulse wave and the R wave of the QRS complex and the rise delay of the proximal pulse wave to the QRS complex. Data analysis used an analysis of variance (ANOVA) model including treatment and week as fixed factors and subject (nested in treatment) as a random factor. |
Countries
United States
Participant flow
Recruitment details
Screening for eligibility took place up to 6 weeks prior to study start. Participants stopped taking all medications during the 6 week screening period and washed out of all medications, including antihypertensive medication prior to randomization and start of study dosing.
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren 300 mg Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks. | 23 |
| Amlodipine 5 mg Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks. | 25 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Aliskiren 300 mg | Amlodipine 5 mg | Total |
|---|---|---|---|
| Age Continuous | 45.0 years STANDARD_DEVIATION 11.3 | 44.1 years STANDARD_DEVIATION 5.3 | 44.5 years STANDARD_DEVIATION 8.6 |
| Sex: Female, Male Female | 16 Participants | 8 Participants | 24 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 23 | 6 / 25 |
| serious Total, serious adverse events | 0 / 23 | 0 / 25 |
Outcome results
Primary
Mean Change in Endothelial Function as Measured by Myocardial Blood Flow (MBF) From Baseline and After 12 Weeks of Treatment
MBF is measured by Positron Emission Tomography (PET) first at rest, then 45 minutes later, during cold pressor testing (CPT). The patient is placed in the PET scanner and injected with N-13 ammonia as a tracer. PET images are taken to assess myocardial blood flow at rest. After 40 minutes, the patient immerses one hand in ice water and PET images are taken to assess myocardial blood flow at sympathetic activation. Change from baseline data is analyzed by an analysis of variance (ANOVA) model including treatment and week as fixed factors and subject (nested in treatment) as a random factor.
Time frame: At baseline and after 12 weeks of treatment
Population: The Pharmacodynamic (PD) analysis set includes all participants with available PD data and no major protocol deviation with impact on PD data. Participants with observations at both baseline and endpoint were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren 300 mg | Mean Change in Endothelial Function as Measured by Myocardial Blood Flow (MBF) From Baseline and After 12 Weeks of Treatment | 0.06 mL/g/min | Standard Error 0.39 |
| Amlodipine 5 mg | Mean Change in Endothelial Function as Measured by Myocardial Blood Flow (MBF) From Baseline and After 12 Weeks of Treatment | 0.12 mL/g/min | Standard Error 0.39 |
Secondary
Mean Change From Baseline in Inflammatory Marker ( C-peptide) as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment [Time Frame: At Baseline and After 12 Weeks of Treatment
C-peptide level is determined by the Oral Glucose Tolerance Test (OGTT) which begins after a 10 hour overnight fast. Blood samples are taken at baseline and after an oral 75 gram dose of glucose. Additional samples of blood are taken to measure glucose and insulin levels at 30, 60, 120 and 180 minutes post glucose intake. Changes from pre-glucose intake values are analyzed by an analysis of variance (ANOVA) model including treatment, visit and post-dose time points ( 30, 60, 120 and 180 minutes) as fixed factors and subject (nested in treatment) as a random factor.
Time frame: Baseline and after 12 weeks of treatment
Population: The PD analysis set included all subjects with available PD data and no major protocol deviations with impact on PD data. During different time points, participants with observations at that time point were included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren 300 mg | Mean Change From Baseline in Inflammatory Marker ( C-peptide) as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment [Time Frame: At Baseline and After 12 Weeks of Treatment | 0 minutes ( n = 21, 23) | 0.302 ng/mL | Standard Error 0.3891 |
| Aliskiren 300 mg | Mean Change From Baseline in Inflammatory Marker ( C-peptide) as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment [Time Frame: At Baseline and After 12 Weeks of Treatment | 30 minutes ( n= 20, 22) | 0.862 ng/mL | Standard Error 0.3987 |
| Amlodipine 5 mg | Mean Change From Baseline in Inflammatory Marker ( C-peptide) as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment [Time Frame: At Baseline and After 12 Weeks of Treatment | 0 minutes ( n = 21, 23) | -0.215 ng/mL | Standard Error 0.3718 |
| Amlodipine 5 mg | Mean Change From Baseline in Inflammatory Marker ( C-peptide) as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment [Time Frame: At Baseline and After 12 Weeks of Treatment | 30 minutes ( n= 20, 22) | -0.888 ng/mL | Standard Error 0.3802 |
Secondary
Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment
Arterial Compliance is determined by Pulse Wave Analysis measured by a detector placed at the carotid artery while taking ECG and tonometry at the same time. Procedure is repeated for the femoral artery. Pulse Wave data are calculated by dividing distance between 2 arteries by the difference between the rise delay of the distal pulse wave and the R wave of the QRS complex and the rise delay of the proximal pulse wave to the QRS complex. Data analysis used an analysis of variance (ANOVA) model including treatment and week as fixed factors and subject (nested in treatment) as a random factor.
Time frame: At baseline and after 12 weeks of treatment
Population: The Pharmacodynamic (PD) analysis set includes all participants with available PD data and no major protocol deviation with impact on PD data. Participants with observations at both baseline and endpoint were included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren 300 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Central Mean Pressure | -1.39 mmHg | Standard Error 0.158 |
| Aliskiren 300 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Systolic Blood Pressure (Peripheral) | -16.2 mmHg | Standard Error 2.15 |
| Aliskiren 300 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Central Diastolic Blood Pressure | -11.0 mmHg | Standard Error 1.38 |
| Aliskiren 300 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Diastolic Blood Pressure (Peripheral) | -10.6 mmHg | Standard Error 1.34 |
| Aliskiren 300 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Central Systolic Blood Pressure | -17.7 mmHg | Standard Error 2.22 |
| Amlodipine 5 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Diastolic Blood Pressure (Peripheral) | -6.0 mmHg | Standard Error 1.32 |
| Amlodipine 5 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Central Systolic Blood Pressure | -11.1 mmHg | Standard Error 2.19 |
| Amlodipine 5 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Central Mean Pressure | -0.85 mmHg | Standard Error 0.156 |
| Amlodipine 5 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Central Diastolic Blood Pressure | -6.3 mmHg | Standard Error 1.36 |
| Amlodipine 5 mg | Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment | Systolic Blood Pressure (Peripheral) | -10.0 mmHg | Standard Error 2.12 |
Secondary
Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment
Insulin Concentration is determined by the Oral Glucose Tolerance Test (OGTT) which begins after a 10 hour overnight fast. Blood samples are taken at baseline and after an oral 75 gram dose of glucose. Additional samples of blood are taken to measure glucose and insulin levels at 30, 60, 120 and 180 minutes post glucose intake. Changes from pre-glucose intake values are analyzed by an analysis of variance (ANOVA) model including treatment, visit and post-dose time points ( 30, 60, 120 and 180 minutes) as fixed factors and subject (nested in treatment) as a random factor.
Time frame: At baseline and after 12 weeks of treatment
Population: The Pharmacodynamic (PD) analysis set included all participants with available PD data and no major protocol deviation with impact on PD data. During different time points, participants with observations at that time point were included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren 300 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 30 minutes (n=17, 21) | 31.26 mU/L | Standard Error 15.748 |
| Aliskiren 300 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 120 minutes (n=17, 19) | 33.27 mU/L | Standard Error 15.745 |
| Aliskiren 300 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 60 minutes (n=19, 22) | 16.71 mU/L | Standard Error 15.169 |
| Aliskiren 300 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 180 minutes (n=19, 22) | 22.96 mU/L | Standard Error 15.144 |
| Aliskiren 300 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 0 minutes (n=21, 23) | 3.54 mU/L | Standard Error 14.666 |
| Amlodipine 5 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 180 minutes (n=19, 22) | -43.58 mU/L | Standard Error 14.231 |
| Amlodipine 5 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 0 minutes (n=21, 23) | -3.08 mU/L | Standard Error 14.014 |
| Amlodipine 5 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 30 minutes (n=17, 21) | -15.46 mU/L | Standard Error 14.436 |
| Amlodipine 5 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 60 minutes (n=19, 22) | -27.87 mU/L | Standard Error 14.231 |
| Amlodipine 5 mg | Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment | 120 minutes (n=17, 19) | -52.67 mU/L | Standard Error 14.93 |
Secondary
Mean Change in Insulin Sensitivity as Measured by Glucose Infusion Rate (Last 30 Minutes) From Baseline and After 12 Weeks of Treatment.
Insulin sensitivity is measured by the hyperglycemic euglycemic clamp procedure where a supine patient has 2 IV lines inserted for sampling blood. Regular human insulin (60mU/m\^2 surface area/min) is infused for 120 minutes. Dextrose (20% w/v) is infused to maintain glycemia at \< 100 mg/dL and is adjusted based on plasma glucose levels obtained every 5 minutes. Blood for glucose and insulin is taken at specified time intervals. Change from baseline data is analyzed by analysis of variance model including treatment and week as fixed factors, and subject (nested in treatment) as a random factor.
Time frame: At baseline and after 12 weeks of treatment
Population: The Pharmacodynamic (PD) analysis set includes all participants with available PD data and no major protocol deviation with impact on PD data. Participants with observations at both baseline and endpoint were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren 300 mg | Mean Change in Insulin Sensitivity as Measured by Glucose Infusion Rate (Last 30 Minutes) From Baseline and After 12 Weeks of Treatment. | 0.23 mg/kg/min | Standard Error 0.379 |
| Amlodipine 5 mg | Mean Change in Insulin Sensitivity as Measured by Glucose Infusion Rate (Last 30 Minutes) From Baseline and After 12 Weeks of Treatment. | 0.55 mg/kg/min | Standard Error 0.371 |