Hypertension
Conditions
Brief summary
Numerous anti-hypertensive drugs have been reported to be efficacious in reducing central arterial stiffness and these effects may contribute to improved outcomes in hypertensive patients. However, the results of several studies suggest that beta-blockers may actually increase arterial stiffness. In contrast, there is limited evidence to suggest that nebivolol, a third generation beta-blocker that augments release of vascular nitric oxide, reduces central arterial stiffness in hypertensive individuals. Unfortunately, only a few studies have addressed this issue and all of these studies relied on indirect, blood pressure dependent measures of arterial stiffness. In addition, none of these studies focused on middle-aged and older, obese hypertensives, a population with accelerated arterial stiffening and at risk for cardiovascular diseases. Thus, the potential utility of nebivolol as a therapy to reduce large artery stiffness, particularly among the latter population, remains unclear.
Interventions
DRUGNebivolol
OTHERLifestyle Modification
OTHERNebivolol plus Lifestyle Modification
Sponsors
Forest Laboratories
Virginia Polytechnic Institute and State University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Stage 1 hypertension * 40-75 years * Weight stable (+/-2 kg) * Sedentary to recreationally active * Willing to be randomized to one of three arms * Verbal and written consent * Approval by medical director
Exclusion criteria
* Blood pressure outside stated range * Diabetes or taking diabetes medications * Total cholesterol \>6.2 mmol/L; triglycerides \>4.5 mmol/L * Past or current ischemic heart disease, stroke, respiratory disease, endocrine or metabolic disease, neurological disease, or hematological-oncological disease * Medications (including but not limited to antihypertensives, statins or other with anti-inflammatory actions) or antioxidant vitamins or supplements * Known allergy or hypersensitivity to nebivolol or any of its components * Inability to perform regular physical activity or participate in other components of lifestyle modification * Pregnant or planning to become pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Beta-stiffness Index | 12 weeks | Longitudinal B-mode images of the left common carotid artery diameter (1-2 cm proximal to the carotid bulb) were obtained over 15 consecutive cardiac cycles. Brachial blood pressure was measured via an automated sphygmomanometer. Quantification of systolic and diastolic carotid artery diameters were analyzed with the Vascular Research Tools 5 software program. Beta-stiffness index was calculated as: Beta = ln(P1/P0)/((D1-D0)/D0), where D0 represents the minimal diameter recorded during diastole, D1 represents the maximal diameter recorded during systole, P0 represents the pressure measured during diastole, and P1 represents the pressure measured during systole. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity (HOMA-IR) | 12 weeks | The HOMA index was calculated as the product of plasma blood glucose and insulin divided by 22.5. |
Other
| Measure | Time frame |
|---|---|
| Oxidized LDL Concentration | 12 weeks |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nebivolol Subjects will be provided with daily 5 mg of nebivolol for the first 2 weeks. Subjects receive additional daily doses of 10 mg nebivolol for the remainder of the study period. The dose remains at 5 mg per day, however, if BP falls below 110/70 during the first 2 weeks. Subjects will continue taking the drug during the 2-week follow-up period.
Nebivolol | 15 |
| Lifestyle Modification Subjects will receive weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approach to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects.
Lifestyle Modification | 15 |
| Nebivolol Plus Lifestyle Modification Subjects began with 5 mg/day of nebivolol and increased to 10 mg/day if brachial blood pressure was greater than 120/80 mmHg during the first two weeks of therapy. Subjects also received weekly lifestyle counseling by a registered dietitian to ensure adequate progress and compliance. Sample menus, 14-days of meal plans, and grocery shopping lists were provided to each individual. Individuals were instructed to reduce their daily caloric intake by 500-1000 calories and to perform a minimum of 150 minutes per week of moderate-intensity physical activity or 3000 steps/day above baseline levels. The diet plan conformed to the Dietary Approaches to Stop Hypertension dietary guidelines emphasizing low fat dairy products, fruits and vegetable and contained 55% calories as carbohydrates, 30% calories as fat, and 15% calories as protein21. Sodium consumption was set at 2,400 mg/day for all subjects.
Nebivolol plus Lifestyle Modification | 15 |
| Total | 45 |
Baseline characteristics
| Characteristic | Nebivolol | Lifestyle Modification | Nebivolol Plus Lifestyle Modification | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 5 Participants | 3 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 10 Participants | 12 Participants | 36 Participants |
| Age, Continuous | 57.7 yr STANDARD_DEVIATION 3.1 | 52.7 yr STANDARD_DEVIATION 2.2 | 58.4 yr STANDARD_DEVIATION 2.2 | 56.3 yr STANDARD_DEVIATION 2.5 |
| Region of Enrollment United States | 15 participants | 15 participants | 15 participants | 45 participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 8 Participants | 23 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 7 Participants | 22 Participants |
| Supine blood pressure (mmHg) | 146 mmHg STANDARD_DEVIATION 1.4 | 138 mmHg STANDARD_DEVIATION 3.1 | 142 mmHg STANDARD_DEVIATION 2.6 | 142 mmHg STANDARD_DEVIATION 2.37 |
| Supine heart rate (bpm) | 64 bpm STANDARD_DEVIATION 1 | 67 bpm STANDARD_DEVIATION 3 | 66 bpm STANDARD_DEVIATION 2 | 66 bpm STANDARD_DEVIATION 2 |
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 / 15 | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Beta-stiffness Index
Longitudinal B-mode images of the left common carotid artery diameter (1-2 cm proximal to the carotid bulb) were obtained over 15 consecutive cardiac cycles. Brachial blood pressure was measured via an automated sphygmomanometer. Quantification of systolic and diastolic carotid artery diameters were analyzed with the Vascular Research Tools 5 software program. Beta-stiffness index was calculated as: Beta = ln(P1/P0)/((D1-D0)/D0), where D0 represents the minimal diameter recorded during diastole, D1 represents the maximal diameter recorded during systole, P0 represents the pressure measured during diastole, and P1 represents the pressure measured during systole.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Beta-stiffness Index | -2.03 Arbitrary units | Standard Error 0.6 |
| Lifestyle Modification | Beta-stiffness Index | -1.87 Arbitrary units | Standard Error 0.83 |
| Nebivolol Plus Lifestyle Modification | Beta-stiffness Index | -2.51 Arbitrary units | Standard Error 0.9 |
Secondary
Insulin Sensitivity (HOMA-IR)
The HOMA index was calculated as the product of plasma blood glucose and insulin divided by 22.5.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Insulin Sensitivity (HOMA-IR) | -0.36 Arbitrary units | Standard Error 0.33 |
| Lifestyle Modification | Insulin Sensitivity (HOMA-IR) | -1.98 Arbitrary units | Standard Error 1.43 |
| Nebivolol Plus Lifestyle Modification | Insulin Sensitivity (HOMA-IR) | -2.12 Arbitrary units | Standard Error 0.73 |
Other Pre-specified
Oxidized LDL Concentration
Time frame: 12 weeks