The Efficacy and Tolerability of Nebivolol in Hypertensive African American Patients


  • Elijah Saunders MD,

    1. From the Section of Hypertension, University of Maryland School of Medicine, Baltimore, MD;1New Orleans Center for Clinical Research, New Orleans, LA;2Tulane University, New Orleans, LA;3 and Mylan Pharmaceuticals, Morgantown, WV4
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  • 1 William B. Smith MD,

    1. From the Section of Hypertension, University of Maryland School of Medicine, Baltimore, MD;1New Orleans Center for Clinical Research, New Orleans, LA;2Tulane University, New Orleans, LA;3 and Mylan Pharmaceuticals, Morgantown, WV4
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  • 2 Karen B. DeSalvo MD,

    1. From the Section of Hypertension, University of Maryland School of Medicine, Baltimore, MD;1New Orleans Center for Clinical Research, New Orleans, LA;2Tulane University, New Orleans, LA;3 and Mylan Pharmaceuticals, Morgantown, WV4
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  • and 3 Will A. Sullivan MD 4

    1. From the Section of Hypertension, University of Maryland School of Medicine, Baltimore, MD;1New Orleans Center for Clinical Research, New Orleans, LA;2Tulane University, New Orleans, LA;3 and Mylan Pharmaceuticals, Morgantown, WV4
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Elijah Saunders, MD, Section of Hypertension, University of Maryland School of Medicine, University of Maryland Professional Building, 419 West Redwood Street, Suite 620, Baltimore, MD 21201


Hypertensive African Americans often respond poorly to β-blocker monotherapy, compared with whites. There is evidence, however, that suggests that this response may be different if β-blockers with vasodilating effects are used. This 12-week, multi-center, double-blind, randomized placebo-controlled study assessed the antihypertensive efficacy and safety of nebivolol, a cardioselective, vasodilating β1-blocker, at doses of 2.5, 5, 10, 20, or 40 mg once daily in 300 African American patients with stage I or II hypertension (mean sitting diastolic blood pressure [SiDBP] ≥95 mm Hg and ≤109 mm Hg). The primary efficacy end point was the baseline-adjusted change in trough mean SiDBP. After 12 weeks, nebivolol significantly reduced least squares mean SiDBP (P≤.004) at all doses of 5 mg and higher and sitting systolic blood pressure (P≤.044) at all doses 10 mg and higher, compared with placebo. The drug was safe and well-tolerated, with no significant difference in the incidence of adverse events compared with placebo. Nebivolol monotherapy provides antihypertensive efficacy, with few significant adverse effects, in hypertensive African Americans.

Hypertension and its associated cardiovascular and renal complications occur disproportionately among African American adults in the United States, compared with whites.1,2 Hypertension in this population is commonly characterized by salt sensitivity, a tendency toward expanded plasma volume, low renin production, and low cardiac output with increased peripheral and renal vascular resistance.2–4 These patients also have impaired endothelial function, which may be attributed to reduced endothelial nitric oxide (NO) bioavailability.5–8 In addition, they tend to have decreased activity in the kallikrein and bradykinin systems, potentially affecting vascular reactivity.9 These pathophysiologic characteristics play a role in different responses to antihypertensive therapy.2

Substantial clinical evidence indicates that monotherapy with β-blockers, as well as with other antihypertensive agents, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs), are less effective in lowering blood pressure (BP) among hypertensive black patients than among hypertensive whites.10–12 The decrease in BP level with β-blockers is primarily due to reduced cardiac output rather than reduced peripheral resistance; β-blockers fail to counteract the most common pressors in this ethnic group.4,6 The β-blocker class is, however, highly heterogeneous in terms of its pharmacologic and hemodynamic properties.13,14 For example, some β-blocking agents exhibit higher selectivity for β1 adrenoceptors, found primarily on the heart, compared with β2-adrenoceptors, which predominate in the bronchi.15 Other β-blockers block α receptors, found on vascular smooth muscle, as well as β-adrenoceptors.14

Nebivolol is a cardioselective β1-adrenoceptor blocker15 that produces endothelium-dependent vasodilation.16–20 In the human myocardium, nebivolol has demonstrated a 321-fold higher affinity for β1- than for β2-adrenergic receptors and higher β1 selectivity than other selective β1-blockers, including bisoprolol and metoprolol.21 In addition to the known antihypertensive effects that arise from β1-blockade, nebivolol may also lower BP through other mechanisms of action. Preclinical and clinical studies have shown that nebivolol has a vasodilating action that may be associated with stimulation of endothelium-derived NO.17,22,23 In hypertensive patients, nebivolol has exhibited a hemodynamic profile characterized by preserved cardiac output, stroke volume, left ventricular function, and decreased systemic vascular resistance.24 This hemodynamic profile appears to reflect a combination of β1-blockade with arterial vasodilation24 and may present more favorable characteristics than other nonvasodilating β-blockers for the treatment of hypertension.

In randomized placebo-controlled trials in general hypertensive populations, the use of nebivolol has resulted in BP lowering with placebo-like tolerability.25,26 Most of the clinical experience with nebivolol, however, has been in largely white populations with uncomplicated essential hypertension. The present dose-ranging study was therefore conducted to investigate the antihypertensive efficacy and safety of nebivolol in African American patients with stage I (BP 140/90–159/99 mm Hg) or stage II (BP ≥160/100 mm Hg) hypertension.


Study Population

Eligible patients were ambulatory African American men and women aged 18 years and older, with stage I or II hypertension (mean sitting diastolic BP [SiDBP] ≥95 mm Hg and ≤109 mm Hg). Patients were excluded if they had secondary or malignant hypertension, body mass index >40 kg/m2, chronic obstructive pulmonary disease, myocardial infarction or stroke within 6 months of study entry, clinically significant renal or hepatic dysfunction, hemodynamically significant valvular disease, clinically relevant arrhythmias, uncontrolled type 2 diabetes mellitus (hemoglobin A1c≥10%), or a history of sensitivity to β-blockers. Women of childbearing potential who were not using an effective method of contraception and pregnant and breast-feeding women were also excluded.

Study Design

This was a randomized, placebo-controlled, double-blind, dose-ranging, parallel-group trial conducted at 39 sites in the United States in accordance with both Good Clinical Practice Guidelines and the Declaration of Helsinki revisions. The protocol and written informed consents were reviewed and approved by a central institutional review board/independent ethics committee before enrollment of any patients in the study.

Following screening, all patients entered a 28-day, single-blind, placebo run-in period. Patients previously on antihypertensive therapy were allowed an additional 14-day washout period to qualify for the study. At the end of the placebo run-in period, eligible patients were randomized (day 0) in a double-blind manner to receive once-daily placebo or nebivolol 2.5, 5, 10, 20, or 40 mg for 84 days. The patients were stratified evenly across treatment arms according to clinical baseline characteristics that may have affected patient response to nebivolol.

Since nebivolol is metabolized by polymorphic CYP2D6 to active metabolites, patients were stratified across treatment arms by nebivolol metabolism (poor metabolizers compared with extensive metabolizers), although previous studies have demonstrated no correlation between antihypertensive efficacy or safety and CYP2D6 metabolizer status. No patients were excluded based on the result of their metabolizer status. Patients were also stratified across treatment groups by history of diabetes mellitus, age (younger than 65 years or 65 years and older) and sex. Patients were provided with diaries and asked to document when treatment was administered daily. Patients returned to the study unit for assessments on days 14, 28, 56, and 84 of the double-blind treatment period, at which time BP and heart rate (HR) were measured, compliance with study medication was monitored, and use of concomitant medications was recorded. Clinical laboratory parameters were measured at randomization and on day 84. Salt intake was not controlled or restricted during the course of the study.

End Points

The primary efficacy end point was baseline-corrected decrease in mean trough (24±2 hours post-previous morning's dose) SiDBP at the end of treatment (day 84). Secondary efficacy end points included baseline-corrected changes in mean sitting systolic BP (SiSBP) at trough; mean SiDBP and SiSBP at peak (2–3 hours postdose) and mean supine and standing diastolic and systolic BP at trough and at peak; and the response rates of each treatment group, defined as the proportion of patients with mean trough SiDBP <90 mm Hg at the end of the study or an absolute reduction of ≥10 mm Hg from baseline. A post hoc analysis of the percentage of patients in whom BP control was achieved (<140/90 mm Hg) was also performed.

Efficacy and Safety Assessments

BP was measured using a calibrated mercury sphygmomanometer and appropriately sized cuff in the supine, sitting, and standing positions. Three separate measurements were taken 2 minutes apart, and the mean value was calculated and recorded.

Safety was assessed by monitoring reports of clinical adverse events (AEs) and by evaluating changes in vital signs, physical examination results, 12-lead electrocardiograms, and laboratory parameters including biochemistry, hematology, and urinalysis. All AEs from screening until the end of the study were recorded, and their severity and possible relationship to the study drug were assessed by the investigators.

Statistical Methods

The primary population for efficacy and safety analyses was the intent-to-treat (ITT) population, which included all randomized patients who took at least 1 dose of study medication. Missing values were computed using a last-observation-carried-forward method.

Based on a standard deviation of 7.0 mm Hg for diastolic BP reduction, it was estimated that with 45 patients per treatment group, the study would have 90% power at the 5% significant level (2-tailed) to detect a baseline and placebo-corrected treatment decrease in mean trough cuff supine diastolic BP of 6.3 mm Hg. Assuming a 10% dropout rate, 50 patients were estimated for randomization to each treatment arm.

Background and demographic data were summarized using descriptive statistics, and homogeneity was assessed using analysis of variance overall F test for continuous variables and the chi-squared test for categoric variables. To test for treatment differences, continuous efficacy variables were analyzed using an analysis of covariance (ANCOVA) model with treatment as a main effect and baseline BP and dichotomous baseline variables as covariates. The primary statistical method of treatment comparison for continuous variables was a step-down dose-response trend test, using a linear contrast in an ANCOVA model up to and including the 40-mg dose group. Response rates of the treatment groups were analyzed using a logistic regression model with responder as the response variable and included treatment, baseline dichotomous covariates, and baseline BP as a continuous covariate. Response rates were compared using the Wald chi-squared test.

For safety analyses, the change from baseline for continuous variables was analyzed using the same step-down trend test as for the efficacy variables. Categoric variables such as shifts in laboratory values and the frequency of AEs were analyzed using the Cochran-Mantel-Haenszel chi-squared test adjusted for baseline covariates (age, sex, diabetes, and metabolism of nebivolol). AEs were also analyzed by combining all active-treatment patients and comparing them with placebo-treated patients.


Patient Disposition and Baseline Characteristics

A total of 568 patients were screened and 485 patients entered the single-blind placebo run-in period. At the end of the placebo run-in period, 301 patients were randomized to double-blind treatment (Figure 1). One patient did not take the study drug; therefore, the ITT population comprised 300 patients. Of these, 259 patients (86.3%) completed 12 weeks of treatment. There was no association between nebivolol dose and the rate of discontinuations; discontinuation rates were 16.3% with placebo and 14.3%, 18.0%, 7.8%, 10.0%, and 15.7% with nebivolol 2.5, 5, 10, 20, and 40 mg, respectively (Figure 1). The major reasons for not completing the study were treatment failure (3.3%), loss to follow-up (3.0%), and occurence of AEs (2.0%). Treatment compliance was 87% in the placebo group and 84% to 98% across the nebivolol dose groups, with no association between compliance rate and nebivolol dose.

Figure 1.

Trial profile. qd indicates once daily.

Demographic characteristics and baseline parameters were comparable among the treatment groups (Table I). Patients were predominantly female (54.7%). The mean age of the study population was 50.9 years; 12.7% were younger than 40 years, and 11.7% were aged 65 years or older. Baseline SiDBP was numerically similar but showed a statistically significant difference across treatment groups (P=.027). There were no significant differences in baseline SiSBP level or HR across treatment groups.

Table I.  Demographic and Baseline Characteristics of All Randomized Patients by Treatment Group (Intent-to-Treat Population)
ParameterPlacebo (n=49)Nebivolol 2.5 mg (n=49)Nebivolol 5 mg (n=50)Nebivolol 10 mg (n=51)Nebivolol 20 mg (n=50)Nebivolol 40 mg (n=51)Total (N=300)P Valuea
Mean age, y (SD)49.7 (9.1)49.9 (9.6)51.6 (10.5)50.5 (10.5)51.3 (10.8)52.3 (12.0)50.9 (10.4).80
 Younger than 65, No. (%)44 (89.8)45 (91.8)44 (88.0)45 (88.2)45 (90.0)42 (82.4)265 (88.3).76
 65 and older, No. (%)5 (10.2)4 (8.2)6 (12.0)6 (11.8)5 (10.0)9 (17.6)35 (11.7) 
Sex, No. (%).89
 Male23 (46.9)26 (53.1)22 (44.0)22 (43.1)21 (42.0)22 (43.1)136 (45.3) 
 Female26 (53.1)23 (46.9)28 (56.0)29 (56.9)29 (58.0)29 (56.9)164 (54.7) 
Diabetes, No. (%)6 (12.2)7 (14.3)8 (16.0)6 (11.8)7 (14.0)9 (17.6)43 (14.3).96
Mean BMI, kg/m2 (SD)30.6 (5.4)30.3 (5.2)30.3 (4.8)29.8 (5.1)30.5 (5.1)31.6 (5.4)30.5 (5.2).62
 <30 kg/m2, No. (%)21 (42.9)26 (53.1)26 (52.0)26 (51.0)25 (50.0)20 (39.2)144 (48.0).67
 ≥30 kg/m2, No. (%)28 (57.1)23 (46.9)24 (48.0)25 (49.0)25 (50.0)31 (60.8)156 (52.0) 
EM or PM classification.80
 Poor0 (0.0)1 (2.0)1 (2.0)2 (3.9)1 (2.0)2 (3.9)7 (2.3) 
 Extensive49 (100)48 (98.0)49 (98.0)49 (96.1)49 (98.0)49 (96.1)293 (97.7) 
Mean sitting diastolic BP, mm Hg (SD)100.8 (4.0)99.5 (4.3)100.5 (4.4)100.3 (4.6)101.5 (4.7)98.7 (3.9)100.2 (4.4).03
Mean sitting systolic BP, mm Hg (SD)151.4 (13.9)148.6 (13.6)151.7 (13.6)154.2 (13.6)156.4 (12.7)150.9 (15.3)152.2 (13.9).09
Mean sitting heart rate, bpm (SD)72.6 (7.7)73.3 (9.6)74.5 (9.8)72.0 (9.0)75.8 (9.7)74.3 (8.4)73.7 (9.1).31
aFrom analysis of variance with main effect treatment for continuous variables, from a chi-squared test for discrete variables. Abbreviations: BMI, body mass index; BP, blood pressure; bpm, beats per minute; EM, extensive metabolizer; PM, poor metabolizer; SD, standard deviation.

Efficacy Results

All doses of nebivolol decreased BP (summarized in Table II and Figure 2), showing a dose response, with numerically greater reductions in both SiDBP and SiSBP levels with increasing nebivolol doses. Mean BP changes with the 40-mg dose were numerically less compared with the 10-mg and 20-mg doses. The baseline-adjusted decreases in least squares mean SiDBP for nebivolol 5 to 40 mg were statistically significant compared with placebo (P=.004 for nebivolol 5 mg; P<.001 for nebivolol 10, 20, and 40 mg).

Table II.  Effects of Nebivolol on Blood Pressure and Heart Rate in African American Patients With Mild to Moderate Hypertension at End of Study
ParameterPlacebo (n=49)Nebivolol Dose
2.5 mg (n=49)5 mg (n=50)10 mg (n=51)20 mg (n=50)40 mg (n=51)
Sitting DBP, mm Hg
 Trough effect
  Mean change from baseline (SD)−4.4 (8.8)−6.8 (7.9)−9.1 (9.1)−10.3 (8.2)−10.6 (8.8)−9.1 (7.4)
  LS mean change from baseline (SE)a−2.8 (2.1)−5.7 (2.1)−7.7 (2.1)−8.9 (2.0)−8.9 (2.1)−8.3 (2.0)
  P valuea .084.004<.001<.001<.001
 Peak effect
  Mean change from baseline (SD)−5.7 (8.8)−9.6 (8.0)−12.2 (10.3)−13.9 (9.2)−13.0 (9.9)−12.2 (8.6)
  LS mean change from baseline (SE)a−3.8 (2.3)−8.6 (2.3)−10.6 (2.2)−12.3 (2.2)−10.9 (2.2)−11.4 (2.2)
  P valuea .008<.001<.001<.001<.001
Sitting SBP, mm Hg
 Trough effect
  Mean change from baseline (SD)−3.6 (15.6)−4.6 (15.5)−5.9 (17.8)−10.2(12.9)−12.0(16.1)−9.6 (14.4)
  LS mean change from baseline (SE)a−0.4 (3.8)−1.9 (3.7)−3.0 (3.7)−6.4 (3.6)−7.6 (3.7)−7.2 (3.5)
  P valuea .611.383.044.005.002
 Peak effect
  Mean change from baseline (SD)−5.3 (17.1)−9.1 (14.4)−12.6 (17.8)−14.6 (13.6)−16.0 (18.4)−13.8 (14.4)
  LS mean change from baseline (SE)a−3.0 (3.8)−7.8 (3.7)−10.6 (3.7)−11.4 (3.6)−12.1 (3.7)−12.2 (3.5)
  P valuea .<.001
Sitting heart rate, bpm
 Trough effect
  Mean change from baseline (SD)−2.4 (8.0)−5.2 (9.7)−4.7 (8.1)−6.8 (9.0)−7.9 (8.8)−9.6 (9.6)
  LS mean change from baseline (SE)a−2.4 (2.7)−4.4 (2.6)−3.9 (2.6)−7.2 (2.5)−5.9 (2.6)−7.8 (2.6)
  P valuea .240.369.008.009<.001
 Peak effect
  Mean change from baseline (SD)−0.4 (8.2)−3.8 (10.7)−5.1 (8.3)−6.2 (9.0)−8.3 (7.9)−8.5 (9.3)
  LS mean change from baseline (SE)a3.1 (2.7)0.5 (2.6)−1.1 (2.5)−3.2 (2.5)−2.8 (2.5)−3.8 (2.6)
  P valuea .119.015<.001<.001<.001
aFrom an analysis of covariance with factor treatment and covariates baseline blood pressure, nebivolol metabolism rate, diabetes status, sex, age group, and step-down trend test results. Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; LS, least squares; SBP, systolic blood pressure; SD, standard deviation; SE, standard error.
Figure 2.

Placebo-subtracted least squares mean reductions from baseline to study end in trough sitting diastolic blood pressure (SiDBP) (A) and trough sitting systolic blood pressure (SiSBP) (B). aP=not significant vs placebo. bP=.004 vs placebo. cP≤.001 vs placebo. d.045 vs placebo.

The corresponding decreases in SiSBP from baseline to end point for nebivolol 10 to 40 mg were statistically significant compared with placebo (P=.044 for nebivolol 10 mg; P=.005 for nebivolol 20 mg; P=.002 for nebivolol 40 mg). Placebo-corrected changes in trough mean SiSBP and SiDBP are shown in Figure 2. Compared with placebo, the significant incremental reductions in BP in the nebivolol treatment groups were apparent by week 2 and were sustained throughout the remainder of the 12-week treatment period. Again, responses to the 40-mg dose were not greater than to the 10- and 20-mg doses.

Response rates at the end of the treatment period were significantly higher for nebivolol doses ≥5 mg than with placebo. The response rates were 58.0%, 58.8%, 64.0%, and 56.9% with nebivolol 5, 10, 20, and 40 mg, respectively, compared with 26.5% with placebo (P≤.002) (Figure 3). In addition, the percentage of nebivolol-treated patients in whom BP control was achieved was double that of placebo for doses of 5 mg and above, ranging from 32.0% to 36.0% vs 16.3% for placebo. Response rates were consistent throughout several of the doses used.

Figure 3.

Response rates by treatment (patients with an average trough sitting diastolic blood pressure ≤90 mm Hg at study end or a decrease from baseline of ≥10 mm Hg). aP=not significant vs placebo. bP=.002 vs placebo.cP<.001 vs placebo.

All doses of nebivolol slowed HR (Table II). Reductions from baseline to study end in trough sitting HR with nebivolol 10-, 20-, and 40-mg treatment, compared with placebo, were statistically significant (P≤.009). The corresponding reductions in sitting HR at peak plasma drug level for nebivolol 5, 10, 20, and 40 mg were statistically significant (P<.015). Reductions in trough and peak HR with nebivolol in both supine and standing positions were generally consistent with those for sitting HR (data not shown).

Safety Results. Nebivolol was well-tolerated, with no significant differences in the incidence of AEs between the nebivolol and placebo groups. Overall, 113 patients (45.0%) in the nebivolol group and 19 (38.8%) patients in the placebo group experienced at least 1 treatment-emergent AE (P=.474). Most treatment-emergent AEs were mild in intensity and thought to be unrelated to the study drug. The most frequently reported treatment-emergent AEs are summarized in Table III. No dose-related trend for the incidence of individual AEs was observed. The rates of AEs commonly associated with β-blockers were low with nebivolol treatment, including fatigue (7 patients [2.8%] compared with none in the placebo group), bradycardia (1 patient [0.4%] compared with 1 patient on placebo [2.0%]), and decreased libido and dyspnea (1 patient [0.4%] compared with none with placebo).

Table III.  Summary of Most Commonly Reported Treatment-Emergent AEs
Adverse EventPlacebo (n=49)Nebivolol 2.5 mg (n=49)Nebivolol 5 mg (n=50)Nebivolol 10 mg (n=51)Nebivolol 20 mg (n=50)Nebivolol 40 mg (n=51)Total Nebivolol (n=251)
All AEs19 (38.8)20 (40.8)21 (42.0)24 (47.1)25 (50.0)23 (45.1)113 (45.0)
Headache2 (4.1)3 (6.1)5 (10.0)3 (5.9)1 (2.0)2 (3.9)14 (5.6)
Dizziness001 (2.0)3 (5.9)4 (8.0)1 (2.0)9 (3.6)
Arthralgia1 (2.0)3 (6.1)1 (2.0)1 (2.0)2 (4.0)2 (3.9)9 (3.6)
Diarrhea1 (2.0)02 (4.0)1 (2.0)2 (4.0)3 (5.9)8 (3.2)
Fatigue01 (2.0)1 (2.0)1 (2.0)2 (4.0)2 (3.9)7 (2.8)
Nasopharyngitis01 (2.0)1 (2.0)1 (2.0)2 (4.0)1 (2.0)6 (2.4)
UTI02 (4.1)1 (2.0)1 (2.0)1 (2.0)1 (2.0)6 (2.4)
Constipation1 (2.0)1 (2.0)03 (5.9)1 (2.0)05 (2.0)
Chest pain02 (4.1)1 (2.0)01 (2.0)1 (2.0)5 (2.0)
Values are expressed as No. (%). Abbreviations: AEs, adverse events; UTI, urinary tract infection.

There were no deaths during the trial; however, there were 4 serious AEs: 2 in the nebivolol 40-mg group (chest pain and bladder cancer) and 2 in the nebivolol 5-mg group (motor vehicle accident and cerebral hemorrhage). Of these, only cerebral hemorrhage was considered possibly related to the study drug.

Changes from baseline to study end in laboratory parameters associated with cardiovascular risk that occurred during the double-blind treatment period with nebivolol were assessed. Nebivolol demonstrated statistically nonsignificant increases in serum glucose in all treatment groups. In most of the treatment groups, including the placebo group, statistically nonsignificant reductions in total and low-density lipoprotein cholesterol, as well as non-significant increases in triglycerides, were exhibited (Table IV). In addition, changes in high-density lipoprotein (HDL) cholesterol occurred in all groups (−0.8 mg/dL with placebo and −3.2, −5.2, −1.4, −3.9, and −6.1 mg/dL with nebivolol 2.5, 5, 10, 20, and 40 mg, respectively); these reductions with nebivolol did not appear to be dose-related but were statistically significant in the nebivolol 5-mg and 40-mg dose groups (P=.03).

Table IV.  Changes in Serum Lipoprotein and Glucose Levels by Treatment Group at End of Study
ParameterPlaceboNebivolol Dose
2.5 mg5.0 mg10 mg20 mg40 mg
Total cholesterol, mg/dL
 Baseline mean188.9211.3205.5201.7197.7192.4
 LS mean change from baseline (SE)a−4.7 (9.1)−4.8 (9.1)−10.3 (8.7)4.2 (8.7)−3.0 (8.8)−6.9 (9.0)
 P valuea .
LDL cholesterol, mg/dL
 Baseline mean111.9120.5125.3113.9123.5114.5
 LS mean change from baseline (SE)a−0.8 (7.4)−7.5 (7.4)−6.3 (7.1)1.3 (7.0)−1.5 (7.1)−8.3 (7.3)
 P valuea .
HDL cholesterol, mg/dL
 Baseline mean55.159.756.459.354.052.6
 LS mean change from baseline (SE)a−0.8 (2.9)−3.2 (3.0)−5.2 (2.8)−1.4 (2.8)−3.9 (2.8)−6.1 (2.9)
 P valuea .
Triglycerides, mg/dL
 Baseline mean111.0103.8142.9163.3142.6124.4
 LS mean change from baseline (SE)a18.5 (61.5)36.5 (61.4)−30.0 (59.0)54.0 (58.8)6.5 (59.0)30.8 (60.3)
 P valuea .
Glucose, mg/dL
 Baseline mean99.3105.6104.9110.0103.5106.3
 LS mean change from baseline (SE)a17.4 (10.6)26.2 (10.6)24.7 (10.2)17.2 (10.2)25.4 (10.2)15.2 (10.4)
 P valuea.
aFrom an analysis of covariance with factor treatment and covariates baseline value, nebivolol metabolism rate, diabetes status, sex, age group, and step-down trend test results. Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; LS, least squares; SE, standard error; UTI, urinary tract infection.


This study demonstrated that nebivolol, a cardioselective β1-blocker with vasodilating effects, given once-daily as monotherapy effectively reduced both diastolic and systolic BP in African American patients with stage I and stage II hypertension. In addition, the use of nebivolol resulted in response rates of >50%, and the drug was well-tolerated, with an AE rate comparable to that of placebo. Nebivolol treatment was associated with some effects on serum lipids (nonsignificant increases in triglyceride levels and decreases in HDL cholesterol as well as a reduction in low-density lipoprotein and total cholesterol levels) and statistically non-significant increases in serum glucose level.

These findings are of clinical importance, considering the excessive burden of hypertensive disease and low rates of BP control in the African American population.2,27,28 These patients are less likely to receive β-blockers as monotherapy than are white patients in the general community29,30; this under-use is likely due to data suggesting that β-blockers as a class are less effective than other agents in African Americans and that they may be associated with poor tolerability and adverse metabolic effects.31,32 The present study provides evidence to counter these generalizations by demonstrating significant antihypertensive efficacy and satisfactory tolerability of nebivolol in this patient population. Furthermore, BP control rates achieved in this study were comparable with those achieved with monotherapy in the general hypertensive population.28

An important strength of this trial was that the results were adjusted to account for the heterogeneity of the study population and potential confounding variables such as age, sex, diabetes, and obesity, which are known to determine BP response to treatment within racial groups.33

An earlier study demonstrated that nebivolol had a similar dose response and comparable efficacy in hypertensive black and white patients, with mean BP reductions at trough of −9.7/8.5 mm Hg compared with −9.0/9.4 mm Hg, respectively. An important pharmacologic attribute that may contribute to nebivolol's effectiveness in African American patients, as demonstrated in this trial and the earlier study, is its vasodilating action. Cardioselective non-vasodilating β-blockers, such as atenolol, primarily decrease BP by reducing cardiac output, not by reducing peripheral vascular resistance,13,24 actions that are not favorable in hypertensive African American patients, who often have a decreased cardiac output with increased peripheral vascular resistance.2–4 Nebivolol, in contrast, possesses a distinctly different hemodynamic profile, characterized by an increase in stroke volume with preservation of cardiac output and reduction of peripheral vascular resistance.24,35,36 These hemodynamic actions may also be shared by other vasodilatory β-blockers.35,36 Last, the vasodilatory actions of nebivolol have been demonstrated to improve coronary flow reserve in patients with essential hypertension.37,38

Attenuated vasodilation due to impaired endothelial function is a relatively generalized phenomenon in African American hypertensive patients.4 Antihypertensive agents with vasodilating action, therefore, may counteract an important pressor mechanism in this group of patients with hypertension and thus effectively lower BP.35,36 Previous clinical studies have suggested that nebivolol produces vasodilation through stimulation of the L-arginine/NO pathway in the endothelium.16–20 This action is different than that of other vasodilating β-blockers, such as carvedilol and labetalol, which act by blocking α-vasoconstrictor activity.36

In addition to being at higher risk for cardiovascular and renal disease, African American patients also generally report poorer antihypertensive medication adherence compared with the general hypertensive population.2,39,40 Patient compliance with therapy, which is often associated with tolerability,41 is thus a particularly important consideration in this population. In the present study, nebivolol was well-tolerated, and the incidence of AEs generally associated with β-blockade (such as fatigue, reduced libido, and bradycardia) was low with nebivolol treatment. Traditional β-blockers have been associated with some adverse metabolic effects, such as the potential to develop new-onset diabetes.14 In this study, nebivolol had a small but nonsignificant impact on glucose and was generally not associated with adverse metabolic effects or changes in other laboratory parameters. The decrease in HDL cholesterol levels and increase in triglyceride levels, which were not dose-related, may require further investigation.

Some limitations of the study should be acknowledged. A low proportion of diabetic patients (14.3%) were enrolled in this study, which may limit the extrapolation of results to this population. Another potential limitation of this study was the absence of baseline plasma renin activity measurements. Clinical studies have noted that young African American patients (aged 40 years and younger) respond better than do the elderly to β-blocker therapy as a result of their tendency toward normal renin levels; renin levels decline with age.42,43 Nebivolol therapy is also associated with a significant reduction in plasma renin levels.44 Interestingly, in the current study, only 12.7% of the patients were younger than 40 years, and yet nebivolol was efficacious, producing high response rates in the overall study population.

In conclusion, nebivolol monotherapy is safe and effective in lowering BP in hypertensive African American patients. While nebivolol has hemodynamic actions that may be favorable in this population, further studies are needed to determine whether these specific actions contribute significantly to BP reduction and improvement of clinical outcomes.


Editorial assistance was provided by Medicus International, New York, NY. Bertek Pharmaceuticals Inc (now part of Mylan Laboratories Inc) provided all financial and material support for the research. Elijah Saunders, MD: Speakers' Bureau and/or sponsored research for the following companies: Bristol-Myers Squibb/Sanofi-Aventis, Novartis, Pfizer, Forest Laboratories, Astra-Zeneca. William B. Smith, MD: Consultant/Speakers' Bureau: Boehringer Ingelheim, Merck, Novartis, Pfizer; research funding: Acambis, Amgen, Amylin, Bayer, Berlex, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Otsuka, Pfizer, Point Therapeutics, Sanofi-Aventis, Sanofi-Pasteur, Sepracor, Takeda, The Medicines Company. Karen B. DeSalvo, MD: Sponsored research: Forest Laboratories.