Effect of forced titration of nebivolol on response rate in obese hypertensive patients

Although hypertension is a common finding in obesity, current guidelines do not provide specific recommendations for the treatment of obesity hypertension that go beyond the rather general recommendation to reduce body weight.1 Furthermore, response rates to antihypertensive treatment are notoriously low in overweight or obese patients. For example, a study by Lloyd-Jones et al reported that obese patients have a 50% increased risk for lacking blood pressure (BP) control on antihypertensive treatment compared to lean patients.2 Nebivolol is a lipophilic selective β1 blocker that also induces endothelial nitric oxide release.3 It is currently licensed for use in arterial hypertension with a recommended daily dose of 5 mg, but is also used for treatment of angina pectoris, heart failure, and cardiac arrhythmias.4 Given the larger volume of distribution that can be expected in obese individuals, the primary purpose of the present study was to assess whether higher doses of nebivolol (10 or 20 mg) would increase the response to treatment over the standard dose of 5 mg daily in obese hypertensive patients. Our study included overweight or obese (body mass index [BMI], 28–45 kg/m2) patients with mild-to-moderate treated or untreated essential hypertension (systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg) who were otherwise healthy and between 18 and 80 years of age. Target criteria for study completion were a fall in SBP of ≥20 mm Hg or normotension (SBP ≤130 mm Hg and DBP ≤85 mm Hg). After screening, antihypertensive therapy was withdrawn in previously treated patients. Patients then received placebo for 2 weeks, followed by 5 mg nebivolol for 4 weeks. The dose was increased to 10 mg for 2 weeks, and again to 20 mg for 2 weeks if target criteria were not reached with the preceding dose. If target criteria were met, patients were classified as responders and otherwise as nonresponders. The analysis was based on a Macrov-chain design with three points in time (weeks 4, 6, and 8) and two conditions (nonresponse, response). Mean BP and heart rate were calculated of five measurements with an automatic oscillometric BP measurement device (Dinamap 1846 SX, Critikon, Germany) at intervals of 2 min in a sitting position after 10 min rest; the cuff was placed on the right arm, with an individual cuff size depending upon circumference. Body weight was measured with the Tanita TBF-305 scale (Tanita Corp., Tokyo, Japan) and blood and urine samples were analyzed with standard laboratory techniques. Quality of life was assessed with the Short Form–36 (SF-36) questionnaire.5 Patients were asked regarding adverse events, and compliance was checked at every visit. The study was approved by the Institutional Ethics Committee and was performed in accordance with the Guidelines for Good Clinical Practice (GCP). Written informed consent was obtained from all participants. A total of 66 patients were screened, 46 of whom met the inclusion criteria at baseline (Table 1). Of the 41 patients who completed the first dose per protocol, 18 responded to 5 mg nebivolol (response rate 43.9% [95% confidence interval, 28.5% to 60.3%]). In all, 21 patients completed the second titration step per protocol. Of these, three (14.3% [0.3% to 36.3%] responded to 10 mg nebivolol. The last titration step was completed per protocol by 16 patients. Of these, none (0% [0% to 0.21%]) responded to 20 mg nebivolol. During the verum phase, nine patients were excluded from the study: five on 5 mg nebivolol (three because of noncompliance and two because of adverse events), two on 10 mg nebivolol (because of adverse events) and two on 20 mg nebivolol (for administrative reasons). The overall response rate to nebivolol was 51% (35% to 67%). Blood pressure was significantly reduced in all patients treated with nebivolol (data not shown). The occurrence of any adverse event was reported by 36% of the patients on placebo, 62% on 5 mg, 54% on 10 mg, and 58% on 20 mg nebivolol. The most common adverse event was headache (placebo, 10%; 5 mg, 15%; 10 mg, 17%; 20 mg, 26%). However, only four patients were withdrawn because of adverse events during the verum phase of the study. During nebivolol treatment, there was a significant decrease in total cholesterol and HDL cholesterol levels as well as microalbumin excretion. No other clinical significant laboratory changes were observed. There were no significant differences in quality of life between the placebo phase and the verum phase during treatment. Body weight did not substantially change during the study. Patient characteristics at baseline (n = 46) Patient characteristics at baseline (n = 46) Studies have shown that nebivolol leads to significant dose-dependent BP reductions in doses between 1 and 5 mg,6 and that response rates of 5 mg nebivolol (defined here as DBP ≤90 mm Hg or reduction in DBP ≥10 mm Hg) were 64% after 2 weeks treatment and were up to 77% after 3 months. However, these studies also showed that the efficacy of BP response was impaired in obese patients. An increase of 10 kg body weight led to an efficacy reduction of 0.6 mm Hg (nebivolol product monography). We hypothesized that because of the highly lipophilic nature of this agent, obese patients would require higher dosages to maintain response rates comparable to those of nonobese patients. However, the present study shows that despite lipophilic nature of nebivolol, the response rate did not increase with higher doses than the currently recommended 5 mg in obese hypertensive patients. Possible explanations for our findings might be the observations that lipophilic β blockers diffuse less into adipose than into lean tissues,7 and that differences in the pharmacokinetics of nebivolol between lean and obese individuals may not be relevant.8 Furthermore, plasma levels of β blockers are poor predictors of antihypertensive effects. Thus, a study by Galletti et al found no relevant effect of obesity on the kinetics of the water-soluble atenolol while it markedly interfered with the lipo-soluble metoprolol; however, they found no differences in the pharmacodynamic response between the two drugs in obese patients.9 It is interesting to note that in the present study, despite a rather conservative definition, almost 50% of obese patients responded to 5 mg nebivolol, with a fall in SBP of ≥20 mm Hg. Although our study included no control group, this response rate is well in line with that found for most antihypertensive drugs in nonobese patients. Apart from efficacy, important features of antihypertensive treatment are potential side effects and an impairment in quality of life. Frequent side effects of β blockers are a reduction in heart rate as well as airway obstruction. In the present study, heart rate was slightly reduced; however, the observed effects were not clinically significant. Nebivolol was well tolerated, and no patient reported symptoms of airway obstruction. There were no significant changes in quality of life during nebivolol treatment. In summary, we found that despite the lipophilic nature of nebivolol, the response rate did not increase with higher doses than the currently recommended 5 mg nebivolol in obese hypertensive patients. Despite a rather conservative definition (20 mm Hg SBP reduction), almost 50% of obese patients responded to 5 mg nebivolol. These data suggest that instead of an increase in nebivolol dosage, a combination with other antihypertensive drugs may be required to control BP in obese hypertensive patients. We are indebted to our coinvestigators Drs. Konrad Buchholz, Carmen Kresse, and Heidrun Mehling, and to our study nurses Nicole Kempa, Iris Gottschalk, Anke Strauss, and Gritt Stoffels.