New beta blocker has unique properties, is effective for long-term blood pressure control
CHICAGO— A novel cardioselective beta blocker currently under FDA review provides effective control of hypertension over the long term and is as effective at lowering blood pressure in obese patients as in the nonobese without causing adverse metabolic changes.
A 9-month open-label extension of a 3-month placebo-controlled trial revealed that nebivolol was associated with sustained blood pressure reduction when used as either monotherapy or in combination with a diuretic, said Vasilios Papademetriou, MD.
The extension study included 845 patients with mild-to-moderate hypertension who previously completed 1 of 3 randomized, placebo-controlled 12-week dose-ranging studies of nebivolol, 1.25 to 40 mg/day. In the extension phase, patients were treated with open-label nebivolol, 5, 10, or 20 mg once daily. After 28 days, those who did not achieve an average sitting diastolic blood pressure (DBP) < 90 mm Hg received open-label diuretics or amlodipine as adjuncts.
"There was no attenuation of blood pressure reduction in the extension phase," said Dr Papademetriou, professor of medicine, Georgetown University, Washington, DC. "If anything, blood pressure control improved with time." Average blood pressure reduction at the end of 1 year in the 607 patients treated with nebivolol monotherapy was 14.8/15.0 mm Hg, and 78.2% of the patients who received nebivolol monotherapy were considered responders to treatment. (Response was defined as a final trough sitting DBP < 90 mm Hg or an absolute decrease of 10 mm Hg or more from baseline of the "feeder" study.)
Among the 206 patients who also received a diuretic, average blood pressure reduction was 16.2/12.0 mm Hg, and 65.5% were considered responders. Too few patients were treated with amlodipine or other add-ons for meaningful comparisons.
A post-hoc pooled analysis of the 3 12-week feeder trials also showed comparable blood pressure reductions in obese and nonobese subjects with mild-to-moderate hypertension, reported James R. Sowers,MD, director, Center for Diabetes and Cardiovascular Health, University of Missouri, Columbia. Of the 2016 patients enrolled, 878 were defined as obese (body mass index ≥ 30 kg/m2) and 1136 were not obese. At the end of the study, trough sitting DBP declined by 7.7 mm Hg to 11.5 mm Hg from baseline (vs 4.9 mm Hg with placebo) in the nonobese patients, and from 6.7 mm Hg to 9.5 mm Hg (vs 4.0 mm Hg with placebo) in the obese patients, a nonsignificant difference between the obese and nonobese groups. Response rates were also similar between the obese and nonobese patients.
Adverse metabolic side effects were rare with nebivolol, an important consideration when treating obese patients. Its effects on lipids and glucose were neutral, as they were in Dr Papademetriou's study.
"Traditional beta blockers reduce cardiac output because they reduce heart rate and they are vasoconstrictors. Nebivolol is different from other beta blockers in that it is a vasodilator, and therefore increases cardiac output," said Alan Gradman, MD, chief, division of cardiovascular diseases, The Western Pennsylvania Hospital, Pittsburgh. "The mechanism of action for its vasodilation is enhancement of nitric oxide release."
According to Dr Papademetriou, the increase in nitric oxide bioavailability has lead to improved endothelial function with nebivolol. In addition, the increased cardiac output means that side effects associated with first-generation beta blockers (ie, fatigue, erectile dysfunction) are less frequent with nebivolol. Indeed, in his study, fatigue was reported by 4.6% of the patients and erectile dysfunction by 0.7%. The overall discontinuation rate due to adverse events was 3.7%.
One ARB superior to another in reducing urinary albumin
One angiotensin receptor blocker (ARB)—telmisartan—has a greater effect on urinary protein excretion than another ARB—losartan—in patients with type 2 diabetes, hypertension, and chronic kidney disease, said George Bakris, MD.
The greater reduction in albuminuria observed with telmisartan in his randomized, controlled study was independent of its effects on blood pressure, and suggests that telmisartan may confer greater protection against progression to end-stage renal disease, although this hypothesis must be tested in a prospective study.
The presence of proteinuria is associated with a high risk of renal disease progressing to an end stage, and to an elevated risk of cardiovascular events as well, said Dr Bakris, professor of medicine, University of Chicago, and director of the Hypertension Center in the Diabetes Institute. "The greater the decrease in proteinuria, the longer it takes to get to dialysis," he said.
"What is newly appreciated is that it's not good enough to just lower blood pressure," he said. "We have to see what's happening to albuminuria. Albumin is an even better predictor than proteinuria of outcomes in terms of both kidney disease and cardiovascular disease."
Seventh Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure
In previous placebo-controlled clinical trials of ARBs conducted in patients with kidney disease, a 30% reduction in proteinuria at 6 months to 1 year following initiation of treatment was strongly associated with a slowing of progression of diabetic nephropathy, independent of treating blood pressure alone, and a reduction in the incidence of cardiovascular events. Current hypertension treatment guidelines () therefore recommend ARBs for the treatment of diabetic nephropathy to slow the progression of kidney disease.
The study reported here was a head-to-head randomized comparison of telmisartan (titrated to 80 mg/day) and losartan (titrated to 100 mg/day) in 860 patients with type 2 diabetes, hypertension (blood pressure >130/80 mm Hg), and overt nephropathy. Hydrochlorothiazide and calcium antagonists could be added if blood pressure remained greater than 130/80 mm Hg.
The average urinary protein:creatinine at baseline was approximately 2000 mg/gCr. "If you were to look at estimated glomerular filtration rate, they had lost about 60% to 65% of their kidney function," said Dr Bakris.
Treatment was stopped at 1 year, after which patients were followed for an additional 8 weeks to determine the persistent effect of the agents on urinary protein excretion independent of blood pressure reduction.
Despite comparable blood pressure reductions between the 2 groups, the mean 1-year urinary protein:creatinine ratio was 0.71 in the telmisartan-treated patients compared with 0.80 in the losartan-treated patients ( = .0284). Furthermore, a significantly greater percentage of patients ( <.05) in the telmisartan group had a persistent antiproteinuric effect 2 months after the drugs were stopped, as measured by urinary protein excretion and the urinary albumin:creatinine ratio.
Losartan is currently approved as a firstline treatment for diabetic nephropathy. The advantage of telmisartan in this study may lie in its longer duration of action and its greater binding to the angiotensin-1 receptor, Dr Bakris speculated.
Few hypertensive patients follow blood pressure lowering diet
Accordance with the DASH diet is low in persons with hypertension, despite the diet's proven efficacy in reducing blood pressure levels, said Philip Mellen, MD, MS.
The DASH diet was named after the diet used in a clinical trial named the Dietary Approaches to Stop Hypertension study, the results of which were published in 1997. The diet is rich in fruits, vegetables, grains, and low-fat dairy products, and low in fat, cholesterol, and sodium, and was found to lower systolic blood pressure in hypertensive participants in the trial by 11.4 mm Hg and diastolic blood pressure by 5.5 mm Hg.
The DASH diet was among the therapeutic lifestyle changes recommended by national hypertension guidelines (Joint National Committees 6 and 7) for all patients with hypertension or at risk of hypertension, whether or not they were being treated with antihypertensive drug therapy, said Dr Mellen, assistant professor of internal medicine, Wake Forest University, Winston-Salem, NC.
"The dietary quality of hypertensive adults has appeared to deteriorate since the DASH diet became incorporated into national guidelines," he said.
Mellen and colleagues compared compliance with the DASH diet components among 2 groups of people with hypertension who participated in the National Health and Nutrition Examination Surveys. One group of 4556 was surveyed between 1988 and 1994 (3 years before publication of the DASH results) and the second group of 4386 was surveyed from 1999 to 2004.
Nine components of the DASH diet were targeted (intake of saturated fat, total fat, sodium, cholesterol, protein, fiber, magnesium, calcium, and potassium). Individuals who met approximately half of the targets were considered accordant with the DASH diet.
In the survey period covering 1999 to 2004, 21.7% of those with known hypertension reported following the DASH diet. This percentage was 7.6% lower ( = .0002) than the percentage who followed the dietary components of DASH in the previous survey.
Those more likely to follow the DASH diet were non-Hispanic whites, individuals with an education beyond high school, and persons with diabetes.
Dr Mellen said several factors probably play a role in the low accordance with the DASH diet. "Physicians don't feel adequately trained to do this [dietary counseling] and dietary counseling is not allowed for in the reimbursement structure. It requires a significant investment in time for physicians," he said. "All in all, it may appear easier to give a prescription."