Continuing Evolution of the Role of Β-Blockers in the Treatment of Hypertension

REVIEW

Continuing evolution of the role of β-blockers in the treatment of hypertension

The β-blockers have evolved into one of the most prescribed classes of drugs for the treatment of cardiovascular disease in general, and hypertension in particular. However, the class is one of the more heterogenous groups in pharmacological agents. The evolution of the β-blockers has included increased selectivity for the β1 receptor (cardioselective) and, more recently, development of β-blockers with vasodilating properties. As a result of this evolution, the current vasodilating β-blockers, i.e., nebivolol and carvedilol, have a better hemodynamic profi le and are devoid of many of the troublesome side effects, for example, fatigue, sexual dysfunction and increased insulin resistance and disturbances in glucose metabolism, found in the traditional β-blockers. Nebivolol produces vasodilation by a mechanism that includes increased bioavailability of nitric oxide that may bring other benefi ts. With these improvements in design, the future for the use of β-blockers appears bright.

KEYWORDS: β-blockers, carvedilol, hypertension, nebivolol, nitric oxide Thomas D Giles Tulane University School of The classifi cation of α- and β-adrenoceptors by insulin resistance and hasten the appearance of Medicine, 109 Holly Drive, Ahlquist and colleagues in 1948 provided the hyperglycemia (diabetes mellitus). Additionally, Metairie, New Orleans, foundation for the development of drugs that the use of β-blockers in African–American LA 70005, USA could modulate the sympathetic nervous system hypertensive patients may be limited owing to Tel:. +1 504 834 8668 (SNS) [1] . The fi rst β-blocker, pronethalol, devel- the fact that traditional β-blockers are less effec- Fax: +1 504 836 0822 oped by Sir James Black, was limited clinically tive in lowering blood pressure (BP) in hyper- [email protected] due to safety concerns. However, the subsequent tensive African–American patients compared development of its successor, propranolol, earned with hypertensive Caucasian patients [9,10]. Black the Nobel Prize for Medicine in 1988, The newer (‘third-generation’) β-blocking and revolutionized the process of the laboratory drugs are characterized by the ability to pro- development of cardiovascular drugs [2]. The duce vasodilation, and include carvedilol, development of the β-blocking class of drugs labetalol and nebivolol. Carvedilol and labeta- provided clinicians with new tools to treat lol achieve vasodilation by interfering with the many cardiovascular disorders that now include: α1 adrenoceptor, whereas nebivolol utilizes a hypertension, heart failure, angina pectoris, cer- mechanism that is endothelial dependent and tain arrhythmias, post-myocardial infarction results in increased bioavailability of nitric ventricular dysfunction and high-risk patients, oxide (NO) (vide infra). including those with diabetes mellitus [3–5]. The fi rst widely used β-blocker, propranolol, Recent studies of traditional had equal blocking properties at both the β1 β-blockers and β2 adrenoceptor subtypes. Since blocking Despite their less-than-desirable side effect β2 receptors produced unwanted side effects profi le, the traditional β-blockers have been (e.g., vasoconstriction and bronchoconstriction), considered as ‘fi rst-line’ therapy in the man- new (second-generation) drugs were developed agement of hypertension by every report of the that were more selective for the β1 receptor, for US Joint National Committee on Prevention, example, metoprolol and atenolol. These drugs Detection, Evaluation and Treatment of were called cardioselective. However, at higher Hypertension (JNC), including the JNC 7 doses, blockade occurred at both receptors [6]. report [3]. However, a meta-ana lysis of 13 ran- The traditional β-blocking drugs are associ- domized clinical trials of β-blockers in the ated with many side effects, including fatigue, management of hypertension, published in sexual dysfunction (erectile dysfunction), cold 2005 [11], concluded that atenolol was not as hands and weight gain [7], and have limited effi - effective as other antihypertensive drugs in the cacy in obese patients [8]. Moreover, these tradi- treatment of hypertension and that, in com- tional β-blockers have a propensity to increase parison with other antihypertensive drugs, the

10.2217/14750708.5.6.773 © 2008 Future Medicine Ltd Therapy (2008) 5(6), 773–778 ISSN 1475-0708 773 REVIEW Giles

effects of β-blockers were associated with an treatment arm [16] . The trial was terminated increased incidence of stroke. It was suggested prematurely owing to excess mortality in the that atenolol should not be used in the treat- patients randomized to the β-blocker arm. ment of primary hypertension, and should not Explanations for this disappointing result are be used as a comparator in future randomized not entirely clear. However, a clue is available controlled trials of antihypertensive drugs. This from a substudy of ASCOT, the Conduit Artery suggestion was taken in the preparation of the Function Evaluation (CAFÉ) trial. In this trial, a UK’s National Institute for Health and Clinical noninvasive technique was used to compare the Excellence (NICE) guidelines for the treatment effects of atenolol-based therapy and amlodipine- of hypertension [12] . However, the suggestion based therapy on central (aortic) and peripheral was extended to all β-blockers, even though blood pressure [17] . Importantly, whereas the the data upon which it was based virtually all two treatment arms had similar blood-pressure- originated from studies of atenolol. lowering effects when measured in the brachial One randomized clinical trial that uti- artery, the β-blocker treatment was signifi cantly lized atenolol as the comparator drug was the less effective than the calcium channel blocker Losartan Intervention for Endpoint Reduction treatment in reducing central pressure. This dif- (LIFE) Study [13] . In this study of hypertensive ference in effectiveness of blood pressure lower- patients with left ventricular hypertrophy, the ing is particularly important, since both cardiac atenolol arm was approximately 25% more likely and stroke events are directly affected by the cen- than the angiotensin receptor blocker, losartan, tral blood pressure. These data may provide an arm to be associated with stroke events [13] . explanation for the apparent failure of traditional Nevertheless, atenolol was more effective in β-blockers to reduce major clinical events to the preventing ischemic events and more effective same extent as other antihypertensive therapies, than losartan in African–American subjects. for example, the LIFE trial. However, the atenolol-based therapy was at least equivalent to angiotensin-converting enzyme Third-generation β-blockers (ACE) inhibitor-based therapy in improving The third-generation β-blockers are character- cardiovascular and metabolic outcomes in the ized by the ability to produce arterial dilation UK Prospective Diabetes Study (UKPDS) when and reduce peripheral vascular resistance, in examining the importance of achieving tight addition to blocking the β-receptor. Traditional blood pressure control in patients with Type 2 β-blocking drugs targeted two primary adren- diabetes mellitus [14] . ergic receptors of norepinephrine. β1 recep- Atenolol, more than any other traditional tors predominate in healthy cardiac muscle, β-blocker, appears to be associated with signifi - while β2 receptors predominate in the bronchi. cantly higher rates of all-cause mortality, cardio- Traditional β-blockers, such as propranolol, are vascular mortality and stroke [11] . It should be nonselective and block both β1 and β2 recep- noted that in most clinical trials, atenolol was tors [6]. Second-generation β-blockers, such as dosed once daily, often at a dose of 50 mg. It acebutolol, atenolol, bisoprolol and metoprolol, has been demonstrated in many subjects that offer more selective β1 or β2 blockade [6]. atenolol is not a once-a-day drug, and thus the Third-generation, vasodilating β-blockers, patient is subjected to intermittent periods of i.e., bucindolol, labetolol, carvedilol and nebiv- withdrawal – defi nitely an untoward event. In olol, vary in their selectivity [18]. Carvedilol is the International Verapamil–Trandolapril Study nonselective with inhibition of the α1 receptor. (INVEST), where atenolol was dosed twice Labetolol is nonselective with a higher affi nity for daily, the β-blocker fared as well as the other the α1 receptor than for β1 and β2 receptors. treatment regimens tested [15] . Carvedilol is a nonselective β-blocker and Atenolol therapy was also evaluated in the provides α1-receptor blockade. The α1 recep- Anglo Scandinavian Cardiac Outcomes Trial tors mediate endothelial function and vaso- (ASCOT) [16] . In this study, conducted in a constriction in peripheral vessels, regulate blood large cohort of relatively high-risk middle- fl ow to the kidneys, and have been linked to aged hypertensive patients, a comparison of conditions such as myocardial hypertrophy and atenolol (usually paired with a thiazide) with benign hyperplasia of the periurethral prostate. the calcium channel blocker amlodipine (usu- Nebivolol, recently approved for use in the ally paired with perindopril) revealed that major treatment of hypertension in the USA, has cardiac and stroke outcomes clearly favored been shown to have higher β1 selectivity than the calcium channel blocker/ACE inhibitor other β-blockers, and endothelium-dependent

774 Therapy (2008) 5(6) future science group Continuing evolution of the role of β-blockers in the treatment of hypertension REVIEW

vasodilation associated with increased bioavail- risk patients, carvedilol successfully achieved ability of NO [19] . Nebivolol is a racemic mix- the blood pressure goal while maintaining ture of d-nebivolol (+SRRR) and l-nebivolol glycemic control. (-RSSS), and both enantiomers appear to vasodi- late equally [20]. The l-enantiomer is responsible Nebivolol for the increased bioavailability of NO, while the Nebivolol is a novel third-generation, cardio- d-enantiomer is primarily responsible for block- selective (β1-adrenoceptor) lipophillic, vaso- ade of the β-receptor [18]. The exact mechanism dilatory β-blocker [22], and produces endothe- for the increased bioavailability is not completely lium-dependent vasodilation [21–23] mediated known, but may involve the β3 receptor subtype through the l-arginine/NO pathway. Nebivolol and modulation of asymmetric dimethylarginine is the most cardioselective β-blocker when (ADMA). assessed in human myocardium [24]. In Europe, nebivolol is currently approved and well tolerated Adverse side effects in the treatment of hypertension, coronary artery The third-generation β-blockers as a group are disease, myocardial infarction, heart failure and associated with fewer adverse drug reactions and left ventricular dysfunction. are associated with potentially benefi cial effects The hemodynamic effects of nebivolol differ on arterial vasculature. In particular, third- from those of older traditional β-blockers. In generation β-blockers differ from traditional hypertensive patients, nebivolol administration β-blockers with regard to benefi t–risk, concern- was associated with a decrease in peripheral vas- ing the adverse effect on diabetes and insulin sen- cular resistance, and preserved cardiac output, sitivity. For example, traditional, older β-blockers stroke volume and left ventricular function [25]. (propranolol, atenolol and metoprolol) decrease Nebivolol, unlike atenolol, has demonstrated insulin sensitivity. However, as discussed below, effi cacy in reducing central aortic pressure [25]. recent metabolic studies report that third-genera- tion vasodilating β-blockers have benefi cial effects Study of nebivolol in on insulin sensitivity as well as on atherogenic risk an African–American factors and endothelial function. hypertensive population Hypertension and its associated cardiovascular Carvedilol and renal complications occur disproportion- The Glycemic Effects in Diabetes Mellitus/ ately more often among African–Americans Carvedilol–Metoprolol Comparison in compared with Causcasians. Hypertensives (GEMINI) trial, a double-blind In a study of 300 African–Americans with randomized trial involving 1235 participants Stage I or II hypertension (sitting diastolic blood at 205 sites, studied the metabolic effects of pressure [SiDBP] ≥95 mmHg and ≤109 mmHg) carvedilol versus metoprolol in patients with treated with placebo or once-daily nebivolol Type 2 diabetes and hypertension [21]. Patients (2.5, 5, 10, 20 and 40 mg), all doses of nebivo- were randomized to receive metoprolol (50 mg lol decreased BP, and a clear dose response was twice daily [b.i.d.], titrated up to 200 mg b.i.d.) observed, with numerically greater reductions in or carvedilol (6.25 mg b.i.d., titrated up to 25 mg both SiDBP and sitting systolic blood pressure b.i.d.) for 35 weeks. Similar blood pressure levels (SiSBP) with increasing nebivolol doses up to were achieved in the two groups. Mean hemo- 20 mg [26]. Response rates in African–American globin A1C (HbA1c) increased signifi cantly in patients at the end of the treatment period were the metoprolol group (0.15%, p < 0.001), but not signifi cantly higher for nebivolol at doses of 5, in the carvedilol group (0.02%, p = 0.65), and 10, 20 and 40 mg compared with placebo (58.0, insulin sensitivity improved signifi cantly with 58.8, 64.0 and 56.9 versus 26.5%, respectively; carvedilol (-9.1%, p = 0.004), but not meto- p ≤ 0.002). It is possible that these effects in prolol (-2.0%, p = 0.48). Progression to micro- black patients are related to the NO mechanism albuminuria was less frequent with carvedilol of vasodilation of nebivolol. Nebivolol has been than with metoprolol (6.4 vs 10.3%, p = 0.04). found to decrease oxidative stress and restore NO GEMINI is the fi rst large-scale randomized trial bioavailability in black subjects [27,28]. to evaluate the addition of β-blockers to ACE inhibitors or angiotensin receptor blockers to Adverse & metabolic effects achieve the recommended blood pressure target of nebivolol of less than 130/80 mmHg for patients with The side-effect profi le of nebivolol is similar to Type 2 diabetes; in these high cardiovascular placebo [29]. In particular, there appears to be no

future science group www.futuremedicine.com 775 REVIEW Giles

adverse effect on sexual function in general, and and may have accounted for a reduction in use. erectile function in particular [30]. Nebivolol, in However, the third-generation β-blockers have comparison with metoprolol, increased insulin reawakened interest in the use of β-blockers in sensitivity in patients with hypertension [31,32]. the treatment of hypertension and other cardio- Although there has yet to be any clinical tri- vascular diseases. als investigating the antihypertensive effects It is now possible for patients to enjoy the ben- of nebivolol in elderly patients, data from the efi ts of β-blockade in reducing cardiovascular Study of Effects of Nebivolol Intervention on mortality, in particular sudden death and morbid- Outcomes and Rehospitalization Seniors with ity, while avoiding the unwanted side effects on Heart Failure (SENIORS) trial have shown glucose metabolism, sexual function and fatigue that nebivolol is well tolerated in elderly and cold extremities. The hemodynamic profi les, patients with chronic heart failure, and nebivo- and placebo-like adverse effect profi le, will almost lol reduced the risk of mortality and morbidity, assure the continued use of this drug class for the as well as hospitalization rates [33]. foreseeable future. Of course, many of the tradi- tional β-blockers have reached generic status and Hypertension treatment guidelines & often cost much less. However, given the need for the third-generation β-blockers combination therapy and quality-of-life issues, a The latest edition of the guidelines of the new generation of β-blockers is likely to prevail. European Society of the Cardiology/European Nebivolol is of particular interest since the Society of Hypertension, after considerable eval- mechanism of vasodilation involves the increased uation of all available data, continue to included bioavailability of NO. Regardless of the mecha- the β-blockers among the other major drug nism, the increase of endothelial-derived NO classes as fi rst-line considerations [34]. However, by nebivolol may provide additional benefi ts to of note is the fact that these guidelines empha- those derived from modulating the SNS. NO size the positive attributes of the newer vaso- modulates endothelial adhesion molecules, dilatory β-blockers, nebivolol and carvedilol, growth of smooth muscle cells and the infl am- and recommend that they be the agents of matory response. Moreover, the production of choice. Likewise, the American Association of NO by the endothelium does not produce tachy- Clinical Endocrinologists, while recommend- phylaxis, as has been seen with NO donors, for ing that β-blockers be strongly considered as example, the organic nitrates. additive therapy in diabetic patients already receiving an ACE inhibitor or an angiotensin Financial & competing interests disclosure receptor blocker, emphasize a preference for the Dr Giles is a consultant to Novartis, Forest Labs, NicOx, vasodilatory agents [35]. Daiichi Sankyo, Sanofi and Bristol–Myers Squibb. The author has no other relevant affi liations or fi nancial involve- Future perspective ment with any organization or entity with a fi nancial inter- At present, the β-blockers are among the most est in or fi nancial confl ict with the subject matter or materi- prescribed drugs for the treatment of cardio- als discussed in the manuscript apart from those disclosed. vascular disease. The traditional β-blockers, par- No writing assistance was utilized in the production of ticularly atenolol, have been criticized recently this manuscript.

Executive summary Despite providing great clinical benefi ts, older generation β-blockers are associated with many adverse side effects, for example, fatigue, sexual dysfunction and cold hands, and may have a deleterious effect on metabolic parameters such as serum glucose and lipids, thereby making them potentially unsuitable in certain patient groups (e.g., those with diabetes or metabolic syndrome). Moreover, β-blockers have been shown to have reduced effi cacy in black and older populations. Newer (third-generation) vasodilating β-blockers, such as nebivolol and carvedilol, have placebo-like side effects and appear to be free of adverse effects on metabolic parameters. As such, these third-generation β-blockers may be a potential treatment option for hypertension treatment in patients, particularly those with diabetes or metabolic syndrome. Whereas traditional β-blockers are not deemed suitable in certain patient populations, such as African–American patients, owing to the fact treatment response rates are generally low, nebivolol is effective, an effect that may be due to its ability to increase nitric oxide availability. Hypertensive patients often show endothelial dysfunction and a reduction in nitric oxide bioavailability, and this can be more pronounced in African–American patients. Additionally, nebivolol, unlike traditional non-vasodilating β-blockers, has been shown to lower central aortic pressure.

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