madman
Super Moderator
According to the most recent international guidelines, β-blockers maintain a central role in the management of hypertension, being recommended at any treatment step when there is a specific indication, such as heart failure, angina, post-acute myocardial infarction, atrial fibrillation, or pregnancy. However, βblockers are not a homogeneous class: individual molecules differ in terms of pharmacological and clinical profile and are therefore suitable for different patient subtypes. In particular nebivolol, a third-generation β1-selective β-blocker with vasodilating properties, neutral metabolic effects, and good tolerability, proved to have advantages over other β-blockers, which makes the drug suitable in a wide variety of hypertensive patients with or without comorbidities.
Lay abstract: β-blockers are the main class of antihypertensive agents currently available. Nebivolol is one of the most recent β-blocking agents and it has vasodilating effects which may be useful in hypertensive patients with heart disease of ischemic (restriction in blood supply) origin or with erectile dysfunction. It has a good tolerability profile which makes it safe to use in patients with metabolic abnormalities (such as diabetes or dyslipidemia) or chronic obstructive pulmonary diseases.
Despite the substantial progress made in understanding the complex pathophysiologic mechanisms of hypertension, the best strategy to reduce the cardiovascular (CV) risk associated with hypertension remains blood pressure (BP) lowering, through the use of all major antihypertensive drug classes (angiotensin-converting enzyme [ACE]- inhibitors, angiotensin receptor blockers [ARBs], β-blockers, calcium channel blockers [CCBs] and diuretics) [1]. However, BP control rates remain poor worldwide and across Europe [2], one of the main contributing factors being poor adherence to treatment [3]. Simplifying treatment algorithms and favoring single pill combinations to quickly achieve BP targets may help in improving adherence to treatment and optimizing its efficacy [4]. For this reason, the latest update of the European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines for the diagnosis and treatment of hypertension proposed simplified drug treatment algorithms with the preferred use of an ACE inhibitor or ARB, combined with a CCB and/or a thiazide/thiazide-like diuretic, as the core treatment strategy for most patients, based on evidence on the ability of these classes to reduce CV events and improve patients’ prognosis [1]. In addition, recognizing the potential advantages of β-blockers in hypertensive patients with concomitant CV pathologies (such as heart failure [HF], coronary artery disease (CAD), atrial fibrillation [AF]), current guidelines recommend their preferential use in these patients, in order to maximize treatment efficacy and tolerability [1]. Among β-blockers, third-generation cardio-selective drugs with vasodilating and anti-oxidant properties, such as nebivolol, may show particular benefits, thanks to ancillary actions that go beyond the blockade of adrenergic receptors, to provide better CV protection associated with a positive metabolic profile [1]. The efficacy and tolerability of third-generation β-blockers have been demonstrated also in hypertensive patients with specific non-CV comorbidities (such as diabetes, respiratory obstructive diseases, or erectile dysfunction [ED]) [5– 7], in which conventional anti-adrenergic agents are usually contraindicated or not recommended as first choice drugs [1]. The aim of the present review was to elucidate the heterogeneity of the β-blockers class, by analyzing the pharmacological profiles of third-generation agents, such as nebivolol, and the associated benefits in terms of efficacy and tolerability, which support guidelines’ recommendations.
*β-Blockers’ role in the management of hypertension according to current guidelines
*Treatment algorithms
Patients with uncomplicated hypertension
Hypertensive patients with coronary artery disease
Hypertensive patients with heart failure
Hypertensive patients with atrial fibrillation
*β-blockers are not a homogeneous class: clinical profiles & pharmacological properties of individual agents
*Pharmacological properties
Nebivolol
Nebivolol belongs to the third-generation β-blockers exhibiting highly selective β1-AR blockade and NO-mediated vasodilatation [17]. Nebivolol is the β-blocker with the highest selectivity for β1-receptors compared with former generations, and with no ISA or MSA [17]. The drug exists as both L- and D-enantiomers (Figure 1). D-nebivolol has a 175-times higher affinity for β1-receptors than L-nebivolol and is therefore mainly responsible for the cardiac effects [17]. On the other hand, L-nebivolol primarily mediates the endothelium-derived release of NO [17].
*Specific pharmacological properties of nebivolol
*Nebivolol in the treatment of hypertension
*Nebivolol in hypertensive patients with cardiovascular comorbidities
Heart failure
Coronary artery disease
Atrial fibrillation
*Nebivolol in hypertensive patient with noncardiovascular comorbidities
Obstructive airway diseases
Diabetes & metabolic abnormalities
Erectile dysfunction
*Limitations Although the unique pharmacological profile of nebivolol coupled with clinical evidence supports its utility in the treatment of hypertension in patients with both CV (HF with reduced ejection fraction, CAD; AF) and non-CV comorbidities (diabetes, COPD, ED), the largest limitation in interpreting nebivolol trial data comes from the absence of long term outcome trials in patients with hypertension, as well as of direct comparative trials assessing its effect on CV morbidity and mortality versus other β-blockers [48].
Conclusion
Current hypertension guidelines recommend the preferential use of β-blockers for hypertensive patients with CV comorbidities such as HF, CAD, and AF. Within the heterogenous β-blockers class, nebivolol stands out for its beneficial effects on central pressure, endothelial function, and aortic stiffness, as well as for its favorable tolerability profile, which makes it appropriate also for patients with specific non-CV comorbidities (such as diabetes, respiratory obstructive diseases or ED), in which conventional anti-adrenergic agents are usually contraindicated or not recommended as first choice drugs (Table 4).
Future perspective
Among β-blockers, nebivolol presents several advantages deriving from its peculiar pharmacologic properties, which make its use to be preferred in specific conditions, in which its vasodilating, anti-oxidant, and anti-ischemic effects are of particular interest, and its good tolerability profile warrants the patient’s adherence to treatment (Table 4).
Lay abstract: β-blockers are the main class of antihypertensive agents currently available. Nebivolol is one of the most recent β-blocking agents and it has vasodilating effects which may be useful in hypertensive patients with heart disease of ischemic (restriction in blood supply) origin or with erectile dysfunction. It has a good tolerability profile which makes it safe to use in patients with metabolic abnormalities (such as diabetes or dyslipidemia) or chronic obstructive pulmonary diseases.
Despite the substantial progress made in understanding the complex pathophysiologic mechanisms of hypertension, the best strategy to reduce the cardiovascular (CV) risk associated with hypertension remains blood pressure (BP) lowering, through the use of all major antihypertensive drug classes (angiotensin-converting enzyme [ACE]- inhibitors, angiotensin receptor blockers [ARBs], β-blockers, calcium channel blockers [CCBs] and diuretics) [1]. However, BP control rates remain poor worldwide and across Europe [2], one of the main contributing factors being poor adherence to treatment [3]. Simplifying treatment algorithms and favoring single pill combinations to quickly achieve BP targets may help in improving adherence to treatment and optimizing its efficacy [4]. For this reason, the latest update of the European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines for the diagnosis and treatment of hypertension proposed simplified drug treatment algorithms with the preferred use of an ACE inhibitor or ARB, combined with a CCB and/or a thiazide/thiazide-like diuretic, as the core treatment strategy for most patients, based on evidence on the ability of these classes to reduce CV events and improve patients’ prognosis [1]. In addition, recognizing the potential advantages of β-blockers in hypertensive patients with concomitant CV pathologies (such as heart failure [HF], coronary artery disease (CAD), atrial fibrillation [AF]), current guidelines recommend their preferential use in these patients, in order to maximize treatment efficacy and tolerability [1]. Among β-blockers, third-generation cardio-selective drugs with vasodilating and anti-oxidant properties, such as nebivolol, may show particular benefits, thanks to ancillary actions that go beyond the blockade of adrenergic receptors, to provide better CV protection associated with a positive metabolic profile [1]. The efficacy and tolerability of third-generation β-blockers have been demonstrated also in hypertensive patients with specific non-CV comorbidities (such as diabetes, respiratory obstructive diseases, or erectile dysfunction [ED]) [5– 7], in which conventional anti-adrenergic agents are usually contraindicated or not recommended as first choice drugs [1]. The aim of the present review was to elucidate the heterogeneity of the β-blockers class, by analyzing the pharmacological profiles of third-generation agents, such as nebivolol, and the associated benefits in terms of efficacy and tolerability, which support guidelines’ recommendations.
*β-Blockers’ role in the management of hypertension according to current guidelines
*Treatment algorithms
Patients with uncomplicated hypertension
Hypertensive patients with coronary artery disease
Hypertensive patients with heart failure
Hypertensive patients with atrial fibrillation
*β-blockers are not a homogeneous class: clinical profiles & pharmacological properties of individual agents
*Pharmacological properties
Nebivolol
Nebivolol belongs to the third-generation β-blockers exhibiting highly selective β1-AR blockade and NO-mediated vasodilatation [17]. Nebivolol is the β-blocker with the highest selectivity for β1-receptors compared with former generations, and with no ISA or MSA [17]. The drug exists as both L- and D-enantiomers (Figure 1). D-nebivolol has a 175-times higher affinity for β1-receptors than L-nebivolol and is therefore mainly responsible for the cardiac effects [17]. On the other hand, L-nebivolol primarily mediates the endothelium-derived release of NO [17].
*Specific pharmacological properties of nebivolol
*Nebivolol in the treatment of hypertension
*Nebivolol in hypertensive patients with cardiovascular comorbidities
Heart failure
Coronary artery disease
Atrial fibrillation
*Nebivolol in hypertensive patient with noncardiovascular comorbidities
Obstructive airway diseases
Diabetes & metabolic abnormalities
Erectile dysfunction
*Limitations Although the unique pharmacological profile of nebivolol coupled with clinical evidence supports its utility in the treatment of hypertension in patients with both CV (HF with reduced ejection fraction, CAD; AF) and non-CV comorbidities (diabetes, COPD, ED), the largest limitation in interpreting nebivolol trial data comes from the absence of long term outcome trials in patients with hypertension, as well as of direct comparative trials assessing its effect on CV morbidity and mortality versus other β-blockers [48].
Conclusion
Current hypertension guidelines recommend the preferential use of β-blockers for hypertensive patients with CV comorbidities such as HF, CAD, and AF. Within the heterogenous β-blockers class, nebivolol stands out for its beneficial effects on central pressure, endothelial function, and aortic stiffness, as well as for its favorable tolerability profile, which makes it appropriate also for patients with specific non-CV comorbidities (such as diabetes, respiratory obstructive diseases or ED), in which conventional anti-adrenergic agents are usually contraindicated or not recommended as first choice drugs (Table 4).
Future perspective
Among β-blockers, nebivolol presents several advantages deriving from its peculiar pharmacologic properties, which make its use to be preferred in specific conditions, in which its vasodilating, anti-oxidant, and anti-ischemic effects are of particular interest, and its good tolerability profile warrants the patient’s adherence to treatment (Table 4).
