Received: 3 April 2019
DOI: 10.1111/bcpt.13248
|
Accepted: 2 May 2019
MINIREVIEW
Nebivolol in the treatment of arterial hypertension
Nasima Olawi1
|
Markus Wehland2
Marcus Krüger2
1
Department of Biomedicine,
Pharmacology, Aarhus University,
Aarhus C, Denmark
2
Clinic for Plastic, Aesthetic and Hand
Surgery, Otto von Guericke University
Magdeburg, Magdeburg, Germany
Correspondence
Markus Wehland, Clinic for Plastic,
Aesthetic and Hand Surgery, Otto von
Guericke University Magdeburg, Leipziger
Straße 44, D‐39120 Magdeburg, Germany.
Email: markus.wehland@med.ovgu.de
|
Daniela Grimm1,2
|
Manfred Infanger2
|
Abstract
This MiniReview reports the current knowledge about the treatment of arterial hypertension with the third‐generation beta‐adrenoceptor antagonist (BAA) nebivolol.
Furthermore, it reviews the advantages of nebivolol compared to the earlier generation
of BAAs with respect to their different pharmacological properties. Beta‐adrenoceptor
antagonists are a class of drugs applied for several different conditions, including hypertension and heart failure. They differ significantly in their pharmacological properties, including varying β1/β2‐selectivity and/or exertion of additive effects on the
heart and circulation. Although these drugs have been a part of hypertensive therapy
for about 40 years, the outcome of large clinical trials has put the role of BAAs into
question. However, most of these results were based on first‐ and second‐generation
BAAs and cannot be translated directly into third‐generation drugs. The third‐generation BAA nebivolol has the highest β1‐selectivity seen so far, together with additional
vasodilating and anti‐oxidative properties. It is currently applied in the treatment of
hypertension and congestive heart failure. Nebivolol has a unique pharmacological
profile, despite showing similar blood pressure‐lowering effects, and has certain advantages in the treatment of hypertension compared to the previous generations of
BAAs. This includes significant improvements in endothelial dysfunction, central
haemodynamics and the degree of erectile dysfunction in men, a neutral/beneficial
metabolic profile and lastly a more favourable side effect profile. It is widely beneficial for, for example, sexually active men and patients with comorbidities such as
type II diabetes mellitus, metabolic syndrome and chronic obstructive lung disorders.
Whether the advantages translate to an improved long‐term clinical outcome remains
to be clarified, and ongoing prospective studies will show this in the future.
KEYWORDS
beta adrenoceptor antagonists, clinical trials, hypertension, nebivolol
Abbreviations: AC, Adenylate cyclase; AT1‐R, Angiotensin (II) type 1 receptor; ATP, Adenosine triphosphate; BAA, Beta‐adrenoceptor‐antagonist; BP,
Blood pressure; Ca2+, Calcium ion; cAMP, Adenosine 3',5'‐cyclic monophosphate; cBP, Central blood pressure; cGMP, Guanosine 3',5'‐cyclic monophosphate; CO, Cardiac output; DBP, Diastolic blood pressure; ED, Erectile dysfunction; EH, Essential hypertension; eNOS, Endothelial nitric oxide synthase;
ERβ, Oestrogen receptor beta; HCN, Hyperpolarisation‐activated cyclic nucleotide‐gated channels; If, Funny current; ISA, Intrinsic sympathomimetic
activity; JG‐cell, Juxtaglomerular cell; MAP, Mean arterial pressure; MSA, Membrane stabilising activity; MSIC, Mechanosensitive ion channel; NO, Nitric
oxide; O2–, Superoxide ion; P2Y, Purinoceptor; PKA, Protein kinase A; RAAS, Renin‐angiotensin‐aldosterone system; ROS, Reactive oxygen species;
RYR, Ryanodine receptors; SAE, Small arterial elasticity; SA‐node, Sinoatrial node; SBP, Systolic blood pressure; SERCA, Sarco/endoplasmic reticulum
Ca2+‐ATPase; sGC, Soluble guanylyl cyclase; SNS, Sympathetic nervous system; VSMC, Vascular smooth muscle cell; β‐ARs, Beta‐adrenoceptors.
Basic Clin Pharmacol Toxicol. 2019;125:189–201.
wileyonlinelibrary.com/journal/bcpt
© 2019 Nordic Association for the Publication of BCPT
(former Nordic Pharmacological Society)
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189
190
1
| |
IN TRO D U C T ION
Hypertension has been a known pathological condition for
centuries. In ancient cultures, physicians used to measure the
quality of the pulse by palpation of the arteries. A described
“hard” pulse may possibly nowadays be diagnosed as hypertension.1 Limited knowledge about hypertension has left it
poorly treated, resulting in renal, cardio‐ and cerebro‐vascular maladies. Even today, hypertension remains a vast socio‐
economic burden with a prevalence estimated at 1.13 billion,
with 8.4 million deaths/year in 2018.2
In the mid‐20th century, a breakthrough was made with
the introduction of the first efficient antihypertensive drugs:
the thiazides. About 20 years later, the first beta‐adrenoceptor
antagonist (BAA) propranolol was synthesized by Sir James
Black, a medical student, who, driven by the myocardial infarction that caused his father's death, “wanted to stop the effects adrenaline had on the heart”.3 Today BAAs are used in a
variety of conditions, including hypertension. Newer drugs of
this class have been developed since, dividing them into three
generations, each with unique properties. Despite a long history as guideline‐recommended treatment, the outcome of recent trials and meta‐analyses has questioned the role of BAAs
in the treatment of hypertension.4-9 However, the studies were
conducted using previous‐generation BAAs and the question
is whether third‐generation BAAs, such as nebivolol, with a
different pharmacodynamic and kinetic profile, could offer
advantages compared to previous BAAs in hypertensive drug
therapy. Therefore, this MiniReview aims to review the current
literature on nebivolol in the treatment of arterial hypertension.
2
|
METHODS
The literature for this MiniReview was found in online repositories: PubMed, Scopus and Embase, in reviews, original
articles, meta‐analyses and to a minor degree in textbooks.
The search process was conducted using the keywords listed
in Table 1, and an advanced search included the use of MesH
terms, wildcards and truncations in order to ensure entire coverage of the subject. Clinical trials from 2016 to 2018 were
covered. Earlier trials were included as background material.
OLAWI et al.
2.1.1
|
Beta‐adrenoceptors (β‐ARs)
The beta‐adrenoceptors (β‐ARs), along with their endogenous
ligands, the catecholamines, play an essential role in regulating
cardiac function. The receptors are divided overall into three
main subtypes: β1‐, β2‐ and β3‐ARs, which exist at distinctive
sites in the body. β1 dominates in cardiac tissue, β2 in the lungs
and β3‐ARs have been identified in both adipose tissue and the
heart. They are all parts of the superfamily of G protein‐coupled
receptors, which are associated with an intracellular G protein.
Upon activation this protein dissociates, leading the α‐subunit
to activate transmembrane adenylyl cyclase (AC). AC then
converts ATP to cAMP, which in turn activates protein kinase
A (PKA). PKA phosphorylates key enzymes and this has diverse effects in different tissues, as depicted in Table 2.
Specifically, for the conductive tissue of the heart, cAMP
levels lead to increased cation influx via HCN channels.10
This increases the conduction velocity of action potentials,
which results in an elevated heart rate (chronotropy). In the
myocardium, PKA phosphorylates L‐type Ca2+ channels,
ryanodine receptors, phospholamban and troponin I, which
results in improved contractility (inotropy) and diastolic relaxation (lusitropy).11 In summary, these effects increase the
cardiac output (CO) of the heart.
2.1.2 | Beta‐adrenoceptor antagonists
(BAAs)
The BAAs are a heterogeneous class of drugs indicated for
the treatment of a variety of conditions, including hypertension. They are divided into three generations with different
biochemical and pharmacological properties. First‐generation drugs (propranolol, sotalol, etc.) are non‐selective, hence
target both β1‐ and β2‐receptors. This feature brings a series
of adverse effects, such as bronchoconstriction and metabolic disruptions. Second‐generation drugs (atenolol, metoprolol, bisoprolol, etc.) are dose‐dependent, cardio‐selective
(relatively β1‐selective) drugs, which thereby offer a more
TABLE 1
Overview of search terms and number of hits
Search term
Hits
Nebivolol
981
2.1 | Current treatment options for
hypertension with special focus on BAAs
Nebivolol and hypertension
504
Today, the treatment of essential hypertension (EH) comprises both lifestyle modifications and drug therapy. When
lifestyle modi­fications are not sufficient, different classes of
antihypertensive agents, including diuretics, ACE‐inhibitors,
angiotensin II type 1 receptor (AT1‐R) blockers, calcium‐
channel blockers, and in some countries BAAs as well, are
used as first‐line treatment.2
Nebivolol and erectile dysfunction
Nebivolol and central pressure
50
Nebivolol and metabolic properties
24
Nebivolol and endothelial dysfunction
Nebivolol and oxidative stress
25
168
110
Beta blockers
55 509
Beta blockers and hypertension
12 005
Third‐generation beta blockers
221
OLAWI et al.
favourable side effect profile.12 Third‐generation drugs (nebivolol, carvedilol, labetalol) show additionally vasodilatory
properties beyond the β‐blockade, and allegedly offer a better
haemodynamic profile along with fewer unfavourable metabolic side effects.13-19 The common drugs vary in several
other parameters regarding pharmacokinetics, intrinsic sympathetic activity (ISA) and in anti‐arrhythmic effects (often
referred as "membrane stabilizing activity" (MSA)), that can
be explained by additional targeting of cardiac and/or neuronal voltage‐gated sodium channels.20 This effect is similar
to the MSA of Na+‐channels blockers that represent class I
anti‐arrhythmic drugs.
2.1.3
|
Mechanism of action
Overactivation of SNS and RAAS is considered to contribute to EH. By antagonising the β‐ARs, the BAAs interfere
with this regulation. In the heart, this reduces the intracellular cAMP and PKA levels, followed by a decrease in
TABLE 2
The beta‐adrenoceptors and
their main effects
Subclass
β1
β2
Gs‐coupled
Gs‐coupled
Gs‐coupled
191
chronotropy, lusitropy and inotropy. So far, the mechanism
behind the blood pressure (BP)‐lowering effect caused by
BAA is not completely understood. Directly after BAA administration, a reduction in both stroke volume and HR lowers the CO. Independently of the β‐blocking properties, the
peripheral vascular tone is increased via baroreflex to maintain BP. The BP reduction finally occurs because of the late
lowering of peripheral vascular tone, minutes to hours after
BAA intake. This way, BAAs with ISA can reduce BP at rest
while preserving CO.21 The baroreceptor reflex response will
initially increase the total peripheral resistance; however, this
decreases again over time. The exact mechanisms behind the
antihypertensive effects of β‐receptors are therefore not fully
clarified. Table 3 summarises the proposed mechanisms.
2.2
|
Nebivolol
Nebivolol belongs to the third‐generation BAAs exhibiting highly selective β1‐AR blockade and NO‐mediated
Molecular
mechanism
Activation of
AC
↑ cAMP and
PKA
Tissue
Effect
Conductive tissue and myocardium of heart
↑↑ Inotropy, chronotropy, lusitropy
Juxtaglomerular apparatus in
kidney
↑ Renin release
Parathyroid glands
↑ PTH‐secretion
Adipose tissue
↑ Lipolysis
Activation of
AC
Smooth muscle of bronchial
tree
↑ Bronchodilation
↑ cAMP and
PKA
Liver
↑ Glycogenolysis and
gluconeogenesis
Endocrine pancreas
↑ Insulin/glucagon
release
Conductive tissue and
↑ Inotropy,
chronotropy,
Myocardium of hearta
Lusitropy
a,b
β3
|
Blood vessels
↑ Vasodilation
Gastrointestinal tract
↑ Relaxation
­(decreased motility)
M. detrusor of bladder
↑ Relaxation
Uterus
↑ Relaxation
Nerve ends
↑ Norepinephrine
release
M. ciliaris of the eye
↑ Mild relaxation
Activation of
AC
Adipose tissue
↑ Lipolysis,
thermogenesis
↑ cAMP and
PKA
Smooth muscle of GI tract
↑ Relaxation
Table modified from Wehland et al13 and Brøsen et al94.
a
β2‐receptors in the heart are present to much lesser extent.
b
Skeletal muscle and coronary arteries
192
| OLAWI et al.
vasodilatation. The drug was developed and patented in
the 1980s and came into medical use in Europe in 1997.22
However, it was lately introduced in the US market after FDA
approval for treatment of hypertension in 2007. Nebivolol is,
so far, the BAA with the highest selectivity for β1‐receptors
compared to former generations (Table 4), and with no ISA
or MSA.23-28 Figure 1 depicts the chemical structure of the
drug, revealing both high lipophilicity and chiral centres. The
latter means that the drug exists as both L‐ and D‐enantiomers. D‐nebivolol has a 175 times higher affinity for β1‐receptors than L‐nebivolol and is therefore mainly responsible for
the cardiac effects. On the other hand, L‐nebivolol primarily
mediates the endothelium‐derived release of NO.13
2.2.1
|
Pharmacokinetics
|
Pharmacodynamics
A standard 5 mg/day dose of nebivolol is admitted orally
and absorbed within 1.5‐4 hours, unaffected by food intake.
The bioavailability of the drug varies from 12% to 98%.17
In the blood, approx. 98% of it binds to albumin. Nebivolol
is metabolized in the liver through glucuronidation and via
the cytochrome P450 enzyme CYP2D6. The genetic polymorphism of this enzyme leads to divergent metabolizers and
therefore to variations in bioavailability and plasma half‐life
(11‐40 hours).
The therapeutic effect of nebivolol has been reported to be
independent of the varying bioavailability, which is attributed
to its active metabolites.17,29 The main route of excretion is
through faeces and urine.
2.2.2
The detailed mechanism of action of the racemate nebivolol
is shown in Figure 2. D‐nebivolol antagonises the β1‐ARs in
the conductive tissue of the heart along with the myocytes.
L‐nebivolol mediated increase in NO‐availability has been
demonstrated in several studies,30-34 but the exact mechanism
TABLE 3
Proposed antihypertensive effects of BAAs
↓ chronotropy, inotropy, lusitropy and therefore CO
↓ renin release
↓ venous return and plasma volume
↓ peripheral vascular resistance
↓ vasomotor tone
↑ vascular compliance
↓ norepinephrine release
→ pressor response attenuation towards catecholamines during
exercise and stress
↓ CNS activity
baroreceptor resetting
antianxiety effect
Table modified from Frishman and Mann 12,77
behind it is unclear. Several propositions have been put forward and are depicted in Figure 2. All essentially lead to enhanced activity of endothelial nitric oxide synthase (eNOS)
and thereby an increased NO release. In addition, nebivolol
was shown to induce lipolysis and promote thermogenic and
mitochondrial genes through β3‐AR35 So far, the β3‐ARs are
poorly investigated, but first studies indicated that they can
activate different signalling pathways involved in heart protection. Thus, targeting of β3‐ARs could represent a novel potential strategy to improve cardiac function and metabolism.36
2.2.3
|
Effects of NO
The most important effect of NO is vasodilation via stimulation of soluble guanylyl cyclase in the vascular smooth
muscle cells (VSMCs). This stimulation is followed by an
increase in cGMP and activation of protein kinase G, which,
via different mechanism, decreases intracellular Ca2+ and inhibits vasoconstriction.37
Furthermore, the nebivolol‐mediated increase in NO‐
bioavailability contributes to the reduction in reactive oxygen species (ROS). This is due to a reaction of NO with
superoxides.
Endothelial dysfunction as a result of ROS and lack of
NO has, among others, been implicated in the development
of EH.38-40 Therefore, these anti‐oxidative effects improve
endothelial function and hence, in the long‐term may contribute to reducing BP. Numerous studies41-46 have already
demonstrated an improvement in endothelial dysfunction
by nebivolol, which is attributed to the synergistic effects of
BP reduction and NO release.13 High amounts of NO inhibit
VSMC proliferation and reduce neointimal hyperplasia.47
This may contribute to a decrease in vascular tonus, and
again to an improvement in endothelial dysfunction. Figure
2 displays the overall effects of nebivolol.
2.2.4 | Nebivolol and central
haemodynamics
Several studies48-52 have shown that central blood pressure
(cBP) is a stronger indicator of cardiovascular disease than
is brachial BP. The role of regular BAAs in decreasing cBP
compared to brachial BP has been questioned. Morgan et al53
demonstrated that the cBP reductions by BAAs were suboptimal compared to other antihypertensive agents and that by
using brachial BP measurements the actual therapeutic effect
of BAAs would be overestimated. These findings were confirmed by another study along with a meta‐analysis.54,55
These results were also based on earlier BAAs, and nebivolol was thought to offer a greater reduction in cBP due to its
vasodilating properties. In a recent review by Borghi et al,56
this hypothesis was investigated, where several studies57,58
indicated a significant reduction in cBP after nebivolol
OLAWI et al.
TABLE 4
|
193
Characteristics of first‐, second‐ and third‐generation BAAs
Propranolol
Metoprolol
Nebivolol
β1/β2 selectivity
Nonselective β1‐antagonist
Selective β1‐antagonist – 74‐
fold higher affinity
Highly selective β1‐antagonist – 321‑fold
higher affinity.β2‐ and β3‐agonism
ISA
0
0
0
++
0
0
↓
↓
↓↓
Pharmacodynamics
MSA
Central BP reduction
a
Pharmacokinetics
Bioavailability
30%
40%‐50%
12%‐96%
Half‐life
3‐5 h
3‐7 h
11‐40 h
Biotransformation
Glucuronidation
Glucuronidation
Glucuronidation
CYP2D6
CYP2D6
CYP2D6
Lipophilicity
High
Moderate
Moderate
Active metabolites
Yes
No
Yes
Renal excretion
< 5%
10%
40%
Erectile dysfunction
++
++
+/−
Dyspnoea
Frequent,
dose‐dependence under an
appropriate dosage range
Frequent,
dose‐dependent
Less frequent,
++
+
Adverse effects
Dose‐dependent
CNS effects (nightmare,
depression, insomnia)
+++
Raynaud’s phenomenon
++
++
+
Metabolic profile
Metabolic impairment
Metabolic impairment
Unaffected/improved
Weight gain
+
+
0/−
Headache, dizziness and
fatigue
+++
+++
++
Additional properties
Vasodilation
−
−
↑↑
Anti‐oxidative effectsb
+
+
+(+)
Adapted from Wehland et al,13 Brøsen et al,94 Marketou et al,15 and FDA reports.95,96
a
According to Section 3.
b
According to clinical trials.
treatment compared to former generations. Polonia et al59
additionally showed a cBP reduction comparable to ARBs.
Soanker et al60 presented an efficient reduction in cBP and,
moreover, in pulse wave reflection. So far, it seems that
nebivolol improves central haemodynamics to a greater extent, but whether these effects provide advances in clinical
outcomes is yet to be discovered.
2.2.5
|
Nebivolol and metabolic profile
Conventional BAAs cause metabolic impairments and increase the risk of new‐onset type II diabetes compared to other
antihypertensive agents. This was depicted in the INVEST
study61 and further confirmed by a meta‐analysis.62 The main
reason for this is β2‐antagonism in the pancreas, liver and blood
vessels to skeletal muscle, which affects insulin release, gluconeogenesis, glycogenolysis and insulin‐stimulated glucose
uptake.15 Additionally, BAAs are involved in weight gain, as
depicted in the GEMINI trial,63 which contributes to worsening its metabolic profile. Nebivolol, as a highly β1‐selective
agent with vasodilatory properties, largely avoids this and thus
exerts neutral or even beneficial effects on metabolic parameters. The YESTONO study64 (n = 2238) demonstrated this,
where nebivolol 5 mg/day over 3 months effectively lowered
194
| OLAWI et al.
Chemical structures of D‐ and L‐nebivolol. Figure made in online program “Reaxys,” modified from Frishman.12 HCl is added to
enable oral administration as tablet form
FIGURE 1
BP and improved most metabolic parameters including fasting
glucose and lipid profile, and reduced glycosylated haemoglobin (HbA1c). Another study by Ladage et al65 (n = 5031) on
hypertensive diabetic patients showed similar improvements in
metabolic parameters and significant weight loss.
2.2.6
|
Nebivolol and quality of life
Most patients suffering from mild‐to‐moderate hypertension
have a preserved quality of life. Nebivolol has shown a great
tolerability with a few adverse effects, the most common ones
being headache, fatigue, paraesthesia and dizziness.13,14,66,67
In larger doses, side effects such as bradycardia, AV block
and Raynaud's syndrome may occur, but this is rare compared to 1st and 2nd generation BAAs. Due to the low affinity
for β2‐receptors, a series of side effects such as bronchoconstriction, drug‐induced asthma and metabolic impairment are
largely avoided. Though less common, nebivolol is able to
penetrate the blood brain barrier and cause CNS side effects.
A meta‐analysis from 2008 demonstrated that nebivolol compared to other two BAAs and to other antihypertensives had a
more favourable side effect profile.68 Table 4 gives a simplified overview of nebivolol in contrast to previous 1st and 2nd
generation BAAs.
Patients often complain of fatigue during exercise when
they are treated with BAAs. Van Bortel and van Baak found
that nebivolol at effective doses had no significant effect on
exercise endurance performance in healthy individuals.69 Less
fatigue during nebivolol therapy had also been reported by
several reviews, including Wojciechowski et al66 The study by
Velasco et al70 investigated this and showed that nebivolol, as
opposed to metoprolol, did not cause impairment in precapillary vasodilation in skeletal muscle during exercise. The authors suggested this finding as the reason for less fatigue and
exercise intolerance experienced during nebivolol therapy.
Several studies have also suggested that nebivolol, due to
NO potentiation, improves erectile dysfunction (ED). This
was investigated by Gur et al71 who found a 2.09% lower
incidence in overall prevalence of ED by nebivolol only. In
addition, the incidence of severe ED was 7.1% in the metoprolol group, whereas it was only 1.61% in the nebivolol
group. A similar study by Aldemir et al72 likewise depicted
a protective effect by nebivolol, where ED scores remained
constant during nebivolol, but decreased in metoprolol therapy. Finally, a recent survey from 2017 by Sharp et al73 aimed
to review the current knowledge on this matter and found that
2/4 studies showed significant improvement in ED scores on
nebivolol treatment, whereas the remaining two showed equal
occurrence of ED between nebivolol and previous BAAs.
Early studies revealed that nebivolol is not only safe and well
tolerated, a monotherapy with nebivolol does not impair quality of life in patients with hypertension.28 In addition, nebivolol
showed several benefits as compared with other BAAs, possibly due to an increased NO availability. The above‐mentioned
effects of nebivolol improve quality of life and thereby enhance
patient compliance. This was depicted in the SENIORS trial,74
where discontinuation of nebivolol was 27% compared to 25%
with placebo. Overall quality of life parameters were comparable to losartan therapy, whereas the decrease in DBP was found
to be slightly greater with nebivolol.75
2.2.7
|
Nebivolol and antihypertensive efficacy
Nebivolol is an effective antihypertensive agent with long
duration of action. This pharmacokinetic profile may offer
advantages. Administration is effective over 24 hours with a
trough‐to‐peak ratio of 89%.76 It was hypothesized that the inferior outcome from BAAs in earlier clinical trials might have
been related to the short duration of action of BAAs such as atenolol.77 Nebivolol, with its extended half‐life, could possibly
affect the outcome and additionally contribute to increased patient adherence, since the drug is administered less frequently.
No dramatic increase in BP should be expected with one‐day
non‐adherence. In contrast to most other BAAs,78 nebivolol is
OLAWI et al.
|
195
FIGURE 2
Overview of effects of nebivolol on the heart, kidneys and vascular system: D‐nebivolol antagonises β1‐adrenoceptors in the
conductive tissue (SA‐node) and myocardium. In the SA node this leads to decrease in intracellular cAMP levels, which directly inhibits the
funny current (If) via the HCN channel. This slows down the conduction velocity of action potentials and hence leads to decreased chronotropy.
In the myocardium, lack of cAMP and PKA levels will lead to inhibition of RYR, L‐type Ca2+ channels and SERCA. The resulting decrease in
intracellular Ca2+ and reduced Ca2+ reservoir in SR leads to negative inotropy and lusitropy. β1‐AR blockage in the juxtaglomerular apparatus
of the kidney leads to decreased renin release, which inhibits activation of RAAS. L‐nebivolol‐induced endothelial NO release is mediated via
different mechanisms: A, Via mechanosensitive ion channels, which leads to ATP efflux. This stimulates P2Y receptors, which in turn increases
eNOS activity. B, L‐nebivolol induces NO release via β3‐agonism, where increased Ca2+ stimulates eNOS. C, Nebivolol metabolites act via
β2‐receptors inducing NO release in a similar manner. D, The oestrogen receptor decreases endothelial stiffness via the serine‐protease P1177.
The released NO diffuses to the smooth muscle cells in the tunica media of the vessel, where it stimulates sGC and causes vasodilation. Finally,
antioxidation of nebivolol is due to reaction of NO with superoxides. Picture created in www.biore​nder.io and modified from Wehland et al13 and
Lohse et al.11 Abbreviations: AC, adenylyl cyclase; ATP, adenosine triphosphate; Ca2+, calcium; cAMP, adenosine 3',5'‐cyclic monophosphate;
cGMP, guanosine 3',5'‐cyclic monophosphate; eNOS, endothelial nitric oxide synthase; ERβ, oestrogen receptor beta; HCN, hyperpolarisation‐
activated cyclic nucleotide‐gated channels; If, funny current; JG‐cell, juxtaglomerular cell; MSIC, mechanosensitive ion channel; NO, nitric oxide;
O2‐, superoxide; P2Y, purinoceptor; PKA, protein kinase A; RAAS, renin–angiotensin–aldosterone system; RYR, ryanodine receptors; SA‐node,
sinoatrial node; SERCA, sarco/endoplasmic reticulum Ca2+‐ATPase; sGC, soluble guanylyl cyclase; SR, sarcoplasmic reticulum; VSMC, vascular
smooth muscle cell
not taken up into, stored in and released from adrenergic cells
during exercise together with epinephrine and norepinephrine.
Exercise had no effect on plasma concentrations of nebivolol
(rest: 0.273 ± 0.029 ng/mL, exercise: 0.274 ± 0.035 ng/mL,
recovery: 0.272 ± 0.035 ng/mL).79 This might explain why
other BAAs are still effective after withdrawal even when they
are no longer detectable in plasma.
3
|
DISCUSSION
Some years ago, BAAs were relegated to 2nd or 3rd line
positions by hypertension societies such as the Eighth Joint
National Committee (JNC8) and the American Hypertension
Society (ASH). This had its roots in the outcome of some
NEDCAD trial
The study aimed to compare the effects of
nebivolol and metoprolol on oxidative
stress and endothelial function in patients
with Coronary Artery Disease (CAD)
To evaluate effect of nebivolol on blood
NO levels, BP and eGFR compared to
metoprolol
To test whether chronic nebivolol and metoprolol treatment suppresses ET‐1‐mediated increase in vascular tone in adults
with elevated BP
To compare nebivolol and metoprolol
on the degree of ED in men with CAD
using the international index of erectile
function score (IIEF score), where
scores > 21 = normal
<21 = abnormal
Santos et al 81 2016
Diehl et al 86 2016
Gur et al 71 2017
To compare combined drug therapy
between nebivolol + hydrochlorothiazid
(NH) and irbesartan + hydroclorothiazid
(IH) regarding antihypertensive efficacy,
tolerability and side effect profile
George et al 87 2017
2017
Objectives
To compare the effect of nebivolol and
metoprolol on the endothelial fibrinolytic
capacity, via estimation of t‑PA release
83
Recent clinical trials with nebivolol
Stauffer et al 80 2017
Grassi et al
Study
TABLE 5
Randomized, blinded, prospective study.
Nebivolol: 5 mg/d
Metoprolol: 50 mg/d
3‐months, double‐blinded, randomized placebo‐controlled trial.
Nebivolol: 5 mg/d
Metoprolol 100 mg/d
Randomized, prospective, open‐label, active‐comparator study
Randomized, prospective study.
Nebivolol:5 mg/d
Metoprolol: 10 mg/d
Randomized, double‐blinded, placebo‐controlled
trial.
Nebivolol: 5 mg/d
Metoprolol: 100 mg/d
Multicentre, randomized, double‐blinded trial.
NH: 5/12.5 mg/d
IH: 150/12.4 mg/d
Design and intervention
119 adult men with coronary
bypass surgery
Age ≈ 55.02 ± 7.55 y
42 adults with elevated BP.
Age ≈ 56 ± 1 y
30 hypertensive kidney
transplant patients followed
for 12 mo.
Age ≈ 49.7 ± 14.85 y
62 patients with CAD followed for 1 mo
Age ≈ 58 ± 9 y
44 women with elevated BP
followed for 3 mo.
Age ≈ 48 ± 2 y
122 elderly with isolated
systolic hypertension followed for 3 mo.
Age ≈ 69.1 ± 5.1 y
Study population
| (Continues)
Overall cases:
Metoprolol: 85.96%
Nebivolol: 83.87%
IIEF mean ± SD
Metoprolol: 13.97 ± 6
Nebivolol:16.2 ± 5.5
On almost all levels of ED, nebivolol had fewer cases compared to
metoprolol.
Nebivolol, but not metoprolol
treatment reduces ET‐1‐mediated
vasoconstrictor tone.
↑ Blood NO in patients <50 y
treated with nebivolol.
Changes in BP and eGFR not significant between the two groups
Both nebivolol and metoprolol displayed antioxidant properties. No
effect seen on endothelial function.
Significant increase in endothelial t‐
PA release (≈30%, P < 0.05) in the
nebivolol group only
Similar BP reductions between
metoprolol and nebivolol
Office BP measures:
↓SBP for NH = −25.8 ± 12 mm Hg
↓SBP for IH = −21.2 ± 14 mm Hg
P < 0.003.
Holder‐monitor:
No significant difference
Side effects:
NH ↑fatigue
IH ↑diarrhoea
Outcome
196
OLAWI et al.
To compare effect of nebivolol and
carvedilol on insulin resistance and lipid
profile in patients with EH
To investigate the impact of nebivolol and
metoprolol on microvascular function,
specifically of the forearm muscle. This
was done by using contrast‐enhanced
ultrasound perfusion imaging during
exercise and rest
Velasco et al 70 2016
To evaluate the grade of ED in patients
undergoing coronary artery bypass graft
(CABG) treated with either metoprolol or
nebivolol, using the IIEF score
Ozyildiz et al 91 2016
2016
Objectives
To compare the effects of nebivolol and
atenolol on BP and on vascular and
cardiac health in patients with abnormal SAE, consistent with endothelial
dysfunction
72
(Continued)
Duprez et al 82 2017
Aldemir et al
Study
TABLE 5
Randomized, double‐crossover study.
Nebivolol: 5‐20 mg/d
Metoprolol: 100‐300 mg/d
Prospective, randomized, open‐label, single‐centre
study.
Carvedilol: 25 mg/d
Nebivolol:
5 mg/d
Randomized, double‐blinded, placebo‐controlled
study.
Nebivolol: 5 mg/d
Atenolol: 25/50 mg/d
Randomized, double‐blinded, prospective study.
Nebivolol: 5 mg/d
Metoprolol: 50 mg/d
Design and intervention
25 patients with stage 1
hypertension followed for
12 wk.
Age ≈ 53 ± 2 y
80 patients with EH followed for 4 mo
Age ≈ 51 ± 9.8 y
60 subjects with prehypertension/ borderline hypertension and with abnormal
SAE.
Age ≈ 18‐80 y
60 adult men with coronary
bypass surgery.
Age ≈ 59 ± 10 y
Study population
Metoprolol but not nebivolol causes
selective impairment in precapillary
vasodilation, independent of CO
and conduit artery tone.
This is another aspect of fatigue and
exercise intolerance induced by
conventional BAAs.
Vasodilating properties of nebivolol
are thought to be the reason for NO
microvascular impairment
Similar favourable effects on serum
glucose, insulin resistance and lipid
profile between carvedilol and
nebivolol.
↓BP reductions:
SBPNeb (mm Hg):
129.3 (13.3) 120.3 (14.4),
P = 0.0068
SBPAte (mm Hg)
131.3 (10.8) 118.3 (14.8),
P = 0.001
↑SAE:
Neb: 6.0 (2.2) 8.4
(3.4), P = 0.0001
Ate: 6.1 (2.6) 7.1
(3.0), P = 0.063
Similar BP‐lowering effects, only
nebivolol improved SAE
↓EDmetoprolol:
15.2 ± 5.8 12.9 ± 5.8, P < 0.001
↓EDnebivolol
12.9 ± 5.5 12.4 ± 5.5, P = 0.053
Nebivolol shows no significant
change in ED scores from baseline
Outcome
OLAWI et al.
|
197
198
| large studies4-6 and meta‐analyses7-9 that compared BAAs to
other classes of antihypertensive agents and found a suboptimal decrease in cardiovascular events, no effect on all‐time
mortality, increased risk of new‐onset diabetes and less cBP
reduction. Again, these studies were based primarily on atenolol, and the question remains whether 3rd generation BAAs
such as nebivolol, with a different pharmacodynamic and kinetic profile, could serve as a more optimal treatment.
Table 5 presents an overview of the recent clinical trials
on nebivolol. This section will focus on the role of nebivolol
in hypertensive therapy, applying the knowledge of recent
clinical trials. In general, the focus of recent clinical trials
has been to compare nebivolol with previous BAAs regarding efficacy, safety and tolerability. Moreover, they elucidate
the specific properties of nebivolol. The study populations
were rather small, and the results predominantly confirmed
the outcome of earlier studies, with a few of them presenting
a different angle on the individual.
First of all, the comparable BP‐lowering effect between
nebivolol, previous BAAs and other antihypertensive agents
was demonstrated in several studies including Stauffer et
al,80 Santos et al81 and Duprez et al82 Nebivolol in antihypertensive combination therapy was likewise shown to have
promising effects. The results of Grassi et al83 indicated that
when using both office‐measured and holder BP monitoring,
nebivolol is equal to AT1‐R blockers regarding antihypertensive combination therapy with hydrochlorothiazide. Another
study by Paton et al84 further demonstrated the effectiveness
of combination therapy with nebivolol, this time combined
with valsartan (byvalson). These results are in accordance
with a review from 2017 by Giles et al85 that investigated
the efficacy and tolerability of hypertensive treatment with
byvalson and similarly found it to be very efficient. On this
basis, nebivolol may be considered as first‐line treatment in
combination therapy. The effect of nebivolol on endothelial
dysfunction was investigated by Duprez et al82 Here, it was
evident that when comparing nebivolol to metoprolol, only
nebivolol exerted improvements in small artery elasticity
(SAE), which was considered a marker for endothelial function, and the effect was related to the increased NO release in
the microvasculature.
Another noteworthy prospect on the role of nebivolol in
improving endothelial dysfunction was shown by Diehl et
al,86 where only nebivolol compared to metoprolol reduced
endothelin‐1‐mediated vasoconstriction. These results are
hence in line with the previously mentioned studies displaying the beneficial effects of nebivolol on endothelial dysfunction.41-46 These effects have been related to nebivolol's
well‐established anti‐oxidative properties, which were depicted again in the NEDCAD trial,87 but were surprisingly
more evident in the metoprolol group.
As mentioned earlier, endothelial dysfunction is considered a risk factor in developing EH and other cardiovascular
OLAWI et al.
complications. Thus, in contrast to other BAAs, the antihypertensive effect of nebivolol is also attributed to its improvement in endothelial dysfunction.
Stauffer et al80 investigated the antithrombotic actions of
nebivolol and found that chronic treatment with nebivolol,
as opposed to metoprolol, was capable of raising plasma tPA
levels. This may be another aspect of nebivolol's improvements on endothelial dysfunction that consequently affects
thrombogenesis. A few earlier studies88-90 tried to investigate
the antithrombotic effects of nebivolol, some of them suggesting a connection with NO release, but the exact mechanism is so far unclear. The concept should perhaps be further
investigated, as it could be relevant in treating hypertension
complicated by atherosclerosis or heart failure. Moreover,
these patients are most likely to be in multiple‐drug therapy,
already receiving antithrombotic drugs. The clinical relevance of this property awaits therefore future studies. A few
studies elucidated the more favourable side effect profile of
nebivolol. Ozyildiz et al91 compared carvedilol and nebivolol in different metabolic parameters and found both drugs to
have favourable effects on blood glucose, insulin sensitivity
and total cholesterol levels.
Overall, it is clear that nebivolol possesses advantages
over previous BAAs, which makes the drug suitable in specific patient groups, including sexually active men, NO‐deficient populations92 and hypertensives with comorbidities
such as type II diabetes, metabolic syndrome, chronic obstructive lung disease and asthma. Indeed, what is missing in order to conclude nebivolol to be a superior BAA
in hypertensive therapy are prospective, randomized trials
that investigate whether all of the properties mentioned actually have an impact on long‐term clinical outcome. To
date, no trial like this has been published. In a new retrospective cohort study,93 81 402 patients in nebivolol, atenolol or metoprolol therapy were analysed, and it was found
that the risk of hospitalisation due to cardiovascular events
was significantly increased with 1st and 2nd general BAAs
compared to nebivolol (aHR atenolol [95% CI]: 1.68 [1.29,
2.17] and aHR metoprolol: 2.05 [1.59, 2.63]). These are
promising results that create solid foundations for future
research.
4
|
CONCLUSION AND OUTLOOK
Nebivolol is a 3rd generation BAA used in the treatment of
hypertension and heart failure. With its unique pharmacological profile, nebivolol has certain advantages in antihypertensive therapy. These include significant improvements
in endothelial dysfunction, metabolic profile, central haemodynamics, cases of ED and side effect profile compared to
former BAAs. These properties may influence the role of the
drug in specific patient groups. Whether the effects translate into improved clinical outcome remains to be seen, and
OLAWI et al.
ongoing prospective studies will have to elucidate this in the
future.
CONFLICT OF INTEREST
On behalf of all authors, the corresponding author states that
there is no conflict of interest.
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How to cite this article: Olawi N, Krüger M, Grimm
D, Infanger M, Wehland M. Nebivolol in the treatment
of arterial hypertension. Basic Clin Pharmacol Toxicol.
2019;125:189–201. https​://doi.org/10.1111/bcpt.13248​