Nebivolol in Heart Failure: Mechanisms & Clinical Outcomes

Vascular Pharmacology 162 (2026) 107562
Contents lists available at ScienceDirect
Vascular Pharmacology
journal homepage: www.elsevier.com/locate/vph
Nebivolol in the therapeutic landscape of heart failure: Mechanisms and
clinical outcomes
Edoardo Roberto Ginghina a,* , Giuseppe Biondi-Zoccai b , Andrea Vitali c,
Lucia Fatima Di Napoli a, Giacomo Frati d
a
Sapienza University of Rome, Faculty of Pharmacy and Medicine, Latina, Italy
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy Maria Cecilia Hospital, Cotignola, Italy
Unicamillus University, International Medical University of Rome, Rome, Italy
d
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy IRCCS Neuromed, Pozzilli, Italy
b
c
A R T I C L E I N F O
A B S T R A C T
Keywords:
Nebivolol
Heart failure
Endothelial function
Nitric oxide signaling
Heart failure (HF) remains a major global health challenge, marked by clinical heterogeneity and high morbidity,
especially among elderly and comorbid patients. While β-blockers are central to HF management, conventional
agents often present tolerability limitations, particularly in populations with preserved ejection fraction (HFpEF)
or impaired vascular function. Nebivolol, a third-generation β-blocker characterized by high β₁-selectivity and
nitric oxide-mediated vasodilation, offers a differentiated therapeutic profile with potential advantages in these
subgroups.
This review synthesizes current evidence on nebivolol’s pharmacologic mechanisms, including its dual action
on adrenergic and endothelial pathways, as well as its antioxidant and anti-inflammatory effects. Preclinical
studies and translational biomarkers support their vascular and myocardial protective actions, while the SE­
NIORS trial provides pivotal clinical evidence demonstrating efficacy across ejection fraction spectrums in
elderly HF patients. Comparative data further reinforces its tolerability and favorable metabolic impact relative
to traditional β-blockers.
Nebivolol’s role is also explored in guideline contexts and its potential utility in special populations such as
those with renal impairment, diabetes, or cancer therapy–related cardiac dysfunction. Looking ahead, advances
in pharmacogenomics, digital phenotyping, and adaptive trial designs may help personalize nebivolol therapy.
This review underscores nebivolol’s emerging position in the evolving landscape of HF treatment.
1. Introduction and therapeutic gaps
Heart failure (HF) remains a leading cause of cardiovascular
morbidity and mortality worldwide, affecting over 64 million in­
dividuals and imposing significant healthcare burdens [1]. Despite ad­
vances in diagnostic tools and disease-modifying therapies, outcomes in
many patients remain suboptimal, particularly among the elderly and
those with multiple comorbidities. HF is clinically heterogeneous,
encompassing phenotypes such as HF with reduced ejection fraction
(HFrEF), preserved ejection fraction (HFpEF), and mildly reduced
ejection fraction (HFmrEF). While HFrEF has seen therapeutic progress
with evidence-based pharmacologic interventions, HFpEF and complex
multimorbid presentations continue to challenge clinicians due to
limited therapeutic options and uncertain benefit from standard
regimens [2].
Current guideline-directed medical therapy (GDMT) for HFrEF in­
cludes renin-angiotensin system inhibitors, mineralocorticoid receptor
antagonists, SGLT2 inhibitors, and β-blockers [3]. Recent contemporary
reviews have reinforced the centrality of these four foundational drug
classes—ARNI/ACEi/ARB, β-blockers, MRAs, and SGLT2 inhib­
itors—highlighting the consistent and rapid cardiorenal benefits of
SGLT2 inhibitors across HFrEF, HFmrEF, and HFpEF [4–6]. A summary
of contemporary guideline-directed medical therapy (including foun­
dational drugs and the central role of SGLT2 inhibitors across EF phe­
notypes) is provided in Table 3. Among these, β-blockers have long been
established as a cornerstone of therapy due to their ability to reduce
sympathetic overactivation, improve left ventricular function, and lower
mortality [7]. However, the response to β-blockers is not uniform across
* Corresponding author at: Sapienza University of Rome, Faculty of Pharmacy and Medicine, Latina, Italy.
E-mail address: [email protected] (E.R. Ginghina).
https://doi.org/10.1016/j.vph.2025.107562
Received 25 October 2025; Received in revised form 20 November 2025; Accepted 28 November 2025
Available online 2 December 2025
1537-1891/© 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
E.R. Ginghina et al.
Vascular Pharmacology 162 (2026) 107562
all patients. Older adults, individuals with chronic kidney disease, and
patients with HFpEF may experience suboptimal benefit or encounter
adverse effects such as fatigue, bradycardia, or diminished exercise
tolerance [8]. Moreover, traditional β-blockers may exacerbate meta­
bolic parameters and peripheral vascular resistance, contributing to
reduced adherence and limited tolerability in real-world settings [9].
These therapeutic limitations underscore the need for β-blockers
with distinct mechanistic properties and improved tolerability profiles
[7]. Nebivolol, a third-generation β-blocker with high β₁-selectivity and
nitric oxide-mediated vasodilatory effects, has emerged as a candidate to
bridge these gaps [10]. Its unique pharmacologic profile may confer
additional hemodynamic, endothelial, and metabolic advantages that
extend beyond heart rate control [10,11]. This review explores nebi­
volol’s mechanistic rationale and clinical evidence within the evolving
landscape of HF management, aiming to clarify its role across diverse
patient populations [10,11].
common barriers to optimal use [15,16]. Moreover, their tolerability
and efficacy profiles can vary across age groups, comorbidities, and
ethnic backgrounds. Importantly, evidence supporting β-blocker use in
HFpEF remains inconsistent. While these agents may theoretically
benefit HFpEF through heart rate reduction, improved ven­
tricular–arterial coupling, and attenuation of chronotropic incompe­
tence, randomized trials have not demonstrated clear improvements in
mortality or HF outcomes in this phenotype. Observational registries
have suggested potential reductions in all-cause mortality [17], but such
findings are limited by confounding and the absence of EF-specific
randomization. As a result, current guideline recommendations for
β-blockers in HFpEF emphasize their use primarily for comorbid con­
ditions such as hypertension, ischemic heart disease, and atrial fibril­
lation rather than for HF-specific prognostic benefit. In this context,
third-generation β-blockers with vasodilatory properties have attracted
interest in their potential to mitigate the adverse hemodynamic effects
associated with earlier agents. Among these, nebivolol stands out due to
its unique mechanism of nitric oxide-mediated vasodilation alongside
high β₁-selectivity. This mechanistic profile may be particularly relevant
in HFpEF, a syndrome characterized by endothelial dysfunction,
increased arterial stiffness, and impaired microvascular reser­
ve—pathophysiologic domains directly targeted by nebivolol’s NOmediated effects. This dual action may be advantageous in elderly pa­
tients and those with increased arterial stiffness or endothelial dys­
function—profiles often underrepresented in landmark HF trials
[10,18].
Overall, while β-blockers form an indispensable component of HF
pharmacotherapy, a more nuanced understanding of their class-specific
effects and patient-centered tolerability profiles is essential [14]. This
evolving perspective sets the stage for evaluating where agents like
nebivolol may fill existing therapeutic gaps, particularly in complex or
comorbid HF populations [10].
2. Literature review methodology
This narrative review was conducted through a structured search of
PubMed/MEDLINE from January 1990 to December 2024. The
following terms and their combinations were used: “nebivolol”, “betablocker”, “heart failure”, “HFrEF”, “HFpEF”, “endothelial function”,
“vascular stiffness”, “nitric oxide”, “β₃-adrenergic receptor”, “elderly
heart failure”, “diastolic dysfunction”, “cardiorenal syndrome”, “hy­
pertension”, “ischemic heart disease”, and “atrial fibrillation”. Addi­
tional filters included human studies, English language, and availability
of full text when possible.
Priority was given to randomized controlled trials, substudies of
major trials, observational cohort studies, mechanistic and translational
research, and contemporary guideline documents from international
societies. Reference lists of key publications were manually screened to
identify relevant additional studies not captured in the initial search.
Because the objective was to provide a qualitative synthesis of
existing evidence rather than a quantitative pooled estimate, formal
systematic review methods (PRISMA) and meta-analytic techniques
were not applied. The review therefore reflects the current state of ev­
idence with a focus on clinical relevance, pathophysiological plausibil­
ity, and identification of gaps warranting further investigation.
3.1. Nebivolol: pharmacologic profile
Nebivolol is a third-generation β-blocker with a distinct pharmaco­
dynamic profile, setting it apart from earlier agents in this class. It ex­
hibits exceptional selectivity for β₁-adrenergic receptors, particularly at
lower therapeutic doses, with a β₁:β₂ selectivity ratio exceeding 300:1
[18]. This high cardioselectivity confers efficacy in reducing heart rate
and myocardial oxygen consumption, while minimizing bronchial and
peripheral vascular side effects typically associated with non-selective
β-blockers. Importantly, at standard clinical doses (≤10 mg), this
selectivity remains preserved, although it may diminish at higher con­
centrations [19].
Beyond its β₁-adrenergic antagonism, nebivolol uniquely stimulates
endothelial nitric oxide (NO) release through β₃-adrenergic receptor
agonism [20]. This NO-mediated vasodilatory mechanism enhances
arterial compliance and reduces systemic vascular resistance, contrib­
uting to favorable hemodynamic effects that go beyond conventional
β-blockade [21]. These vasodilatory properties are especially relevant in
patients with hypertension and HF, conditions characterized by endo­
thelial dysfunction and impaired vascular reactivity. Nebivolol’s ability
to improve endothelial function may therefore offer additional benefits
in modulating afterload and improving peripheral perfusion [22].
From a pharmacokinetic standpoint, nebivolol is characterized by
high oral bioavailability in extensive metabolizers and near-complete
absorption. It undergoes hepatic metabolism primarily via the cyto­
chrome P450 2D6 isoenzyme, leading to interindividual variability in
plasma concentrations. The drug has a relatively long half-life, ranging
from 12 to 19 h, permitting once-daily dosing which supports adherence
in chronic therapy. It is highly protein-bound and demonstrates a steady
pharmacokinetic profile with predictable dose-response relationships
[19].
Overall, the pharmacologic attributes of nebivolol integrate potent
β₁-selective blockade with vasodilatory effects mediated through NO,
3. β-blockers in HF management: a class overview
Beta-adrenergic blockers are a cornerstone in the management of HF,
particularly in patients with HFrEF. Their benefits are well-documented
through randomized controlled trials, which have demonstrated signif­
icant reductions in all-cause mortality, sudden cardiac death, and HFrelated hospitalizations [7,12,13]. This efficacy stems from their abil­
ity to counteract the detrimental effects of chronic sympathetic over­
activation, a hallmark of HF pathophysiology. By reducing heart rate,
myocardial oxygen demand, and neurohormonal drive, β-blockers pro­
vide foundational hemodynamic and structural support to the failing
heart [14].
The therapeutic landscape of β-blockers is, however, heterogeneous.
The three main agents with robust evidence in HFrEF—bisoprolol, car­
vedilol, and metoprolol succinate—differ in their receptor selectivity
and additional pharmacological properties. Carvedilol, a non-selective
β-blocker with alpha-1 blocking activity, provides vasodilatory effects,
whereas bisoprolol and metoprolol are more cardioselective, targeting
β₁-adrenergic receptors predominantly. Despite their differences, all
three agents have achieved class I recommendation status in major HF
guidelines, such as the 2021 ESC and 2022 American Heart Association
(AHA)/American College of Cardiology (ACC)/Heart Failure Society of
America (HFSA) statements, underscoring their clinical equivalence in
terms of mortality benefit when appropriately dosed [2,3].
Yet, real-world implementation reveals several challenges. Intoler­
ance to up-titration, bradycardia, hypotension, and fatigue remain
2
E.R. Ginghina et al.
Vascular Pharmacology 162 (2026) 107562
yielding a dual mechanism that is particularly advantageous in HF
management [11]. This combination provides not only effective symp­
tom control and blood pressure reduction but may also contribute to
improved vascular health and organ perfusion, particularly in patients
with comorbid conditions such as renal impairment or metabolic syn­
drome [22]. A summary of nebivolol’s role in general cardiology and
specific clinical scenarios is provided in Table 1.
Taken together, the cardiovascular benefits of nebivolol stem not
only from neurohumoral inhibition but also from direct vascular and
myocardial protective actions [11]. This mechanistic duality offers a
rationale for its preferential use in specific HF populations, especially
those who may not tolerate non-selective β-blockers or who may benefit
from improved endothelial health [10].
3.3. Preclinical and translational evidence
3.2. Mechanisms of cardiovascular benefit
Preclinical investigations into nebivolol’s role in cardiovascular
disease have uncovered a range of mechanisms that distinguish it from
other β-blockers [19]. Animal models of HF, particularly those simu­
lating ischemic and hypertensive cardiomyopathy, have demonstrated
nebivolol’s ability to improve ventricular function, reduce myocardial
oxidative stress, and enhance endothelial NO production [11]. These
effects appear mediated through β₃-adrenergic receptor stimulation,
which activates eNOS, leading to improved vasodilation and myocardial
perfusion [21]. In rodent studies, nebivolol has been shown to mitigate
cardiomyocyte apoptosis and preserve mitochondrial integrity, sup­
porting its role in cellular protection during cardiac injury [25].
Further translational studies have evaluated surrogate biomarkers
that respond to nebivolol treatment. Parameters such as asymmetric
dimethylarginine (ADMA), a marker of endothelial dysfunction, and
arterial stiffness indices, including pulse wave velocity, have been
favorably modulated by nebivolol in both animal and early human
mechanistic studies [26]. These findings align with its unique ability
among β-blockers to directly enhance endothelial function. In addition,
models of metabolic syndrome and renal impairment suggest a benefi­
cial impact on systemic inflammation and renal hemodynamics, posi­
tioning nebivolol as a potentially protective agent across organ systems
commonly compromised in HF [23].
Comparative analyses with traditional β-blockers like atenolol and
metoprolol in preclinical models reinforce the distinctive vasoprotective
and anti-remodeling effects of nebivolol [27]. While atenolol lacks
endothelial modulation and metoprolol shows limited anti-
Nebivolol exerts its therapeutic effects in HF through a combination
of traditional β₁-adrenergic blockade and unique endothelial actions that
distinguish it from conventional β-blockers [18]. As a highly selective
β₁-receptor antagonist at standard clinical doses, it reduces heart rate
and myocardial oxygen demand, thereby mitigating cardiac workload
and improving hemodynamic efficiency [19]. This traditional pathway
forms the core of its role in attenuating sympathetic overdrive, a hall­
mark of progressive HF [14].
What sets nebivolol apart is its capacity to enhance endothelial
function via NO release, mediated through stimulation of β₃-adrenergic
receptors. This β₃-agonism activates endothelial nitric oxide synthase
(eNOS), increasing NO bioavailability and thereby promoting vasodi­
lation, reducing peripheral vascular resistance, and improving arterial
compliance. These vasodilatory effects result in favorable modulation of
afterload and central aortic pressure—mechanistically beneficial in HF
patients with preserved or borderline reduced ejection fraction [20,21].
In addition to its vasodilatory capacity, nebivolol exhibits antioxi­
dant and anti-inflammatory properties. By reducing oxidative stress, it
limits endothelial dysfunction and contributes to improved microvas­
cular perfusion [23]. Experimental data also suggest that nebivolol can
modulate mitochondrial function and inhibit apoptosis pathways, which
may provide cytoprotective effects on cardiomyocytes exposed to
chronic neurohormonal activation. These effects are particularly rele­
vant in patients with coexisting comorbidities such as diabetes and renal
dysfunction [24].
Table 1
Role nebivolol in general cardiology practice and in specific clinical scenarios.
Feature
General perspective
Focus on specific settings
HTN
IHD
HF
Arrhythmias
Third-generation β₁-selective
blocker with NO-mediated
vasodilation
β₁-blockade + β₃-agonism → NO
release
Approved for
monotherapy and
combination use
↓ Peripheral resistance; ↑
arterial compliance
↓ Myocardial oxygen
demand
SENIORS trial: effective in
elderly HF
HR control in AF; limited
rhythm effect
↓ HR and afterload; antiischemic
Slows AV node conduction;
↓ ectopy
Antihypertensive
Efficacy
Endothelial Function
Comparable to other β-blockers
Metabolic Profile
Neutral/favorable impact on
glucose/lipids
Effective BP lowering;
enhanced by vasodilation
Reverses endothelial
dysfunction in essential
HTN
Minimal impact on
insulin resistance
Reduces ischemic burden
via BP control
Improves coronary
perfusion and
atheroprotection
Safe in metabolic IHD
↓ Neurohormonal
activation; endothelial
support
↓ Afterload, supportive in
HFpEF
May improve
microvascular function in
HF
Useful in diabetic HF
Renal Effects
Maintains renal perfusion
Safe in CKD-associated IHD
Suitable in HF + CKD
Sexual Function
Preserves erectile function
Use in Special
Populations
Dosing &
Pharmacokinetics
Guideline
Endorsement
Elderly, diabetic, CKD,
metabolic syndrome
5–10 mg QD; metabolized by
CYP2D6
–
Renal safety in
hypertensive
nephropathy
Less ED vs. other
β-blockers
First-line option in
elderly HTN
Once-daily dosing; stable
PK profile
ESC/ESH, NICE, FDA
Improves QoL in IHD
patients
Useful in hypertensive CAD
Favorable adherence in HF
with ED
Especially beneficial in
elderly HF
Long half-life supports
once-daily HF dosing
ESC 2021 HF: for elderly
HF patients
Highlight
Mechanism of Action
Enhances NO bioavailability;
reduces stiffness
Steady effect for 24 h BP
and HR control
Indirect support from
guidelines
Aids rate control in
hypertensive AF
May mitigate arrhythmic
triggers from endothelial
stress
Metabolic neutrality
supports arrhythmic risk
reduction
No renal-adverse
arrhythmic impact
Preserves compliance in
younger arrhythmic males
Option in AF + HTN where
tolerability is key
Maintains stable HR over
24 h
Adjunct in rate control; not
primary antiarrhythmic
Abbreviations: HTN = hypertension; IHD = ischemic heart disease; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure
with reduced ejection fraction; AF = atrial fibrillation; BP = blood pressure; QoL = quality of life; CKD = chronic kidney disease; CAD = coronary artery disease; ED =
erectile dysfunction; PK = pharmacokinetics; NO = nitric oxide; ESC = European Society of Cardiology; ESH = European Society of Hypertension; NICE = National
Institute for Health and Care Excellence; FDA = U.S. Food and Drug Administration; CYP2D6 = cytochrome P450 2D6.
3
E.R. Ginghina et al.
Vascular Pharmacology 162 (2026) 107562
inflammatory action, nebivolol consistently demonstrates superiority in
reducing fibrosis and myocardial hypertrophy. These mechanistic in­
sights provide a compelling rationale for its further evaluation in HF
phenotypes, especially those characterized by preserved ejection frac­
tion or high vascular resistance, where endothelial dysfunction plays a
critical pathophysiologic role [11].
outcomes [10].
Real-world data, albeit more limited, mirrors the trial findings
controlled. Observational cohort studies and registry data suggest that
nebivolol’s tolerability and efficacy extend beyond the trial setting,
particularly among elderly, frail, or comorbid populations where side
effect burden and adherence are of paramount concern [32]. Taken
together, the totality of evidence supports a nuanced but increasingly
favorable view of nebivolol in selected HF patients, especially when
vasodilatory, metabolic, or tolerability considerations are central to
therapeutic decision-making [33]. Key randomized trials and substudies
evaluating nebivolol in HF and related settings are summarized in
Table 2.
3.4. Clinical trials & real-world data
The clinical utility of nebivolol in HF has been most rigorously
assessed in the SENIORS (Study of the Effects of Nebivolol Intervention
on Outcomes and Rehospitalization in Seniors with Heart Failure) trial.
This landmark randomized, placebo-controlled study enrolled 2128
patients aged 70 years or older with a history of HF, regardless of left
ventricular ejection fraction. Over a mean follow-up of 21 months,
nebivolol demonstrated a statistically significant 14 % reduction in the
composite primary outcome of all-cause mortality or cardiovascular
hospital admission (hazard ratio 0.86, 95 % CI 0.74–0.99). Importantly,
the benefit was consistent across pre-specified subgroups, including
those with preserved and reduced ejection fraction, reinforcing its broad
therapeutic scope in elderly HF patients [10].
Subsequent analyses further elucidated nebivolol’s efficacy in highrisk subpopulations. In patients with reduced eGFR, the relative reduc­
tion in the primary outcome was preserved, suggesting renal safety and
potential benefit even in the setting of mild to moderate chronic kidney
disease [28]. A focused sub-analysis of ischemic HF patients within the
SENIORS cohort found that nebivolol significantly reduced the inci­
dence of acute ischemic events, an effect likely attributable to its nitric
oxide–mediated endothelial modulation and antioxidative properties
[29]. This vascular benefit may represent a differentiating feature from
other β-blockers lacking vasodilatory effects.
Comparative trials such as ELANDD and CARNEBI, though smaller in
scale, have also provided supportive data on nebivolol’s hemodynamic
and symptomatic effects. ELANDD, for instance, highlighted improved
endothelial function and arterial stiffness indices, while CARNEBI
compared nebivolol favorably to carvedilol in terms of heart rate control
and tolerability [30,31]. Though these studies are not powered to assess
mortality outcomes, they complement the SENIORS findings by under­
scoring nebivolol’s favorable side effect profile and patient-centric
3.5. Guideline recommendations & regulatory status
Nebivolol’s position within HF management has evolved in parallel
with expanding clinical evidence and nuanced guideline recommenda­
tions. Although nebivolol is not one of the “cores” β-blockers universally
endorsed for all patients with HF with HFrEF, it occupies a distinct niche
in clinical guidance. The 2022 AHA/ ACC/ HFSA guidelines for the
management of HF recognize nebivolol as a β-blocker with evidence of
benefit in elderly patients [3]. Specifically, the guidelines cite the SE­
NIORS trial as a basis for its use in older adults with symptomatic HF,
regardless of ejection fraction, thus reflecting its unique trial population
and outcome data [2]. In contrast, guideline-directed medical therapy
for HFrEF traditionally prioritizes β-blockers with class I evidence for
mortality reduction—namely bisoprolol, carvedilol, and sustainedrelease metoprolol succinate [10].
From a European regulatory and practice standpoint, the 2021 ESC
HF guidelines include nebivolol as an option in the β-blocker category
for chronic HFrEF, particularly in the elderly or those with multiple
comorbidities [2]. While it shares therapeutic class status with more
widely endorsed agents, nebivolol’s nitric oxide-mediated vasodilatory
effect is considered potentially advantageous in select patients,
including those with vascular stiffness or endothelial dysfunction [18].
This mechanistic differentiation, alongside its favorable tolerability
profile, has supported its broader use in some European contexts,
especially when concerns about metabolic effects or hypotension from
non-selective agents arise [11].
Table 2
Key Clinical Trials and Substudies on Nebivolol in Heart Failure and Related Conditions.
Study
Year
Sample Size
Age
LVEF
Comparators
Main Results
Implications
PMID / DOI
↑ Exercise tolerance, ↓
fatigue
Supports functional
gains in elderly HFpEF
PMID: 7819666
Supports use in elderly
HF across EF spectrum
ENECA study
2005
86
≥70 y
≥40 %
Nebivolol vs
Placebo
SENIORS trial
2005
2128
Mean 76 y
Any
Nebivolol vs
Placebo
14 % ↓ in CV mortality/
hosp
ELANDD study
2008
61
Mean 73 y
Mean 52
%
Nebivolol vs
Placebo
↑ Flow-mediated dilation;
↓ central BP
2009
1511
≥70 y
≤35 % vs
>35 %
Similar efficacy in both
LVEF groups
≥70 y
Variable
Mean 75 y
≤35 % vs
>35 %
Nebivolol vs
Placebo
Nebivolol vs
Placebo
Nebivolol vs
Placebo
SENIORS LVEF
Substudy
SENIORS Renal
Substudy
SENIORS Ischemic
HF Substudy
2009
2011
SENIORS
subgroup
SENIORS
subgroup
CARNEBI trial
2013
183
Mean 64 y
≤40 %
Nebivolol vs
Carvedilol
INTENSIC trial
2019
84
≥65 y
≥40 %
Nebivolol vs
Bisoprolol
RENAISSANCE-HF
Registry
2022
~4000
(obs.)
Mean 75 y
All EF
REDUCE-AMI trial
2024
5,02
Mean not
specified
Various
β-blockers incl.
Nebivolol
≥50 %
BBs vs no BBs
4
Safe across CKD stages
Significant ↓ in ischemic
events
Comparable
hemodynamics; better
sexual function
Similar BP control;
improved metabolic
profile
Comparable 1-yr
survival; nebivolol used
more in HFpEF
No significant CV benefit
post-AMI
Confirms vascular/
central hemodynamic
benefits
Demonstrates benefit
in HFpEF
Confirms renal safety
in HF + CKD
Valuable in ischemic
HF
Suggests noninferiority with
improved tolerability
Favorable in elderly
with metabolic
syndrome
Reinforces real-world
use, especially in
HFpEF
Reassesses routine
post-AMI BBs in HFpEF
PMID: 15642700 (pubm
ed.ncbi.nlm.nih.gov,
europepmc.org)
DOI:https://doi.org/10
.1093/eurjhf/hfr161
PMID: 19497441
PMC2729679
DOI:https://doi.org/10
.1093/eurjhf/hfs100
PMID: 23506636
[Likely DOI; N/A]
[Registry publication
DOI]
[Pending DOI]
E.R. Ginghina et al.
Vascular Pharmacology 162 (2026) 107562
in adrenergic or NO signaling pathways may influence response to
therapy [36]. As precision medicine evolves, incorporating pharmaco­
genomic insights could optimize nebivolol’s use, particularly in
phenotypically diverse HF cohorts.
Table 3
Contemporary guideline-directed pharmacological therapy in heart failure, with
emphasis on SGLT2 inhibitors.
HF Phenotype
HFrEF (LVEF
<40 %)
HFmrEF
(LVEF
40–49 %)
HFpEF (LVEF
≥50 %)
Core Drug Classes
Clinical Role and Notes
ACEi/ARB/ARNI
Evidence-based β-blocker
MRA
The four-drug combination is
recommended as foundational
therapy for all patients. SGLT2
inhibitors provide rapid, consistent
reductions in HF hospitalization and
cardiovascular death, independent
of diabetes [4,5].
Therapeutic decisions largely
extrapolated from HFrEF. SGLT2
inhibitors demonstrate clinically
meaningful reductions in HF events
and are endorsed by contemporary
guidelines [4,5].
SGLT2 inhibitors are the first class
with consistent outcome benefit
across HFpEF cohorts, reducing HF
admissions in multiple major trials
and reviews [4,5]. Other therapies
primarily target symptoms, blood
pressure, or comorbidities.
Loop diuretics manage congestion.
β-blockers and RAAS modulators are
tailored to EF, BP, AF, and ischemia.
SGLT2 inhibitors complement all
EF phenotypes with cardiorenal
protection and favorable
tolerability, especially in elderly
and multimorbid patients [4,5].
SGLT2 inhibitor
Same four drug classes as
HFrEF, individualized
dosing
SGLT2 inhibitor
MRA (selected patients)
ARNI/ARB (selected
patients)
Diuretics
Diuretics
Blood pressure control
Rhythm/ischemia control
Across all EF
Device therapy as
indicated
3.7. Safety, tolerability, and quality-of-life outcomes
The safety and tolerability profile of nebivolol in HF is generally
favorable, contributing to its acceptability in long-term management,
particularly among elderly and comorbid populations [10]. Unlike nonselective β-blockers, nebivolol exhibits high β₁-selectivity at therapeutic
doses and promotes vasodilation via NO release, which may mitigate
some of the peripheral side effects commonly associated with β-blockade
[18,19].
AEs reported with nebivolol are typically mild to moderate, with
bradycardia, dizziness, and fatigue being the most frequent. These
events often occur early in treatment and tend to diminish with dose
titration. Importantly, nebivolol is less commonly associated with
bronchospasm compared to non-selective agents, making it a more
suitable option for patients with mild reactive airway disease [18,19].
From a metabolic standpoint, nebivolol demonstrates a neutral or
even slightly beneficial profile. It exerts minimal effects on lipid and
glucose metabolism, a characteristic attributable to its β₃-agonistic
properties and endothelial function enhancement [19,35]. This may
confer advantages in patients with coexisting metabolic syndrome or
diabetes, where other β-blockers may impair insulin sensitivity or lipid
balance [35].
One of the distinct aspects of nebivolol’s tolerability is its favorable
impact on sexual function. Erectile dysfunction, often exacerbated by
conventional β-blockers, appears to be less prevalent with nebivolol
[37]. This has been corroborated by both patient-reported outcomes and
physiologic measures of penile blood flow, indicating potential vaso­
dilatory synergy with NO mechanisms [38].
In addition to physiological tolerability, nebivolol may enhance pa­
tient adherence through improved quality-of-life metrics. Its vaso­
dilatory action may contribute to better exercise tolerance and reduced
peripheral resistance, translating into subjective improvements in daily
functioning and well-being [19,35].
Collectively, these features position nebivolol as a β-blocker with a
uniquely balanced safety and tolerability profile. When integrated into
HF regimens, particularly in populations sensitive to side effects or
burdened by comorbidities, it may improve not only clinical outcomes
but also the experience of patients lived [19].
Regulatory approvals also reflect divergent regional perspectives.
Nebivolol is approved for the treatment of hypertension and mild to
moderate HF in many European countries, whereas in the United States,
its FDA approval is currently restricted to hypertension. Nevertheless,
off-label use in HF is observed in clinical practice, especially among
geriatric populations where its hemodynamic neutrality and lower side
effect burden may offer clinical advantages [19]. This contrast un­
derscores the importance of aligning pharmacologic profiles with
patient-specific characteristics when navigating international guideline
interpretations and regulatory environments.
3.6. Special populations & personalized therapeutics
The therapeutic utility of nebivolol extends meaningfully to special
populations with HF, particularly those frequently underrepresented in
clinical trials. In elderly patients, who often exhibit altered pharmaco­
dynamics and a higher burden of comorbidities, nebivolol offers distinct
advantages [10]. Its favorable hemodynamic profile and tolerability,
evidenced in the SENIORS trial, supports its use in older adults with both
reduced and preserved ejection fraction, mitigating concerns associated
with non-selective beta-blockers.
Renal impairment is another critical consideration in HF manage­
ment. Nebivolol demonstrates a consistent safety and efficacy profile
across varying degrees of renal dysfunction, likely owing to its vaso­
dilatory nitric oxide-mediated effects that help preserve renal perfusion
[28]. Its pharmacokinetic characteristics, with hepatic metabolism
predominating, reduce the need for dose adjustment in mild to moderate
renal dysfunction, offering practical benefit in this population [11].
Patients with metabolic syndrome or diabetes may also benefit from
nebivolol’s neutral or potentially favorable impact on insulin sensitivity
and lipid metabolism [34]. Unlike traditional β-blockers, it does not
significantly impair glycemic control or exacerbate dyslipidemia, which
is critical in managing cardiometabolic risk [35].
Personalized therapeutics is an emerging frontier where nebivolol
shows promise. Variations in CYP2D6 metabolism and polymorphisms
3.8. Future directions in research & practice
The evolving role of nebivolol in HF management presents multiple
avenues for future exploration, particularly in the context of personal­
ized therapy and precision medicine. With growing recognition of het­
erogeneity in HF phenotypes—especially in HFpEF—there is an urgent
need for therapies tailored to individual pathophysiological profiles
[39]. Nebivolol’s unique pharmacodynamic properties, including nitric
oxide-mediated vasodilation and β₃-adrenergic receptor stimulation,
may render it particularly beneficial in patient subsets characterized by
endothelial dysfunction or microvascular disease [11].
Advances in molecular profiling and biomarker discovery offer op­
portunities to refine patient selection. For example, microRNAs associ­
ated with β-adrenergic signaling or NO pathways may serve as
predictive markers of response to nebivolol [40]. Additionally, phar­
macogenomic
data—particularly
involving
CYP2D6
poly­
morphisms—could inform dose optimization and identify individuals at
risk for altered metabolism or adverse effects [36]. These developments
align with the broader movement toward precision β-blockade strate­
gies, which seek to maximize benefit while minimizing harm [36,39].
Innovative clinical trial designs will be essential to capture the
nuanced effects of nebivolol in underrepresented populations. Adaptive
5
Vascular Pharmacology 162 (2026) 107562
E.R. Ginghina et al.
and pragmatic trials, enriched with digital phenotyping and remote
monitoring, could improve recruitment and allow dynamic treatment
adjustments [41]. Integration of artificial intelligence and machine
learning could further enhance risk stratification and identify novel
responder subgroups, especially among older adults or patients with
comorbidities such as diabetes or renal impairment [42].
Finally, the role of nebivolol in emerging therapeutic contexts war­
rant investigation. Its potential to mitigate cardiotoxicity in cancer
therapy-related cardiac dysfunction (CTRCD) [43], or as an adjunct to
device therapy in HFpEF [44], represents a promising frontier. As the HF
landscape continues to evolve, robust mechanistic and clinical inquiry
will be vital to defining nebivolol’s optimal placement within future
treatment algorithms [41].
(ESC). With the special contribution of the Heart Failure Association (HFA) of the
ESC, Eur. J. Heart Fail. 24 (1) (2022 Jan) 4–131.
[3] P.A. Heidenreich, B. Bozkurt, D. Aguilar, L.A. Allen, J.J. Byun, M.M. Colvin, et al.,
2022 AHA/ACC/HFSA guideline for the Management of Heart Failure: a report of
the American College of Cardiology/American Heart Association joint committee
on clinical practice guidelines, J. Am. Coll. Cardiol. 79 (17) (2022 May 3)
e263–e421.
[4] R. Madonna, F. Biondi, M. Alberti, S. Ghelardoni, L. Mattii, A. D’Alleva,
Cardiovascular outcomes and molecular targets for the cardiac effects of sodiumglucose cotransporter 2 inhibitors: a systematic review, Biomed. Pharmacother.
175 (2024 June) 116650.
[5] M.M. Kittleson, Guidelines for treating heart failure, Trends Cardiovasc. Med. 35
(3) (2025 Apr) 141–150.
[6] A. Beghini, A.M. Sammartino, Z. Papp, S. von Haehling, J. Biegus, P. Ponikowski, et
al., 2024 update in heart failure, ESC Heart Fail. 12 (1) (2025 Feb) 8–42.
[7] M. Packer, A.J. Coats, M.B. Fowler, H.A. Katus, H. Krum, P. Mohacsi, et al., Effect
of carvedilol on survival in severe chronic heart failure, N. Engl. J. Med. 344 (22)
(2001 May 31) 1651–1658.
[8] D. Kotecha, J. Holmes, H. Krum, D.G. Altman, L. Manzano, J.G.F. Cleland, et al.,
Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an
individual-patient data meta-analysis, Lancet Lond. Engl. 384 (9961) (2014 Dec
20) 2235–2243.
[9] L.H. Lindholm, B. Carlberg, O. Samuelsson, Should beta blockers remain first
choice in the treatment of primary hypertension? A meta-analysis, Lancet Lond.
Engl. 366 (9496) (2005 Nov 29) 1545–1553.
[10] M.D. Flather, M.C. Shibata, A.J.S. Coats, D.J. Van Veldhuisen, A. Parkhomenko,
J. Borbola, et al., Randomized trial to determine the effect of nebivolol on
mortality and cardiovascular hospital admission in elderly patients with heart
failure (SENIORS), Eur. Heart J. 26 (3) (2005 Feb) 215–225.
[11] J.E. Toblli, F. DiGennaro, J.F. Giani, F.P. Dominici, Nebivolol: impact on cardiac
and endothelial function and clinical utility, Vasc. Health Risk Manag. 8 (2012)
151–160.
[12] The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial, Lancet
Lond. Engl. 353 (9146) (1999 Jan 2) 9–13.
[13] Effect of metoprolol CR/XL in chronic heart failure, Metoprolol CR/XL randomised
intervention trial in congestive heart failure (MERIT-HF), Lancet Lond. Engl. 353
(9169) (1999 June 12) 2001–2007.
[14] M.R. Bristow, beta-adrenergic receptor blockade in chronic heart failure,
Circulation 101 (5) (2000 Feb 8) 558–569.
[15] A.P. Maggioni, S.D. Anker, U. Dahlström, G. Filippatos, P. Ponikowski, F. Zannad,
et al., Are hospitalized or ambulatory patients with heart failure treated in
accordance with European Society of Cardiology guidelines? Evidence from 12,440
patients of the ESC heart failure long-term registry, Eur. J. Heart Fail. 15 (10)
(2013 Oct) 1173–1184.
[16] F.A. McAlister, N. Wiebe, J.A. Ezekowitz, A.A. Leung, P.W. Armstrong, Metaanalysis: beta-blocker dose, heart rate reduction, and death in patients with heart
failure, Ann. Intern. Med. 150 (11) (2009 June 2) 784–794.
[17] L.H. Lund, L. Benson, U. Dahlström, M. Edner, L. Friberg, Association between use
of β-blockers and outcomes in patients with heart failure and preserved ejection
fraction, JAMA 312 (19) (2014 Nov 19) 2008–2018.
[18] A. Veverka, D.S. Nuzum, J.L. Jolly, Nebivolol: a third-generation beta-adrenergic
blocker, Ann. Pharmacother. 40 (7–8) (2006) 1353–1360.
[19] W. Gielen, T.J. Cleophas, R. Agrawal, Nebivolol: a review of its clinical and
pharmacological characteristics, Int. J. Clin. Pharmacol. Ther. 44 (8) (2006 Aug)
344–357.
[20] J.R. Cockcroft, P.J. Chowienczyk, S.E. Brett, C.P. Chen, A.G. Dupont, L. Van
Nueten, et al., Nebivolol vasodilates human forearm vasculature: evidence for an Larginine/NO-dependent mechanism, J. Pharmacol. Exp. Ther. 274 (3) (1995 Sept)
1067–1071.
[21] M.A. Broeders, P.A. Doevendans, B.C. Bekkers, R. Bronsaer, E. van Gorsel, J.
W. Heemskerk, et al., Nebivolol: a third-generation beta-blocker that augments
vascular nitric oxide release: endothelial beta(2)-adrenergic receptor-mediated
nitric oxide production, Circulation 102 (6) (2000 Aug 8) 677–684.
[22] O. Kamp, M. Metra, S. Bugatti, L. Bettari, A. Dei Cas, N. Petrini, et al., Nebivolol:
haemodynamic effects and clinical significance of combined beta-blockade and
nitric oxide release, Drugs 70 (1) (2010) 41–56.
[23] H. Mollnau, E. Schulz, A. Daiber, S. Baldus, M. Oelze, M. August, et al., Nebivolol
prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits
NADPH oxidase activity in inflammatory cells, Arterioscler. Thromb. Vasc. Biol. 23
(4) (2003 Apr 1) 615–621.
[24] M. Oelze, A. Daiber, R.P. Brandes, M. Hortmann, P. Wenzel, U. Hink, et al.,
Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial
dysfunction in angiotensin II-treated rats, Hypertens. Dallas Tex 1979 48 (4) (2006
Oct) 677–684.
[25] G. Mercanoglu, N. Safran, M. Gungor, B. Pamukcu, H. Uzun, C. Sezgin, et al., The
effects of nebivolol on apoptosis in a rat infarct model, Circ. J. Off. J. Jpn. Circ. Soc.
72 (4) (2008 Apr) 660–670.
[26] A. Fratta Pasini, U. Garbin, M.C. Nava, C. Stranieri, A. Davoli, T. Sawamura, et al.,
Nebivolol decreases oxidative stress in essential hypertensive patients and
increases nitric oxide by reducing its oxidative inactivation, J. Hypertens. 23 (3)
(2005 Mar) 589–596.
[27] R.P. Mason, L. Kalinowski, R.F. Jacob, A.M. Jacoby, T. Malinski, Nebivolol reduces
nitroxidative stress and restores nitric oxide bioavailability in endothelium of black
Americans, Circulation 112 (24) (2005 Dec 13) 3795–3801.
[28] D.J. van Veldhuisen, A. Cohen-Solal, M. Böhm, S.D. Anker, D. Babalis,
M. Roughton, et al., Beta-blockade with nebivolol in elderly heart failure patients
4. Conclusions
Nebivolol represents a pharmacologically distinctive β-blocker with
potential advantages in the evolving management of HF, particularly
among elderly and comorbid populations. Its dual mechanism—β₁-se­
lective adrenergic blockade combined with nitric oxide-mediated vas­
odilation—confers both hemodynamic and endothelial benefits that
may extend beyond those of traditional agents. Evidence from the SE­
NIORS trial and subsequent analyses supports its efficacy across a broad
spectrum of left ventricular ejection fractions, with favorable tolera­
bility and quality-of-life outcomes. Despite underrepresentation in U.S.
guidelines, its clinical utility in European practice underscores its value
in real-world settings. As HF treatment moves toward more individu­
alized approaches, nebivolol’s pharmacologic and safety profile make it
a compelling candidate for targeted therapy. Continued research,
including precision medicine applications and innovative trial designs,
will be essential to fully delineate its role in contemporary HF care and
to guide its integration into future therapeutic strategies.
CRediT authorship contribution statement
Edoardo Roberto Ginghina: Writing – original draft, Project
administration, Investigation, Conceptualization. Giuseppe BiondiZoccai: Writing – review & editing, Supervision, Methodology. Andrea
Vitali: Writing – review & editing, Resources. Lucia Fatima Di Napoli:
Writing – review & editing, Data curation. Giacomo Frati: Writing –
review & editing, Supervision, Funding acquisition.
Declaration of competing interest
Giuseppe Biondi-Zoccai has consulted, lectured and/or served as
advisory board member for Abiomed, Advanced Nanotherapies, Aleph,
Amarin, AstraZeneca, Balmed, Cardionovum, Cepton, Crannmedical,
Endocore Lab, Eukon, Guidotti, Innovheart, Meditrial, Menarini,
Microport, Opsens Medical, Synthesa, Terumo, and Translumina,
outside the present work.
All other authors declare no competing financial interests or personal
relationships that could have influenced the work reported in this
manuscript.
Data availability
No data was used for the research described in the article.
References
[1] N.L. Bragazzi, W. Zhong, J. Shu, A. Abu Much, D. Lotan, A. Grupper, et al., Burden
of heart failure and underlying causes in 195 countries and territories from 1990 to
2017, Eur. J. Prev. Cardiol. 28 (15) (2021 Dec 29) 1682–1690.
[2] Authors/Task Force Members, McDonagh TA, M. Metra, M. Adamo, R.S. Gardner,
A. Baumbach, et al., 2021 ESC Guidelines for the diagnosis and treatment of acute
and chronic heart failure: developed by the Task Force for the diagnosis and
treatment of acute and chronic heart failure of the European Society of Cardiology
6
E.R. Ginghina et al.
Vascular Pharmacology 162 (2026) 107562
with impaired and preserved left ventricular ejection fraction: data from SENIORS
(study of effects of Nebivolol intervention on outcomes and Rehospitalization in
Seniors with heart failure), J. Am. Coll. Cardiol. 53 (23) (2009 June 9) 2150–2158.
[29] A. Cohen-Solal, D. Kotecha, D.J. van Veldhuisen, D. Babalis, M. Böhm, A.J. Coats,
et al., Efficacy and safety of nebivolol in elderly heart failure patients with
impaired renal function: insights from the SENIORS trial, Eur. J. Heart Fail. 11 (9)
(2009 Sept) 872–880.
[30] V.M. Conraads, M. Metra, O. Kamp, G.W. De Keulenaer, B. Pieske, J. Zamorano, et
al., Effects of the long-term administration of nebivolol on the clinical symptoms,
exercise capacity, and left ventricular function of patients with diastolic
dysfunction: results of the ELANDD study, Eur. J. Heart Fail. 14 (2) (2012 Feb)
219–225.
[31] M. Contini, A. Apostolo, G. Cattadori, S. Paolillo, A. Iorio, E. Bertella, et al.,
Multiparametric comparison of CARvedilol, vs. NEbivolol, vs. BIsoprolol in
moderate heart failure: the CARNEBI trial, Int. J. Cardiol. 168 (3) (2013 Oct 3)
2134–2140.
[32] M.J. Lenzen, A. Rosengren, Scholte op Reimer WJM, F. Follath, E. Boersma, M.
L. Simoons, et al., Management of patients with heart failure in clinical practice:
differences between men and women, Heart Br Card Soc. 94 (3) (2008 Mar) e10.
[33] M. Komajda, F. Follath, K. Swedberg, J. Cleland, J.C. Aguilar, A. Cohen-Solal, et al.,
The EuroHeart Failure Survey programme–a survey on the quality of care among
patients with heart failure in Europe. Part 2: treatment, Eur. Heart J. 24 (5) (2003
Mar) 464–474.
[34] G.L. Bakris, V. Fonseca, R.E. Katholi, J.B. McGill, F.H. Messerli, R.A. Phillips, et al.,
Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes
mellitus and hypertension: a randomized controlled trial, JAMA 292 (18) (2004
Nov 10) 2227–2236.
[35] R. Weiss, Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation,
Vasc. Health Risk Manag. 2 (3) (2006) 303–308.
[36] M.J. Bijl, L.E. Visser, R.H.N. van Schaik, J.A. Kors, J.C.M. Witteman, A. Hofman, et
al., Genetic variation in the CYP2D6 gene is associated with a lower heart rate and
blood pressure in beta-blocker users, Clin. Pharmacol. Ther. 85 (1) (2009 Jan)
45–50.
[37] S. Gupta, H.M. Wright, Nebivolol: a highly selective beta1-adrenergic receptor
blocker that causes vasodilation by increasing nitric oxide, Cardiovasc. Ther. 26 (3)
(2008) 189–202.
[38] L.M. Van Bortel, M.A. van Baak, Exercise tolerance with nebivolol and atenolol,
Cardiovasc. Drugs Ther. 6 (3) (1992 June) 239–247.
[39] S.J. Shah, B.A. Borlaug, D.W. Kitzman, A.D. McCulloch, B.C. Blaxall, R. Agarwal, et
al., Research priorities for heart failure with preserved ejection fraction: National
Heart, Lung, and Blood Institute working group summary, Circulation 141 (12)
(2020 Mar 24) 1001–1026.
[40] Z. Chen, C. Li, K. Lin, Q. Zhang, Y. Chen, L. Rao, MicroRNAs in acute myocardial
infarction: evident value as novel biomarkers? Anatol. J. Cardiol. 19 (2) (2018 Feb)
140–147.
[41] Bothwell LE, Greene JA, Podolsky SH, Jones DS. Assessing the gold standard–
lessons from the history of RCTs. N. Engl. J. Med. 2016 June 2;374(22):
2175–2181.
[42] K.W. Johnson, J. Torres Soto, B.S. Glicksberg, K. Shameer, R. Miotto, M. Ali, et al.,
Artificial Intelligence in Cardiology, J. Am. Coll. Cardiol. 71 (23) (2018 June 12)
2668–2679.
[43] D. Cardinale, A. Colombo, G. Bacchiani, I. Tedeschi, C.A. Meroni, F. Veglia, et al.,
Early detection of anthracycline cardiotoxicity and improvement with heart failure
therapy, Circulation 131 (22) (2015 June 2) 1981–1988.
[44] B.A. Borlaug, K.J. Anstrom, G.D. Lewis, S.J. Shah, J.A. Levine, G.A. Koepp, et al.,
Effect of inorganic nitrite vs placebo on exercise capacity among patients with
heart failure with preserved ejection fraction: the INDIE-HFpEF randomized
clinical trial, JAMA 320 (17) (2018 Nov 6) 1764–1773.
7