European Journal of Cardiovascular Medicine

Over the last 3decades,CVD havebeen implicated in about 54% of mortality and 60% of disability-adjusted life-years (DALY) lost.1The CVD continuum comprises the evolution from CV risk factors through atherosclerosis,hypertension, and then the target organ damage (heart, brain, kidneys), and finally, HF (Figure 1).

Figure recreated from: Dzau VJ, et al. Circulation. 2006; 114: 2850-2870.

Hypertension drives CVD and increases the risk of strokes, diabetes, heart disease, and renal impairment, underscoring the need for urgent prevention and management (Figure 1).2

Early identification and management of risk factors such as hypertensionand diabetes can slow or prevent progression along the CVD continuum.3

Sympathetic overactivity is one of the pathogenic features of hypertension.This justifies the use of beta blockers as first-line drugs in the management of patients with hypertension.Beta-blockers play a pivotal role in managing hypertension, chronic coronary syndromes, arrhythmias, and HF.3Over the past decades,improved understanding of the CV continuum has paved the way for the development of early non-selective to β1-selective and subsequently to the recent vasodilatory molecules such as nebivolol. Beta-blockers are considered to be a heterogeneous class of drugs. Beta blockers differ in their pharmacodynamic properties such as beta receptor antagonism, the presence of intrinsic sympathomimetic activity, and directanti-arrhythmic effects (e.g., class III antiarrhythmic action).Differences also exist in their pharmacokinetics and ability to cross the blood-brain barrier.4 The various generations of beta-blockers distinctly differ in their pharmacological properties.Treatment choices for patients with CVD should be based on the presence and severity of risk factors and comorbid conditions.5

Nebivolol is a third-generation β-adrenergic receptor antagonist with high selectivity for β1-adrenergic receptors. Nebivolol also has a vasodilating effect mediated by the endothelial L-arginine/NO pathway. This dual mechanismconfers on nebivolol a unique hemodynamic profile within the class of β-blockers.4 Theefficacy and tolerability of third-generation β-blockers have been demonstrated also in hypertensive patients withnon-CV comorbidities (such as diabetes, obstructive respiratory diseases or erectile dysfunction [ED]), in whom conventional first-generation beta blockers are usually contraindicated or not recommended as drugs of first choice.6

The 2023 Asia–Pacific Delphi consensus emphasized the critical role of β-blockers across the CVD continuum, especially in CAD management.4 In acute coronary syndrome (ACS), early initiation of beta-blockers, within 24 h of symptom onset, is strongly recommended in patients with ST-elevation or non-ST-elevation MI if there is no contraindication to the use of beta-blockers.3

The evolving role of beta blockers such as nebivolol across the CV continuum in the Indian real-worldsetting requires evaluation of emerging evidence and guidelines and needs to be corroborated with the experience of Indian expert physicians and cardiologists treating CVD.This review brings into perspective the emerging role of beta blockers such as nebivolol across the CV continuum ranging from hypertensionto HFand prevention of deaths. The role of beta blockers, especially in the lesser studied HFpEF, also warrants a review of current evidence. 4

Role of nebivolol in the management ofhypertension

Management of essential hypertensionremains a challenge, with control being achieved in <1/10 of the cases, especially when aligned with the recently updated guidelines of the American College of Cardiology (ACC) or International Society of Hypertension (ISH).7,8

The place and positioning of beta-blockers have been evolving over the past decade in the management of hypertension.The ESH upgraded β-blockers to drugs of first choice, putting them on equal level as thiazide diuretics, renin–angiotensin system blockers (eg, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and calcium channel blockers (CCB).The presence of comorbid diseases in patients with hypertensionwas considered when upgrading beta blockers (the twofer concept). The upgrade allows two conditions to be treated simultaneously with beta blockers.9The recent guidelines have considered the potential advantages of β-blockers in hypertensive patients withconcomitant CV pathologies (such as HF, CAD, atrial fibrillation [AF]),and recommend their preferential use in these patients.10The ESH 2023 guidelines are particularly relevant to the Indian hypertensive phenotype characterized by premature CVD, and/or high resting HR.11

Beta blockers act by blocking beta-adrenergic receptors, and this results in a reduction of sympathetic nervous system activity, thereby lowering BP and cardiac workload. Nebivolol has additional unique NO–mediated vasodilatory and β₁- selective properties. This could give additionalCV protection, and hence this makes nebivolol one of the preferred beta blockers for the management of hypertension.Nebivolol therapy lowers systolic and diastolic BP more than other β-blockers.12A recent large-scale, multicentre retrospective study demonstrated that nebivolol was more effective than carvedilol and other beta blockers (including bisoprolol, atenolol, and metoprolol) in achieving BP reduction and controlling HRin hypertensive patients over a mean follow-up period of 4.5years.13Nebivolol use was associated with a significantly lower risk of all-cause mortality and major adverse cardiovascular events (MACEs) as compared with carvedilol and other beta blockers. These results indicate that nebivolol could offer clinically relevant significant advantages in the long-term management of hypertension,especially in terms of improving CV outcomes and hemodynamic control. Nebivolol use was also associated with a significantly lower risk of all-cause mortality and a lower risk of composite CV events versus both carvedilol and other beta blockers.13These benefits may be attributed to the more selective beta-1 blockade by nebivolol,which results in a reduction of HR and myocardial contractility, thereby lowering cardiac workload and oxygen demand.13

In the BENEFITKOREA study, significant reductions in systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR were reported across age and sex subgroups of hypertensive patients.14TheNebivolol vs. Irbesartan for Hypertension in Isolated Systolic Hypertension (NEHIS) trial demonstrated that nebivolol in combination with hydrochlorothiazide resulted in significantly greater reductions in SBP and better 24-hour variability control as compared to irbesartan/hydrochlorothiazide.15

An Indian expert consensus evaluated the place of nebivolol in the management of hypertensionin the real-world setting using the modified Delphi method.96% of respondents opined that the new ESH hypertensionguidelines (2023) improved their confidence in using beta-blockers as first-line drugs for the treatment of hypertension.Beta-blockers, including nebivolol, can be recommended for the management of patients with hypertensionwith high resting HR, including young hypertensive patients under 40 years of age.In people under 60 years old with hypertension, beta-blockers are the recommended drug. 95% of experts opined that nebivolol is the preferred beta-blocker in hypertensive patients with T2DM, followed by bisoprolol and metoprolol. More than 90% of experts opined that the three most commonly preferred beta-blockers by experts in patients with angina were nebivolol, metoprolol, and bisoprolol.15

Role of nebivolol in the management of chronic coronary disease

Heart rate ≥70 beats per minute (bpm) increases CV risk in CAD patients.16The 2024 ESC guidelines recommend β-blockers as first-line agents for relieving symptoms of angina, particularly in patients with prior MI or elevated resting HR.17 If used for anti-angina purposes, the aim should be tolower resting HR to 50-60 bpm.18

Indians experience CVD almost a decade earlier as compared to their Western counterparts.About 62 % of CVD-related deaths in Indians are classified as premature deaths. Poorly controlled traditional risk factors such as hypertensionand diabetes are the chief drivers of this high death rate in Indians with CVD.3

The hypertensioncontrol rates in India are low (<10%). High sympathetic overactivity and increased resting HR have been observed in Indian hypertensive patients with CVD. Hence, β-blockers such as nebivolol should be considered early in the treatment algorithm.3Several trials have demonstrated the benefits of early initiation of beta blockers. A significantly lower in-hospital mortality (odds ratio [OR] = 0.41; 95 % CI: 0.21–0.80) and reduced incidence of severe LV dysfunction (OR = 0.57; 95 % CI: 0.42–0.78) are the key benefits associated with early initiation of beta blockers. β-blockers not only relieve symptoms of angina but also reduce CV events in high-risk individuals, corroborating their central role in the long-term treatment of stable CAD.3

Nebivolol is considered to be the most β1-selective blocker with a relative affinity for β1/β2 receptors >300.  Nebivolol possesses a direct stimulatory effect on endothelial NOS, which results in increased levels of local NO.19Nebivolol has an antioxidant effect, which could be responsible for additional vasodilatory actions. Nebivolol reduces the expression of pro-adhesion and inflammatory molecules on the endothelial wall andreduces apoptosis and oxidative stress. This may reduce ischemia-reperfusion myocardial injury and help to reduce end-organ damage.4Nebivolol is devoid of the potentially harmful effects on cardiac output (CO) and peripheral resistance, unlike older beta blockers.20

Nebivolol has been studied in hypertensive patients with stable CAD. Nebivolol reduced BP and HR in hypertensive patients with CAD in the Nebivolol-TR study.21Nebivolol improves coronary blood flow by decreasing left ventricular filling pressures and thus improves exercise tolerance in patients with CAD.4Nebivolol has been observed to be associated with a 17% reduction in CV events versus non-vasodilatory beta blockers.22Nebivolol effectively reduced cardiac ischemic events in patients with HF of ischemicetiology.23Microvascular and endothelial dysfunction have been implicated in CSF. Nebivolol causes an endothelium-dependent vasodilation through increased NO release and can improve coronary flow in these patients. Nebivolol is useful in improving angina, exercise capacity, and LV functionin patients with CSF.24Nebivolol significantly improves coronary vasospasm in patients with hypertensionand vasospastic angina.25

An emerging benefit of nebivolol is significantly lower levels of residual adenosine diphosphate (ADP)-induced platelet aggregation compared to baseline than patients who used bisoprolol in patients with CAD on dual antiplatelet therapy.26The use of 5 mg oral nebivolol may decrease the incidence of contrast-induced nephropathy in patients who underwent coronary angiography with renal dysfunction.27

Nebivolol, with its vasodilating properties, neutral metabolic effects, and good tolerability, has definite advantages over other β-blockers, which makes it useful across a wide variety of hypertensive patients withCAD.6

Role of nebivolol in the management of patients with acute coronary syndrome and arrhythmias

 β-blockers are the cornerstone of treatment in the management of patients with cardiac arrhythmias, particularly in high-risk populations. Their ability to modulate autonomic tone and suppress arrhythmic triggers has made them a cornerstone of rhythm and rate control strategies.The use of β-blockers in both supraventricular and ventricular arrhythmias is endorsed by the European and American clinical guidelines. 28

In patients with chronic obstructive pulmonary disease(COPD) and ACS, nebivolol is the preferred beta blocker due to its β1-selective actions. Nebivolol treatment in this patient population is not associated with forced expiratory volume (FEV1) worsening or exacerbation of respiratory symptoms, unlike non-selective beta blockers.Another benefit of nebivolol is its ability to improve insulin sensitivity, with no negative effects on glycemic control.29

Postoperative AF is a common complication observed in about 20% to 50% of patients after cardiac surgery. Nebivolol has been reported to be as effective as metoprolol in preventing postoperative AF.30Nebivolol effectively controlledHR in hospitalized patients with chronic AF due to IHD. In most patients, 5 mg /day was sufficient for attainment of acceptable HR.31Nebivolol significantly reduces arterial pressure, HR, and the number of ventricular extrasystoles.32

Role of nebivolol in HFpEF

The American and European HF guidelines and the 2025 HFAI Guidelines for diagnosis and management of HF have defined HFpEF as a condition with left ventricular ejection fraction (LVEF) ≥50 %, withsigns and symptoms of HF, with evidence of increased left ventricular filling pressures, e.g., increased natriuretic peptide levels and hemodynamic measurement.About 50% to 70% of patients with HF have HFpEF.33

The Study of Effects of Nebivolol Intervention on Outcomes and Re-Hospitalization in Seniors with Heart Failure (SENIORS) trial proved the benefit of nebivolol in SENIORS in elderly patients with HFpEF.34 The risk of all-cause death or hospitalisation due to CV causes was significantly reduced in the nebivolol group as compared to the placebo group. (HR 0.86 [0.74 to 0.99], p = 0.039).35

HFpEF represents a highly heterogeneous clinical syndrome associated with multiple metabolic, pulmonary, or renal disorders in 5%–80% of patients.36After HF hospitalization, the 5‐year survival of HFpEF is just 35%.37

A high resting HRmay be responsible forthe high all-cause death in HFpEF patients in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity)and I-PRESERVE (Irbesartan in HFpEF Study) trials.38,39Several registries such as the CHART-2 (Chronic Heart Failure Analysis and Registry in the Tohoku District 2) registryand the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) registry have also corroborated these findings.A high sympathetic activity is implicated in the high resting HR in patients with HFpEF.40, 41The high sympathetic activity leads to a shortened left ventricular diastolic filling time, development of tachyarrhythmias, and hypertension in patients with HFpEF.42

Hence, considering the raised sympathetic activity, beta-blockers could be useful in this patient population of HFpEF. But trials of beta blockers in HF have a low representation of HFpEF patients. Hence, the role of beta blockers has remained unclear in HFpEF.36HFpEF is commonly observed in the elderly population who have an increased risk of having pre-existing cardiac comorbidities such as CAD and AF, for which beta-blocker therapy is commonly prescribed.42It may be reasonable to reassess the necessity for a long-term (>1 year) beta-blocker therapy in order to reduce cardiac events in patients with prior MI and without LVEF ≤50%.43Nebivolol has been studied in the HFpEF population (15% of the study population) in the SENIORS trial. Nebivolol consistently reduced the composite of all-cause mortality (HR 0.86)and CV hospital admission in HF, regardless of the LVEF (<35% or >35%).36 The effects of nebivolol on the primary endpoint, as well as secondary endpoints, were comparable in patients with LVEF <35% or higher LVEF.44Nebivolol improved the New York Heart Association (NYHA) functional class, improved exercise capacity, and quality of life (QOL) in patients with HFpEF.45

It is postulated that increased diastolic filling time and protection from ischaemia may make beta blockers such as nebivolol useful for the treatment of HFpEF. Reduced myocardial collagen volume fraction, decreased cardiac myocyte diameter, and reduced expression of stimulatory G protein may improve cardiac diastolic function in patients with HFpEF.45Left ventricular hypertrophy, myocardial fibrosis, and left ventricular diastolic dysfunction worsening could be countered by beta-blockerssuch as nebivolol.42The release of NO after nebivolol therapy favours relaxation at the cardiac level, resulting in lower LV pressure during diastole.This improvesexercise tolerance with nebivolol, compared with traditional beta-blockers.45

Indian expert consensus on role of nebivolol in HFpEF

The “one-size-fits-all” approach to using beta-blockers in HFpEF is not considered to be the optimal approach. Beta blockers may differ in their benefits in the population of patients with HFpEF. But, there is a relative lack of data on the use of different beta blockers in robust clinical trials. An Indian expert consensus performed by the modified DELPHI method with (n=12) Indian expert cardiologists chronicled the role of nebivolol in HFpEF.The estimated prevalence of HFpEF observed in the clinic in the real-world setting was reported to be between 20%-40%. 93% of experts agreed that HFpEF diagnosis poses a challenge and is often underdiagnosed. 92% of experts concurred that β-blockers are recommended in HFpEF when compelling indications exist. 81% of experts prescribed nebivolol in HFpEF. They opined that nebivolol may offer added benefit through NO–mediated vasodilation, improving coronary microvascular flow and diastolic performance. 90% of experts considered nebivolol to be a metabolically neutral β-blocker—that offers vascular and metabolic benefits in HFpEF without compromising glucose or endothelial function (Table 1).

Table 1: Indian expert consensus about role of Nebivolol in HFpEF

Limitations of this review

Current evidence and emerging guidelines firmly reinstate and establish β-blockers as the cornerstone treatment in CV care across the CV continuum. Indian patients differ from their Western counterparts in terms of early-onset hypertension, high sympathetic activity, and multiple comorbidities, favouring the use of β1-selective agents such as nebivolol even in patients with CVD and CODP.The unique vasodilating property of nebivolol, by releasing NO, gives it an added advantage in patients with hypertension, chronic coronary syndrome, and HFpEF. These ancillary actions of nebivolol that go beyond the blockade of adrenergic receptors provide better CV protection, associated with a positive metabolic profile.Although consensus programs highlight the experience of experts in the real-world setting, several benefits of nebivolol must be studied further in well-designed multicentric clinical trials conducted across diverse patient populations in India.The role of nebivolol in HFpEF has been endorsed by Indian expert cardiologists. But this opinion warrants further study through clinical trials.

β-blockers continue to serve as cornerstone agents across the CV continuum. Pharmacodynamic differences do exist between the currently available beta blockers.Nebivolol is a third-generation beta blocker with unique vasodilating effects owing to its NO-releasingactivity.National expert surveys and consensus statements endorse the role of nebivolol in patients with hypertensionand HFpEF.Multicentric clinical trials to endorse the benefits of nebivolol in patients with HFpEF are warranted.

Abbreviations: CVD Cardiovascular disease; CV Cardiovascular; HF Heart failure; NO Nitric oxide; IHD Ischemic heart disease; MI Myocardial infarction; BP Blood pressure; HR Heart rate; CAD Coronary artery disease; LV Left ventricle; CSF Coronary slow flow; ESH European Society of Hypertension; T2DM Type 2 diabetes mellitus; HFpEF Heart failure with preserved ejection fraction; HFrEF Heart failure with reduced ejection fraction; DALY Disability-adjusted life years; ED Erectile dysfunction; ACS Acute coronary syndrome; ACC American College of Cardiology; ISH International Society of Hypertension; CCB Calcium channel blocker; AF Atrial fibrillation; MACEs Major adverse cardiovascular events; SBP Systolic blood pressure; DBP Diastolic blood pressure; bpm Beats per minute; ESC European Society of Cardiology; OR Odds ratio; CI Confidence interval; NOS Nitric oxide synthase; CO Cardiac output; ADP Adenosine diphosphate; COPD Chronic obstructive pulmonary disease; FEV1 Forced expiratory volume in 1 second; HFAI Heart Failure Association of India; LVEF Left ventricular ejection fraction; NYHA New York Heart Association; QOL Quality of life; DELPHI Delphi consensus method; CMD Coronary microvascular dysfunction.

#BENEFITKOREA: BENEFIT KOREA study

#NEHIS: Nebivolol vs. Irbesartan for Hypertension in Isolated Systolic Hypertension

#Nebivolol-TR: Nebivolol-TR study

#SENIORS: Study of Effects of Nebivolol Intervention on Outcomes and Re-Hospitalization in Seniors with Heart Failure

#CHARM: Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity

#I-PRESERVE: Irbesartan in Heart Failure with Preserved Ejection Fraction Study

#CHART-2: Chronic Heart Failure Analysis and Registry in the Tohoku District 2

#MAGGIC: Meta-Analysis Global Group in Chronic Heart Failure

#DELPHI: Delphi consensus method.

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