Nebivolol or Bisoprolol: What Is the Difference
Nebivolol and bisoprolol are two modern cardioselective beta-blockers, often prescribed for hypertension, ischemic disease and heart failure. Both predominantly block the β1 receptors of the heart, but nebivolol has an additional vasodilating mechanism. The editorial team explains what the difference between these molecules is and what it means in practice.
Beta-blockers of different generations
Beta-blockers reduce the influence of adrenaline and noradrenaline on the heart. The heart beats more slowly and with less force, the myocardial oxygen demand decreases, and the release of renin in the kidneys is inhibited. This underlies their use in angina, arrhythmias, heart failure and hypertension.
Drugs of this class are conventionally divided into generations. The first are non-selective (propranolol), blocking both the β1 receptors of the heart and the β2 receptors of the bronchi and vessels. The second are cardioselective, predominantly β1 (atenolol, metoprolol, bisoprolol). The third are drugs with additional vasodilating properties (carvedilol, nebivolol).
Bisoprolol belongs to the second generation and is one of the most β1-selective representatives of its group. Nebivolol is classified as third generation: it combines high β1 selectivity with the ability to dilate vessels through nitric oxide.
Both drugs are used once a day, both are on the list of beta-blockers with proven benefit in heart failure with reduced ejection fraction according to the ESC 2021 guidelines. The differences concern the mechanisms, pharmacokinetics and certain clinical nuances.
Selectivity and nitric oxide
Cardioselectivity means that at therapeutic doses the drug acts predominantly on the β1 receptors of the heart and less on the β2 receptors of the bronchi and peripheral vessels. Laboratory studies show that nebivolol is one of the most β1-selective beta-blockers, while bisoprolol also has high selectivity. Importantly, as the dose increases, the selectivity of any drug weakens.
Nebivolol is a racemic mixture of two isomers. d-Nebivolol is responsible for blocking β1 receptors, while l-nebivolol stimulates the release of nitric oxide (NO) from the vascular endothelium. According to current understanding, stimulation of the β3-adrenoreceptors of the endothelium is involved in this (Münzel, Gori, 2009).
Nitric oxide relaxes the smooth muscles of the vessels and reduces peripheral resistance. Therefore nebivolol lowers blood pressure not only by reducing the work of the heart but also by dilating the vessels. Traditional beta-blockers, on the contrary, may slightly increase peripheral resistance at the start of treatment.
Bisoprolol has no direct NO-mediated action. Its effect on blood pressure is achieved mainly by reducing cardiac output and suppressing renin production.
Pharmacokinetics and metabolism
Bisoprolol has a balanced route of elimination: approximately half the dose is excreted unchanged by the kidneys, half is metabolized in the liver. Because of this, with moderate impairment of the function of one of the organs the drug does not accumulate as strongly. The half-life is about 10–12 hours, which allows it to be taken once a day.
Nebivolol is metabolized predominantly by the enzyme CYP2D6, whose activity varies genetically. In “fast metabolizers” the half-life is about 10 hours, in “slow” ones — significantly longer. CYP2D6 inhibitors, in particular some antidepressants (fluoxetine, paroxetine), increase the concentration of nebivolol.
| Parameter | Nebivolol | Bisoprolol |
|---|---|---|
| Generation | III (with vasodilation) | II (cardioselective) |
| Additional mechanism | Release of NO | None |
| Metabolism | Predominantly CYP2D6 | ~50% liver, ~50% kidneys |
| Intake | Once a day | Once a day |
| Key study in HF | SENIORS (patients ≥70 years) | CIBIS-II |
| Typical dose in hypertension per labeling | 5 mg | 5–10 mg |
These differences matter when choosing for people with kidney or liver diseases and when taking several drugs simultaneously. The final assessment is made by a doctor taking the tests into account.
The evidence base
Bisoprolol has one of the most convincing evidence bases among beta-blockers in heart failure. In the CIBIS-II study (1999), in patients with chronic heart failure with reduced ejection fraction, it reduced overall mortality by about a third compared with placebo, and the study was stopped early because of the obvious benefit.
Nebivolol was studied in the SENIORS study (Flather et al., 2005) in patients aged 70 and over with heart failure, regardless of ejection fraction. The drug reduced the combined endpoint — death or hospitalization for cardiovascular causes — although it did not show a statistically significant effect on overall mortality separately.
Both drugs are included in the ESC 2021 heart failure guidelines as beta-blockers with proven efficacy, along with carvedilol and metoprolol succinate.
In uncomplicated hypertension, both effectively lower blood pressure. There are no direct large comparisons with hard endpoints between nebivolol and bisoprolol, so claims of the superiority of one over the other regarding heart attacks or strokes have no reliable basis.
Side effects and physical exercise
Common side effects of beta-blockers:
- fatigue, reduced exercise tolerance;
- bradycardia, dizziness;
- cold extremities;
- sleep disturbances, vivid dreams;
- in some patients — worsening of erectile function.
Regarding erection and metabolic effects, nebivolol, according to a number of small studies, may have advantages thanks to the NO mechanism, but the quality of these data is limited. Bisoprolol is also considered more metabolically neutral than older non-selective drugs.
Beta-blockers lower the maximum heart rate and can reduce aerobic performance. For people who train this is noticeable: heart-rate zones change against the background of therapy, and one should be guided by subjective intensity.
Caution is needed in bronchial asthma: although cardioselective drugs at low doses are usually tolerated better, the decision is made by a doctor. Beta-blockers are included in the WADA Prohibited List in certain sports where precision of movement is important (in particular shooting and archery).
Editorial conclusions
Nebivolol and bisoprolol are highly selective β1 blockers, but nebivolol additionally dilates vessels through nitric oxide.
Bisoprolol has a balanced elimination and a very strong evidence base in heart failure; nebivolol depends on CYP2D6 and is well studied in elderly patients.
Both drugs affect physical performance and pulse, and their choice and replacement must be carried out only under the supervision of a doctor.
Practical selection scenarios are described in the article “Nebivolol vs Bisoprolol: What to Choose and for Whom.” We also recommend materials on blood pressure in strength sports and on the comparison of telmisartan and losartan.
References
- CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9–13.
- Flather MD, Shibata MC, Coats AJ, 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. 2005;26(3):215–225.
- Münzel T, Gori T. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol. 2009;54(16):1491–1499.
- McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726.
- Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104.
- World Anti-Doping Agency. The Prohibited List. Montreal: WADA; щорічне видання.
Andriy Melnyk
A strength-sports coach and author of programs for beginner and intermediate levels. Writes about training planning.
