Nebivolol in the treatment of arterial hypertension: From pharmacological profile to clinical recommendations for treatment

β-blockers are a valuable class of antihypertensive drugs, which is confirmed in modern guidelines for the treatment of hypertension. However, β-blockers are not a homogeneous class and differ in their pharmacological and clinical profile. Nebivolol is a representative of the third generation of β-blockers with the highest selectivity, additional vasodilatory and pleiotropic effects, neutral metabolic effects and good tolerability, and has proven its advantages over other β-blockers. The additional vasodilatory effect of nebivolol is mediated by NO-releasing activity with an increase in the bioavailability of NO, which is involved not only in the antihypertensive activity, but also provides important vascular protective effects. Studies demonstrate its effect on oxidative stress, endothelial dysfunction and arterial stiffness, as well as a decrease in central aortic pressure and reflected wave in patients with hypertension. Nebivolol reduces ultrastructural changes in the myocardium and coronary bed, reducing interstitial fibrosis and improving diastolic relaxation of the myocardium. Meta-analyses of clinical trials have noted the high antihypertensive efficacy of nebivolol compared to other β-blockers and other classes of antihypertensive drugs, as evidenced by a lower frequency of discontinuation and switching to other drugs. In large-scale studies of real-world clinical practice on large cohorts of patients with hypertension, nebivolol showed favorable long-term efficacy in terms of impact on cardiovascular outcomes compared to other β-blockers (atenolol, metoprolol). Thus, nebivolol has special pharmacological properties, providing additional vasodilator, antioxidant and anti-ischemic effects, which is of particular interest to certain groups of patients, in whom its good tolerability profile can also improve treatment adherence.

1. Mancia G, Kreutz R, Brunström M, Burnier M, Grassi G, Januszewicz A. et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023;41(12):1874–2071. https://doi.org/10.1097/HJH.0000000000003480.

2. do Vale GT, Ceron CS, Gonzaga NA, Simplicio JA, Padovan JC. Three generations of β-blockers: history, class differences and clinical applicability. Curr Hypertens Rev. 2019;15(1):22–31. https://doi.org/10.2174/1573402114666180918102735.

3. Del Pinto R, Ferri C, Parati G. Reduction of blood pressure variability: an additional protective cardiovascular effect of vasodilating beta-blockers? J Hypertens. 2020;38(3):405–407. https://doi.org/10.1097/HJH.0000000000002334.

4. Ferri C. The role of nebivolol in the management of hypertensive patients: from pharmacological profile to treatment guidelines. Future Cardiol. 2021;17(8):1421–1433. https://doi.org/10.2217/fca-2021-0048.

5. Cicero AFG, Kuwabara M, Borghi C. A critical review of nebivolol and its fixed-dose combinations in the treatment of hypertension. Drugs. 2018;78(17):1783–1790. https://doi.org/10.1007/s40265-018-0999-y.

6. Coats A, Jain S. Protective effects of nebivolol from oxidative stress to prevent hypertension-related target organ damage. J Hum Hypertens. 2017;31(6):376–381. https://doi.org/10.1038/jhh.2017.8.

7. Olawi N, Krüger M, Grimm D, Infanger M, Wehland M. Nebivolol in the treatment of arterial hypertension. Basic Clin Pharmacol Toxicol. 2019;125(3):189–201. https://doi.org/10.1111/bcpt.13248.

8. Oliver E, Mayor F Jr, D’Ocon P. Beta-blockers: historical perspective and mechanisms of action. Rev Esp Cardiol. 2019;72(10):853–862. https://doi.org/10.1016/j.rec.2019.04.006.

9. Celik T, Ozturk C, Balta S, Yilmaz MI. Nebivolol and endothelial dysfunction in patients with essential hypertension: a reputation saver of β-blockers? J Clin Hypertens. 2016;18:1258–1259. https://doi.org/10.1111/jch.12856.

10. Zepeda RJ, Castillo R, Rodrigo R, Prieto JC, Aramburu I, Brugere S et al. Effect of carvedilol and nebivolol on oxidative stress-related parameters and endothelial function in patients with essential hypertension. Basic Clin Pharmacol Toxicol. 2012;111(5):309–316. https://doi.org/10.1111/j.1742-7843.2012.00911.x.

11. Zhou X, Ma L, Habibi J, Whaley-Connell A, Hayden MR, Tilmon RD et al. Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat. Hypertension. 2010;55(4):880–888. https://doi.org/10.1161/HYPERTENSIONAHA.109.145136.

12. Ceron CS, Rizzi E, Guimarães DA, Martins-Oliveira A, Gerlach RF, TanusSantos JE. Nebivolol attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMPs, and decreases vascular remodeling in renovascular hypertension. Free Radic Biol Med. 2013;65:47–56. https://doi.org/10.1016/j.freeradbiomed.2013.06.033.

13. Dursun M, Sahin S, Besiroglu H, Otunctemur A, Ozbek E, Cakir SS et al. Protective effect of nebivolol on gentamicin-induced nephrotoxicity in rats. Bratislavske Lekarske Listy. 2018;119(11):718–725. https://doi.org/10.4149/bll_2018_128.

14. Nascimento MM, Bernardo DRD, de Bragança AC, Massola Shimizu MH, Seguro AC, Volpini RA, Canale D. Treatment with β-blocker nebivolol ameliorates oxidative stress and endothelial dysfunction in tenofovir-induced nephrotoxicity in rats. Front Med. 2022;9:953749. https://doi.org/10.3389/fmed.2022.953749.

15. Agabiti-Rosei E, Mancia G, O’Rourke MF, Roman MJ, Safar ME, Smulyan H et al. Central blood pressure measurements and antihypertensive therapy: a consensus document. Hypertension. 2007;50(1):154–160. https://doi.org/10.1161/HYPERTENSIONAHA.107.090068.

16. Borghi C, Acelajado MC, Gupta Y, Jain S. Role of nebivolol in the control and management of central aortic blood pressure in hypertensive patients. J Hum Hypertens. 2017;31(10):605–610. https://doi.org/10.1038/jhh.2017.26.

17. Kampus P, Serg M, Kals J, Zagura M, Muda P, Karu K et al. Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. Hypertension. 2011;57(6):1122–1128. https://doi.org/10.1161/HYPERTENSIONAHA.110.155507.

18. Mahmud A, Feely J. Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduces wave reflection. Am J Hypertens. 2008;21(6):663–667. https://doi.org/10.1038/ajh.2008.156.

19. Hayek SS, Poole JC, Neuman R, Morris AA, Khayata M, Kavtaradze N et al. Differential effects of nebivolol and metoprolol on arterial stiffness, circulating progenitor cells, and oxidative stress. J Am Soc Hypertens. 2015;9(3):206–213. https://doi.org/10.1016/j.jash.2014.12.013.

20. Redón J, Pascual-Izuel JM, Rodilla E, Vicente A, Oliván J, Bonet J et al. Effects of nebivolol and atenolol on central aortic pressure in hypertensive patients: a multicenter, randomized, double-blind study. Blood Press. 2014;23(3):181–188. https://doi.org/10.3109/08037051.2013.840421.

21. Vitale C, Marazzi G, Iellamo F, Spoletini I, Dall’Armi V, Fini M, Volterrani M. Effects of nebivolol or irbesartan in combination with hydrochlorothiazide on vascular functions in newly-diagnosed hypertensive patients: the NINFE (Nebivolol, Irbesartan Nella Funzione Endoteliale) study. Int J Cardiol. 2012;155(2):279–284. https://doi.org/10.1016/j.ijcard.2011.10.099.

22. Seleme VB, Marques GL, Mendes AEM, Rotta I, Pereira M, Júnior EL, da Cunha CLP. Nebivolol for the treatment of essential systemic arterial hypertension: a systematic review and meta-analysis. Am J Cardiovasc Drugs. 2021;21(2):165–180. https://doi.org/10.1007/s40256-020-00422-0.

23. Liu J-Y, Guo L-N, Peng W-Z, Yang Jiang, Ai-Li Wang, Xue-Min Guo, Ze-Sheng Xu. Efficacy and safety of nebivolol in hypertensive patients: a metaanalysis of randomized controlled trials. JIMR. 2020;48(10). https://doi.org/10.1177/0300060520931625.

24. Wikananda IMF, Nurcahya IGNM, Wijaya PGPM, Widiana IGR, Sindhughosa DA. Effects of nebivolol therapy on hemodynamic parameters and lipid profile compared to other beta blockers in patients with essential hypertension: a systematic review and meta-analysis. Caspian J Intern Med. 2024;15(1):28–37. https://doi.org/10.22088/cjim.15.1.2.

25. Signorovitch JE, Samuelson TM, Ramakrishnan K, Marynchenko M, Wu EQ, Blum SI et al. Persistence with nebivolol in the treatment of hypertension: a retrospective claims analysis. Curr Med Res Opin. 2012;28(4):591–599. https://doi.org/10.1185/03007995.2012.668495.

26. Ayyagari R, Xie J, Cheng D, Wu EQ, Huang XY, Chen S. A retrospective study evaluating the tolerability and effectiveness of adjunctive antihypertensive drugs in patients with inadequate response to initial treatment. J Clin Hypertens. 2018;20(6):1058–1066. https://doi.org/10.1111/jch.13312.

27. Huck DM, Rosenberg MA, Stauffer BL. Nebivolol and incident cardiovascular events in hypertensive patients compared with nonvasodilatory beta blockers. J Hypertens. 2022;40(5):1019–1029. https://doi.org/10.1097/HJH.0000000000003109.

28. Basile J, Egan B, Punzi H, Ali S, Li Q, Patel M, Neutel J. Risk of hospitalization for cardiovascular events with β-blockers in hypertensive patients: a retrospective cohort study. Cardiol Ther. 2018;7(2):173–183. https://doi.org/10.1007/s40119-018-0117-y.

29. Mancia G, Brunström M, Burnier M, Grassi G, Januszewicz A, Kjeldsen SE et al. Rationale for the inclusion of β-Blockers among major antihypertensive drugs in the 2023 European Society of Hypertension Guidelines. Hypertension. 2024;81(5):1021–1030. https://doi.org/10.1161/HYPERTENSIONAHA.124.22821.

30. Mahfoud F, Wang J, Ray S. The current position of β-blockers in hypertension: guidelines and clinical practice. Curr Med Res Opin. 2024;40(Suppl. 1):25–32. https://doi.org/10.1080/03007995.2024.2318003.

31. Messerli FH, Bangalore S, Mandrola JM. β blockers switched to first-line therapy in hypertension. Lancet. 2023;402(10414):1802–1804. https://doi.org/10.1016/S0140-6736(23)01733-6.

32. Barrientos-Regala M, Reaño JDP. Beta-Blockers for hypertension in Asian population. In: Ram CVS, Teo BWJ, Wander GS (eds.). Hypertension and cardiovascular disease in Asia. Updates in hypertension and cardiovascular protection. Springer, Cham; 2022. https://doi.org/10.1007/978-3-030-95734-6_22.

33. Mohan JC, Roy DG, Ray S, Dalal J, Sharma K, Kumar AS et al. Position of betablockers in the treatment of hypertension today: an Indian Consensus. J Assoc Physicians India. 2024;72(10):83–90. https://doi.org/10.59556/japi.72.0715.