Differential Metabolic Effects of Beta-Blockers: an Updated Systematic Review of Nebivolol

  • Maria Marketou
  • Yashaswi Gupta
  • Shashank Jain
  • Panos Vardas
Hypertension and Metabolic Syndrome (J Sperati, Section Editor)
  • 265 Downloads
Part of the following topical collections:
  1. Topical Collection on Hypertension and Metabolic Syndrome

Abstract

Blood pressure management in hypertensive patients with metabolic abnormalities is challenging, since many of the antihypertensive drugs adversely affect metabolism. Besides effective control of blood pressure in patients with hypertension, third-generation beta-blockers such as nebivolol offer additional benefits for central hemodynamics and neutral or beneficial effects on metabolism. Emerging clinical data suggest that nebivolol also has similar effects on metabolism in obese hypertensive and hypertensive diabetic patients. The present article will provide a systematic analysis of the pathophysiological links among hypertension, insulin resistance, and metabolic syndrome. We will also summarize the available clinical evidence regarding the metabolic effects of beta-blockers in hypertensive patients, with an emphasis on nebivolol. Nebivolol exerts neutral or beneficial effects on insulin sensitivity and lipid metabolism in hypertensive patients, owing to its nitric oxide-mediated vasodilatory and antioxidative properties. Thus, nebivolol could be a favorable therapeutic option for the treatment of hypertension in patients with impaired glucose and lipid metabolism.

Keywords

Hypertension Insulin sensitivity Lipid metabolism Nebivolol Obesity 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Rizos CV, Elisaf MS. Antihypertensive drugs and glucose metabolism. World J Cardiol. 2014;6:517–30.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Mulè G, Calcaterra I, Nardi E, Cerasola G, Cottone S. Metabolic syndrome in hypertensive patients: an unholy alliance. World J Cardiol. 2014;6:890–907.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Münzel T, Gori T. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol. 2009;54:1491–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Pauwels PJ, Gommeren W, Van Lommen G, Janssen PA, Leysen JE. The receptor binding profile of the new antihypertensive agent nebivolol and its stereoisomers compared with various beta-adrenergic blockers. Mol Pharmacol. 1988;34:843–51.PubMedGoogle Scholar
  5. 5.
    Fogari R, Zoppi A, Lazzari P, Mugellini A, Lusardi P, Preti P, et al. Comparative effects of nebivolol and atenolol on blood pressure and insulin sensitivity in hypertensive subjects with type II diabetes. J Hum Hypertens. 1997;11:753–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Pesant Y, Marc-Aurele J, Bielmann P, Alaupovic P, Cartier P, Bichet D, et al. Metabolic and antihypertensive effects of nebivolol and atenolol in normometabolic patients with mild-to-moderate hypertension. Am J Ther. 1999;6:137–47.CrossRefPubMedGoogle Scholar
  7. 7.
    Poirier L, Cléroux J, Nadeau A, Lacourcière Y. Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. J Hypertens. 2001;19:1429–35.CrossRefPubMedGoogle Scholar
  8. 8.
    Rizos E, Bairaktari E, Kostoula A, Hasiotis G, Achimastos A, Ganotakis E, et al. The combination of nebivolol plus pravastatin is associated with a more beneficial metabolic profile compared to that of atenolol plus pravastatin in hypertensive patients with dyslipidemia: a pilot study. J Cardiovasc Pharmacol Ther. 2003;8:127–34.CrossRefPubMedGoogle Scholar
  9. 9.
    •• Celik T, Iyisoy A, Kursaklioglu H, Kardesoglu E, Kilic S, Turhan H, et al. Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patients. J Hypertens. 2006;24:591–6. A prospective, blinded, randomized study highlighting that nebivolol, in contrast to metoprolol, improved oxidative stress, insulin sensitivity, decreased plasma soluble P-selectin and increased adiponectin levels in hypertensive patients.CrossRefPubMedGoogle Scholar
  10. 10.
    Peter P, Martin U, Sharma A, Dunne F. Effect of treatment with nebivolol on parameters of oxidative stress in type 2 diabetics with mild to moderate hypertension. J Clin Pharm Ther. 2006;31:153–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Schulman IH, Zhou MS. Vascular insulin resistance: a potential link between cardiovascular and metabolic diseases. Curr Hypertens Rep. 2009;11:48–55.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhou MS, Schulman IH, Raij L. Vascular inflammation, insulin resistance, and endothelial dysfunction in salt-sensitive hypertension: role of nuclear factor kappa B activation. J Hypertens. 2010;28:527–35.CrossRefPubMedGoogle Scholar
  13. 13.
    Wu G, Meininger CJ. Nitric oxide and vascular insulin resistance. Biofactors. 2009;35:21–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Steinberg HO, Baron AD. Vascular function, insulin resistance and fatty acids. Diabetologia. 2002;45:623–34.CrossRefPubMedGoogle Scholar
  15. 15.
    Carlsson PO, Berne C, Jansson L. Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats. Diabetologia. 1998;41:127–33.CrossRefPubMedGoogle Scholar
  16. 16.
    Jacob S, Henriksen EJ. Metabolic properties of vasodilating beta blockers: management considerations for hypertensive diabetic patients and patients with the metabolic syndrome. J Clin Hypertens (Greenwich). 2004;6:690–6. quiz 697.CrossRefGoogle Scholar
  17. 17.
    Modan M, Halkin H, Almog S, Lusky A, Eshkol A, Shefi M, et al. Hyperinsulinemia. A link between hypertension obesity and glucose intolerance. J Clin Invest. 1985;75:809–17.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Salvetti A, Brogi G, Di Legge V, Bernini GP. The inter-relationship between insulin resistance and hypertension. Drugs. 1993;46 Suppl 2:149–59.CrossRefPubMedGoogle Scholar
  19. 19.
    Cheung BMY, Li C. Diabetes and hypertension: is there a common metabolic pathway? Curr Atheroscler Rep. 2012;14:160–6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    NCEP. National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation. 2002;106:3143–421.Google Scholar
  21. 21.
    Mulè G, Cerasola G. The metabolic syndrome and its relationship to hypertensive target organ damage. J Clin Hypertens (Greenwich). 2006;8:195–201.CrossRefGoogle Scholar
  22. 22.
    Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care. 2005;28:1769–78.CrossRefPubMedGoogle Scholar
  23. 23.
    Mancia G, Bombelli M, Corrao G, et al. Metabolic syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study: daily life blood pressure, cardiac damage, and prognosis. Hypertension. 2007;49:40–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Schillaci G, Pirro M, Vaudo G, et al. Prognostic value of the metabolic syndrome in essential hypertension. J Am Coll Cardiol. 2004;43:1817–22.CrossRefPubMedGoogle Scholar
  25. 25.
    Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol. 2010;56:1113–32.CrossRefPubMedGoogle Scholar
  26. 26.
    Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709–16.CrossRefPubMedGoogle Scholar
  27. 27.
    Katagiri H, Yamada T, Oka Y. Adiposity and cardiovascular disorders: disturbance of the regulatory system consisting of humoral and neuronal signals. Circ Res. 2007;101:27–39.CrossRefPubMedGoogle Scholar
  28. 28.
    Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest. 1991;87:2246–52.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Redon J, Cifkova R, Laurent S, Nilsson P, Narkiewicz K, Erdine S, et al. The metabolic syndrome in hypertension: European Society of Hypertension position statement. J Hypertens. 2008;26:1891–900.CrossRefPubMedGoogle Scholar
  30. 30.
    Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:201–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil–Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290:2805–16.CrossRefPubMedGoogle Scholar
  32. 32.
    Navare HA, Frye RF, Cooper-Dehoff RM, Shuster JJ, Hall K, Schmidt SO, et al. Atenolol exposure and risk for development of adverse metabolic effects: a pilot study. Pharmacotherapy. 2010;30:872–8.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sarafidis PA, Bakris GL. Antihypertensive treatment with beta-blockers and the spectrum of glycaemic control. QJM. 2006;99:431–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Sharma AM, Pischon T, Hardt S, Kunz I, Luft FC. Beta-adrenergic receptor blockers and weight gain: a systematic analysis. Hypertension. 2001;37:250–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA. 2004;292:2227–36.CrossRefPubMedGoogle Scholar
  36. 36.
    Weiss R. Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation. Vasc Health Risk Manag. 2006;2:303–8.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Giugliano D, Acampora R, Marfella R, De Rosa N, Ziccardi P, Ragone R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med. 1997;126:955–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Jacob S, Rett K, Wicklmayr M, et al. Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. J Hypertens. 1996;14:489–94.CrossRefPubMedGoogle Scholar
  39. 39.
    Owada A, Suda S, Hata T, Miyake S. The effects of bisoprolol, a selective beta1-blocker, on glucose metabolism by long-term administration in essential hypertension. Clin Exp Hypertens. 2001;23:305–16.CrossRefPubMedGoogle Scholar
  40. 40.
    Kotsis V, Stabouli S, Papakatsika S, Rizos Z, Parati G. Mechanisms of obesity-induced hypertension. Hypertens Res. 2010;33:386–93.CrossRefPubMedGoogle Scholar
  41. 41.
    Sharma AM, Pischon T, Engeli S, Scholze J. Choice of drug treatment for obesity-related hypertension: where is the evidence? J Hypertens. 2001;19:667–74.CrossRefPubMedGoogle Scholar
  42. 42.
    Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord. 1998;22:39–47.CrossRefPubMedGoogle Scholar
  43. 43.
    Blair D, Habicht JP, Sims EA, Sylwester D, Abraham S. Evidence for an increased risk for hypertension with centrally located body fat and the effect of race and sex on this risk. Am J Epidemiol. 1984;119:526–40.CrossRefPubMedGoogle Scholar
  44. 44.
    Sironi AM, Gastaldelli A, Mari A, Ciociaro D, Positano V, Buzzigoli E, et al. Visceral fat in hypertension: influence on insulin resistance and beta-cell function. Hypertension. 2004;44:127–33.CrossRefPubMedGoogle Scholar
  45. 45.
    Higgins M, Kannel W, Garrison R, Pinsky J, Stokes J. Hazards of obesity—the Framingham experience. Acta Med Scand Suppl. 1998;723:23–36.Google Scholar
  46. 46.
    Leren P. Effects of antihypertensive drugs on lipid metabolism. Clin Ther. 1987;9:326–32.PubMedGoogle Scholar
  47. 47.
    Conway J, Lauwers P. Hemodynamic and hypotensive effects of long-term therapy with chlorothiazide. Circulation. 1960;21:21–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Ferrari P, Rosman J, Weidmann P. Antihypertensive agents, serum lipoproteins and glucose metabolism. Am J Cardiol. 1991;67:26B–35.CrossRefPubMedGoogle Scholar
  49. 49.
    Weidmann P, Ferrier C, Saxenhofer H, Uehlinger DE, Trost BN. Serum lipoproteins during treatment with antihypertensive drugs. Drugs. 1998;35 Suppl 6:118–34.Google Scholar
  50. 50.
    Manrique C, Whaley-Connell A, Sowers JR. Nebivolol in obese and non-obese hypertensive patients. J Clin Hypertens (Greenwich). 2009;11:309–15.CrossRefGoogle Scholar
  51. 51.
    Messerli FH, Bell DS, Fonseca V, Katholi RE, McGill JB, Phillips RA, et al. GEMINI Investigators. Body weight changes with beta-blocker use: results from GEMINI. Am J Med. 2007;120:610–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Bell DS, Bakris GL, McGill JB. Comparison of carvedilol and metoprolol on serum lipid concentration in diabetic hypertensive patients. Diabetes Obes Metab. 2009;11:234–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Hauf-Zachariou U, Widmann L, Zülsdorf B, Hennig M, Lang PD. A double-blind comparison of the effects of carvedilol and captopril on serum lipid concentrations in patients with mild to moderate essential hypertension and dyslipidaemia. Eur J Clin Pharmacol. 1993;45:95–100.CrossRefPubMedGoogle Scholar
  54. 54.
    Agabiti Rosei E, Rizzoni D. Metabolic profile of nebivolol, a beta-adrenoceptor antagonist with unique characteristics. Drugs. 2007;67:1097–107.CrossRefPubMedGoogle Scholar
  55. 55.
    Stoschitzky K, Stoschitzky G, Brussee H, Bonelli C, Dobnig H. Comparing beta-blocking effects of bisoprolol, carvedilol and nebivolol. Cardiology. 2006;106:199–206.CrossRefPubMedGoogle Scholar
  56. 56.
    • Marazzi G, Volterrani M, Caminiti G, Iaia L, Cacciotti L, Massaro R, et al. Effectiveness of nebivolol and hydrochlorothiazide association on blood pressure, glucose, and lipid metabolism in hypertensive patients. Adv Ther. 2010;27:655–64. This study indicates that the addition of hydrochlorothiazide on nebivolol treatment optimizes blood pressure control in a high number of patients resistant to monotherapy without a negative impact on patients’ glucose and lipid profile.CrossRefPubMedGoogle Scholar
  57. 57.
    Huang PL. eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol Metab. 2009;20:295–302.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Kim J, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113:1888–904.CrossRefPubMedGoogle Scholar
  59. 59.
    Dessy C, Saliez J, Ghisdal P, Daneau G, Lobysheva II, Frérart F, et al. Endothelial beta 3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol. Circulation. 2005;112:1198–205.CrossRefPubMedGoogle Scholar
  60. 60.
    Kiso T, Namikawa T, Tokunaga T, Sawada K, Kakita T, Shogaki T, et al. Anti-obesity and anti-diabetic activities of a new beta3 adrenergic receptor agonist, (S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino]ethyl]-1-propenyl] phenoxy] acetic acid ethanedioic acid (SWR-0342SA), in KK-Ay mice. Biol Pharm Bull. 1999;22:1073–8.CrossRefPubMedGoogle Scholar
  61. 61.
    de Souza CJ, Burkey BF. Beta 3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans. Curr Pharm Des. 2001;7:1433–49.CrossRefPubMedGoogle Scholar
  62. 62.
    Merchant N, Rahman ST, Ferdinand KC, Haque T, Umpierrez GE, Khan BV. Effects of nebivolol in obese African Americans with hypertension (NOAAH): markers of inflammation and obesity in response to exercise-induced stress. J Hum Hypertens. 2011;25:196–202.CrossRefPubMedGoogle Scholar
  63. 63.
    Schmidt AC, Graf C, Brixius K, Scholze J. Blood pressure-lowering effect of nebivolol in hypertensive patients with type 2 diabetes mellitus: the YESTONO study. Clin Drug Investig. 2007;27:841–9.CrossRefPubMedGoogle Scholar
  64. 64.
    • Van Bortel LM. Efficacy, tolerability and safety of nebivolol in patients with hypertension and diabetes: a post-marketing surveillance study. Eur Rev Med Pharmacol Sci. 2010;14:749–58. A surveillance study showing that nebivolol treatment is associated with a significantly reduced BP, improved blood glucose and LDL cholesterol levels and is well tolerated in hypertensive patients with concomitant diabetes.PubMedGoogle Scholar
  65. 65.
    Kaiser T, Heise T, Nosek L, Eckers U, Sawicki PT. Influence of nebivolol and enalapril on metabolic parameters and arterial stiffness in hypertensive type 2 diabetic patients. J Hypertens. 2006;24:1397–403.CrossRefPubMedGoogle Scholar
  66. 66.
    Malacco E. Nebivolol/hydrochlorothiazide (HCTZ) combination in patients with essential hypertension: a pooled analysis from five non-interventional studies with a focus on diabetic and elderly patients. Eur Rev Med Pharmacol Sci. 2010;14:427–34.PubMedGoogle Scholar
  67. 67.
    • Deedwania P, Shea J, Chen W, Brener L. Effects of add-on nebivolol on blood pressure and glucose parameters in hypertensive patients with prediabetes. J Clin Hypertens (Greenwich). 2013;15:270–8. A multicenter trial showing that nebivolol, added to an ACE inhibitor or ARB, provides additional blood pressure reduction with little or no effect on glucose metabolism in hypertensive patients with prediabetes.CrossRefGoogle Scholar
  68. 68.
    •• Ozyıldız AG, Eroglu S, Bal U, Atar I, Okyay K, Muderrisoglu H. Effects of carvedilol compared to nebivolol on insulin resistance and lipid profile in patients with essential hypertension. J Cardiovasc Pharmacol Ther. 2016. A prospective, randomized study indicating the favourable effects of new generation b-blockers on glucose, insulin, insulin resistance, and the lipid profile.Google Scholar
  69. 69.
    •• Ayers K, Byrne LM, DeMatteo A, Brown NJ. Differential effects of nebivolol and metoprolol on insulin sensitivity and plasminogen activator inhibitor in the metabolic syndrome. Hypertension. 2012;59:893–8. A comparative study indicating that treatment with metoprolol decreased insulin sensitivity and increased oxidative stress and the antifibrinolytic plasminogen activator inhibitor 1 in patients with metabolic syndrome, whereas nebivolol lacked detrimental metabolic effects.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    ••Ladage D, Reidenbach C, Rieckeheer E, Graf C, Schwinger RH, Brixius K. Nebivolol lowers blood pressure and increases weight loss in patients with hypertension and diabetes in regard to age. J Cardiovasc Pharmacol. 2010;56:275–81. A large study in five thousand thirty-one male and female patients indicating that nebivolol is effective in treating patients with diabetes suffering from high blood pressure and metabolic syndrome.CrossRefPubMedGoogle Scholar
  71. 71.
    Lacourcière Y, Poirier L, Lefebvre J, Provencher P, Arnott W. Comparative effects of a new cardioselective beta-blocker nebivolol and nifedipine sustained-release on 24-hour ambulatory blood pressure and plasma lipoproteins. J Clin Pharmacol. 1992;32:660–6.CrossRefPubMedGoogle Scholar
  72. 72.
    Predel HG, Mainka W, Schillings W, Knigge H, Montiel J, Fallois J, et al. Integrated effects of the vasodilating beta-blocker nebivolol on exercise performance, energy metabolism, cardiovascular and neurohormonal parameters in physically active patients with arterial hypertension. J Hum Hypertens. 2001;15:715–21.CrossRefPubMedGoogle Scholar
  73. 73.
    Veverka A, Salinas JL. Nebivolol in the treatment of chronic heart failure. Vasc Health Risk Manag. 2007;3:647–54.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Kamp O, Sieswerda GT, Visser CA. Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension. Am J Cardiol. 2003;92:344–8.CrossRefPubMedGoogle Scholar
  75. 75.
    Agabiti-Rosei E, Porteri E, Rizzoni D. Arterial stiffness, hypertension, and rational use of nebivolol. Vasc Health Risk Manag. 2009;5:353–60.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Rubattu S, Pagliaro B, Pierelli G, et al. Pathogenesis of target organ damage in hypertension: role of mitochondrial oxidative stress. Int J Mol Sci. 2014;16:823–39.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Scherrer U, Randin D, Tappy L, Vollenweider P, Jéquier E, Nicod P. Body fat and sympathetic nerve activity in healthy subjects. Circulation. 1994;89:2634–40.CrossRefPubMedGoogle Scholar
  78. 78.
    Mustone Alexander L. Desirable therapeutic characteristics of an optimal antihypertensive agent. Drugs. 2006;66:1239–52.CrossRefPubMedGoogle Scholar
  79. 79.
    Ladage D, Reidenbach C, Lichtenthal A, Schwinger R, Brixius K. Third generation betablockers: current state of research on vasodilating beta-blockers. Wien Med Wochenschr. 2009;159:211–8.CrossRefPubMedGoogle Scholar
  80. 80.
    Vinker S, Alkalay A, Hoffman RD, Elhayany A, Kaiserman I, Kitai E. Long-term adherence to antihypertensive therapy: a survey in four primary care clinics. Expert Opin Pharmacother. 2008;9:1271–7.CrossRefPubMedGoogle Scholar
  81. 81.
    Weiss RJ, Saunders E, Greathouse M. Efficacy and tolerability of nebivolol in stage I-II hypertension: a pooled analysis of data from three randomized, placebo-controlled monotherapy trials. Clin Ther. 2011;33:1150–61.CrossRefPubMedGoogle Scholar
  82. 82.
    • Bhosale VV, Inamdar SC, Karande VB, Burute SR, Murthy MB, Ghatak A. Beneficial effects of nebivolol in comparison with atenolol on safety and tolerability in essential hypertension. J Clin Diagn Res. 2014;8:HC01–4. A prospective, double blind, comparative controlled clinical study highlighting the superior efficacy and safety of nebivolol compared to atenolol.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens (Greenwich). 2007;9:866–75.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Maria Marketou
    • 1
  • Yashaswi Gupta
    • 2
  • Shashank Jain
    • 2
  • Panos Vardas
    • 1
  1. 1.Cardiology DepartmentHeraklion University HospitalHeraklionGreece
  2. 2.SPRIM Asia-Pacific Pvt. Ltd.SingaporeSingapore

Personalised recommendations