The Road Ahead With β-Blockers: Expanding Treatment Options in Cardiovascular Disease

AJH 2005; 18:163S-164S INTRODUCTION The Road Ahead With ␤-Blockers: Expanding Treatment Options in Cardiovascular Disease Norman K. Hollenberg he ␤-adrenoreceptor blocking agents (␤-blockers) are among the oldest and most useful therapies for treatment of hypertension and other cardiovascular diseases (CVD). ␤-Blockers have been approved for use in a wider range of indications than any other class of antihypertensive drugs.1,2 Unfortunately, ␤-blockers are widely underused, often in patients who might greatly benefit from them, such as in patients after a myocardial infarction, patients with diabetes, and patients with chronic heart failure.3–5 Concerns regarding potential side effects with these agents appear to be important factors behind their underutilization.3– 6 The ␤-blockers differ pharmacologically in several ways, including the degree of ␤1 selectivity, intrinsic sympathomimetic activity, and vasodilatory properties.7 The clinical implications of these differences are slowly emerging. For example, although some data suggest that ␤-blockers increase insulin resistance and raise the risk of diabetes,8 newer agents with vasodilatory properties may actually improve insulin sensitivity.9 This supplement is a written summary of the presentations given at the 20th Annual Scientific Meeting and Exposition of the American Society of Hypertension held in May 2005. The purpose of this supplement is to update physicians on the full range of therapeutic possibilities with ␤-blockers in the treatment of hypertension and CVD, and thus to help improve use of these important agents. Clarification of the emerging pharmacologic and clinical differences among the various ␤-blockers may help dispel some misperceptions regarding the risks and benefits of these agents. In the first article, I review the background and history of the development of ␤-blockers into a cornerstone therapy for CVD and discuss the problem of their underuse.2 I also briefly review the evolution of ␤-blockers into subtypes with clinically meaningful pharmacologic distinctions and the potential implications of these differences for optimal selection and improved use of these agents. From this perspective, the development of nebivolol, a ␤-blocker that stimulates nitric oxide (NO) production, is T noted as an important advance and potential expansion of the therapeutic usefulness of ␤-blockade in the management of CVD. In the second article, Michael A. Weber delves further into the pharmacologic differences between ␤-blockers and their potential implications for clinical selection and utilization.10 As an example, Dr. Weber reviews the results of the Glycemic Effects in Diabetes Mellitus: Carvedilol–Metoprolol Comparison in Hypertensives (GEMINI) study, in which the vasodilating ␤-blocker carvedilol had a more beneficial effect on glycemic control and insulin resistance than did the older, immediate-release ␤-blocker metoprolol tartrate.11 In addition, Dr. Weber examines the pharmacologic profile of the novel ␤-blocker nebivolol, which includes an unusual combination of high ␤1 selectivity and vasodilation through the L-arginine/NO pathway. Dr. Weber also reviews the available clinical data on the antihypertensive efficacy and safety of this agent, including placebo-controlled trials and head-to-head comparison studies with other antihypertensive agents, as well as the benefits of nebivolol in elderly patients with chronic heart failure, as shown in the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS). In the third article, John R. Cockcroft explores the broad clinical implications of stimulation of endotheliumderived NO.12 Dr. Cockcroft reviews the background of the discovery and understanding of the important physiologic role of endothelium-derived NO in arterial function and how endothelial dysfunction contributes significantly to the pathogenesis of hypertension and CVD. Dr. Cockcroft discusses studies that show the importance of endothelium-derived NO in the progression of arterial stiffness, a key stage in the progression of atherosclerosis, as reflected in increased pulse wave velocity (PWV). In addition, Dr. Cockcroft reviews forearm blood flow studies showing that nebivolol increases production of endothelium-derived NO, thus stimulating vasodilation and decreasing PWV. Thus, these articles should provide a much-needed clarification and update of the full clinical potential of the Received September 19, 2005. First decision September 21, 2005. Accepted September 21, 2005. From the Departments of Medicine and Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Address correspondence and reprint requests to Dr. Norman K. Hollenberg, Physiologic Research Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115; e-mail: djpagecapo@rics. bwh.harvard.edu © 2005 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc. 0895-7061/05/$30.00 doi:10.1016/j.amjhyper.2005.09.011 164S ␤-BLOCKERS IN CVD ␤-blocker class. The review of the pharmacologic mechanisms and clinical effects of nebivolol should serve to highlight some of the most recent and intriguing developments in this fascinating and venerable class of agents, particularly involving endothelium-dependent vasodilation. We hope the discussions presented here will help to inform and facilitate improved use of ␤-blockade. References 1. 2. 3. 4. 5. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, and the National High Blood Pressure Education Program Coordinating Committee: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560 – 2572. Hollenberg N: The role of ␤-blockers as a cornerstone of cardiovascular therapy. Am J Hypertens 2005;18(Suppl):165S–168S. Phillips SM, Marton RL, Tofler GH: Barriers to diagnosing and managing heart failure in primary care. Med J Aust 2004;181: 78 – 81. Everly MJ, Heaton PC, Cluxton RJ Jr: ␤-blocker underuse in secondary prevention of myocardial infarction. Ann Pharmacother 2004; 38:286 –293. Komajda M, Follath F, Swedberg K, Cleland J, Aguilar JC, CohenSolel A, Dietz R, Gavazzi A, Van Gilst WH, Hobbs R, Korewicki J, Madeira HC, Moiseyev VS, Preda I, Widimsky J, Freemantle N, AJH–December 2005–VOL. 18, NO. 12, Part 2 Eastaugh J, Mason J, for the Study Group on Diagnosis of the Working Group on Heart Failure of the European Society of Cardiology: 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 2003;24:464 – 474. 6. Ubel PA, Jepson C, Asch DA: Misperceptions about ␤-blockers and diuretics: a national survey of primary care physicians. J Gen Intern Med 2003;18:977–983. 7. López-Sen (...truncated)