β‐Blockers in Hypertension: Truths and Half‐Truths

The use of β-blockers as first-step therapy in the treatment of hypertension has been a recent topic of debate because the cardiovascular protective effects of β-blockers in patients with uncomplicated hypertension has been questioned.1–5 The potential benefits of the use of β-blockers as the cornerstone of treatment in patients with congestive heart failure, post-myocardial infarction, and hypertrophic cardiomyopathy are recognized and well documented.1,6β-Blockers have, however, been found to be less effective in reducing the incidence of stroke4,7 and composite outcomes including myocardial infarction and death3,7 compared with some other antihypertensive agents. As a result of this analysis, the risk-benefit ratio for β-blockers has been proposed as unacceptable in uncomplicated hypertension.1 Results from large clinical trials that compared the efficacy of antihypertensive agents, diuretics, angiotensin-converting enzyme (ACE) inhibitors, adrenergic receptor blockers (ARBs), and various β-blockers have added to the current debate concerning β-blockers.8 The intrinsic differences in the patient demographics of each trial, the length of follow-up, the combination of therapies, study end points, and other factors, however, differ enough to affect the magnitude of the true effect. In addition, one may argue that drawing conclusions about a drug class from studies that use different β-blockers is problematic. Not all β-blockers are alike, and, consequently, there are some truths and half-truths regarding the benefits of β-blocker use. The mechanisms of action and pathophysiologic effects are markedly different among the subclasses of nonselective, selective, and broad-spectrum adrenergic β-blockers. These differences deserve careful attention and clear differentiation before any broad conclusions about the use of β-blockers are made.9–11 The first β-blockers (eg, propranolol) were non-specific and blocked both β1- and β2-adrenergic receptors. Metoprolol and atenolol belong to the group of other β-blockers that are specific to β1-blockade. Other β-blockers include the β1-selectives nebivolol and celiprolol; the nonselective β-blocker dilevalol; and carvedilol, which has a nonselective β-blocking effect on both β1- and β2-adrenergic receptors, as well as an α1-blocking vasodilatory effect. In general, β-blockers may be better or worse than another class of drugs for specific cardiovascular end points, but given their variable pharmacologic effects, attributes of one β-blocker may not hold for others. Much of the risk or concern surrounding β-blockers is based primarily on the pool of data with atenolol. Overall, cardiovascular events were more common with atenolol compared with initial therapy with the calcium channel blocker amlodipine in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), although congestive heart disease events did not differ. In the Losartan Intervention for Endpoint Reduction (LIFE) trials in patients with left ventricular hypertrophy (LVH), stroke was more common in the β-blocker arm than in an ARB-based comparative group.12,13 It is important to note that in these studies, other drugs were added to treatment to reach blood pressure targets, and thus it is difficult to tease out the independent effects of β-blockers on outcomes. It is also important to note that LVH is an independent and significant risk factor for congestive heart failure, coronary artery disease, stroke, arrhythmia, and sudden death.14–16 Although ACE inhibitors or ARBs in combination with diuretics are often used as first-step treatment of hypertension in patients with LVH17–19 and have been shown to regress LVH, carvedilol, for example, has also been shown to prevent and reverse hypertrophy-induced cardiac dysfunction and reduce left ventricular mass.20–22 Whether age affects the effectiveness of β-blockers has produced some half truths. Whereas trials such as the Medical Research Council (MRC), International Prospective Primary Prevention Study in Hypertension (IPSH), and Captopril Prevention Project (CAP) actually reported the benefit of β-blockers in the composite outcome of stroke, death, or myocardial infarction in patients younger than 60 years, the benefits were uncertain in elderly populations without comorbidities.3,23–28 These studies were not performed in patients with heart failure. The β-blockers nebivolol as well as carvedilol have, however, been shown to be well tolerated and efficacious in reducing cardiovascular events in elderly patients with heart failure.29 It is misleading to generalize the vascular effects of β-blockers and emphasize that the class in general has no effect on resistance vessels and endothelial function compared with other antihypertensive agents that substantially improve stroke and myocardial infarction risk. A growing body of evidence indicates that the vasodilating adrenergic blocker carvedilol, the β1-selective β-blockers nebivolol and celiprolol, and the nonselective β-blocker dilevalol also have potent endothelial effects.10,30–32 Vasodilatory action leads to better cardiovascular outcomes, as shown in the Carvedilol or Metoprolol European Trial (COMET). There were improved rates of survival and cardiovascular hospitalizations with carvedilol compared with metoprolol.33 In addition, vasodilatory β-blockers have been shown to increase renal blood flow and decrease renal vascular resistance.9,30 Nebivolol and carvedilol have been shown to exhibit endothelium-dependent vasodilating properties specifically related to renal glomerular microcirculation.34 These findings provide insight into the mechanism of action of these drugs, which may be relevant to microcirculation in other vascular beds. The vasodilatory adrenergic blockers have also been shown to be more effective in lowering central aortic pressure and reducing peripheral vascular resistance while maintaining or improving cardiac output, stroke volume, and left ventricular function.9,10 At present, however, there are no long-term outcome data with these agents in hypertensive patients. A half-truth regarding β-blocker use is its potential diabetogenic effect on glucose metabolism. It is true that β-blockers in general increase peripheral vascular resistance leading to reduced glucose disposal to skeletal muscles and, subsequently, to reduced glucose uptake.35 Studies that include different classes of β-blockers disparage the use of these drugs in patients with diabetes and suggest a possible increased risk of diabetes and morbidity related to the effect of β-blockers on weight gain and insulin resistance.1,36–38 Once again, these findings are based on the use of nonselective or selective β-blockers.36–38 However, in the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes, the use of a β-blocker/atenolol-based regimen was found to reduce the cardiovascular end point to the same degree as an ACE inhibitor-based treatment program, if blood pressure was reduced. Although many β-blockers increase insulin resistance, the effects of β-blockers on glucose metabolism are not homogeneous. Many β-blockers reduce peripheral blood flow in muscles and thus reduce glucose availability.39β-blockers with vasodilating properties, in contrast, produce peripheral vasodilation by a1 blockade and thereby increase glucose uptake in muscle cells.40–42 Although diabetic patients benefit from treatment with carvedilol43 and the nonvasodilating β-blocker metoprolol,44 the GEMINI study showed a metabolic advantage for carvedilol.43 This medication stabilized hemoglobin A1c and improved insulin resistance while conferring blood pressure control comparable to metoprolol.43 Less diabetogenic potential of carvedilol in patients with heart failure was also demonstrated in COMET, when compared with metoprolol.45 The mechanisms explaining the advantages and disadvantages of the different β-blockers are not fully understood; the extent to which changes in blood flow can affect metabolic control warrants further investigation. β-Blockers, in general, are associated with weight gain, which in turn reduces insulin sensitivity. This may be a consequence of the reduced total energy expenditure observed with β-blocker use.38 GEMINI and other studies, however, indicate that the vasodilating β-blockers may not cause weight gain, increase insulin sensitivity, improve lipid levels, and increase skeletal muscle microcirculatory blood flow; this characteristic differentiates this group from other β-blockers in the management of hypertension in diabetic patients.9,43,46–48 The new β1-selective blockers celiprolol and nebivolol and the nonselective dilevalol also improve glycemic control and the lipid profile.47 Although numerous randomized clinical trials comparing β-blockers to placebo, ACE inhibitors, ARBs, and diuretics have been conducted and summarized in a recent meta-analysis,8 half-truths still remain about the class of β-blockers. Only head-to-head comparisons between specific β-blockers will help elucidate truths about whether the effectiveness (or lack thereof) of β-blockers seen in large trials is a property of the specific agent used, the dosages employed, the degree of blood pressure lowering, or a class effect of β-blockers. Results from ongoing comparative studies evaluating the effects of the nonselective β-blocker carvedilol with ACE inhibitors and selective β-blockers may provide some answers.49, In conclusion, it is of timely importance that a clear understanding of the truths differentiating the β-blocker class be established and leveraged in any debate concerning the benefits of β-blockers. It is well established that effective blood pressure control prevents stroke and other cardiovascular outcomes. Several medications are often required in patients with hypertension to achieve blood pressure control. Although β-blockers may not be the ideal first-step treatment for some patients with hypertension, second- or third-step treatment with nonselective β-blockers that provide α-blocking properties may increase antihypertensive as well as vasodilatory effects. Whether the beneficial effects of the new generation of β-blockers on intermediary end points will result in less cardiovascular morbidity and mortality remains to be determined by clinical practice and outcome observations.