Beta-blockers for Atherosclerosis Prevention: a Missed Opportunity?

Current guidelines for the management of arterial hypertension endorse β-adrenergic receptor blocking agents (beta-blockers, BBs) as being particularly useful for hypertension in specific situations such as symptomatic angina, tachycardia, post-myocardial infarction, heart failure with reduced ejection fraction (HFrEF), and as an alternative to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in hypertensive women planning pregnancy or at least of child-bearing potential. One of the most common uses of BBs is in patients with a recent myocardial infarction, with or without hypertension. Although this one use is specifically in a setting of atherosclerotic cardiovascular disease (ASCVD), it is not primarily for atheroprevention, but rather for cases with impaired systolic function, and it is intended primarily to lessen adverse cardiac remodeling and worsening of congestive heart failure (CHF). The BB class consists of numerous agents which differ widely in pharmacologic properties and physiologic effects. These differences include selectivity for β-adrenergic receptors and their subtypes, hydro- or lipophilicity, effects on blood pressure and heart rate, influence on lipoprotein and glucose metabolism, and direct impact on the artery wall, including platelet reactivity, endothelial function, infiltration of inflammatory cells and on inflammation per se, and on smooth muscle cell proliferation. Importantly, BBs are not commonly used for prevention of atherosclerosis or ASCVD per se. Many studies of early-generation BBs showed adverse effects on lipoprotein levels and metabolism of glucose and insulin and thus discouraged their use in atheroprevention. Nevertheless, newer BBs often have neutral or favorable metabolic effects on these important factors in ASCVD pathophysiology, and recent scientific studies now document direct beneficial effects of BBs on the artery wall. This document reviews both types of newer data, not only to encourage consideration of BB treatment to reduce ASCVD in the present, but also to call for future research to better explore the clinical settings in which BBs may be proven to have additional benefit in preventing ASCVD when added to the better-established treatments for dyslipidemia and diabetes.

Relatively recent publications have clarified the diversity among BBs regarding adverse, neutral, or favorable effects on lipoproteins (especially triglycerides (TG) and low-density lipoprotein (LDL)) and on glucose/insulin metabolism. Specifically, the newer BBs (metoprolol ER, carvedilol ER, bisoprolol, and nebivolol) are now documented to be metabolically beneficial. These new data are complex but instructive regarding potential mechanisms of the diverse effects of various BBs on metabolism. Further and more importantly, these new data refute the traditional, but now outmoded, concept that BBs are universally harmful metabolically and therefore must be used sparingly, if at all, for atheroprevention. Recent studies have also reported exciting new data regarding how certain BBs can reduce platelet adhesion and improve the function of the major cell types in the artery wall, including the endothelium, macrophages, and smooth muscle cells. Specifically, BBs can improve endothelial function by enhancing arterial vasodilation and by reducing monocyte adhesion and transmigration. Further, BBs can decrease numbers and activity of inflammatory cells, including decreasing proliferation of smooth muscle cells and their transformation into inflammatory cells. These data help with the crucial step of distinguishing among available BBs regarding their likely overall arterial effects, whether to accelerate or prevent the development of atherosclerosis. In this regard, there is even some limited published information beyond these intermediary steps, going directly to the clinically more important endpoints of atherosclerosis and ASCVD events. The negative metabolic effects observed with the use of traditional/earlier generations of BBs have discouraged use of any BBs to prevent ASCVD. These adverse effects are not seen, however, with newer BBs. Thus, BBs continue to be a useful component of combination regimens not only in the treatment of arterial hypertension, heart failure, and arrhythmia, but also potentially in the prevention of atherosclerosis and ASCVD. Despite this exciting potential, further research is greatly needed to better establish the possible benefits of the most promising BBs as they might work in combination with other better-established atheropreventive agents. Specifically, there is a need for randomized, prospective, cardiovascular outcome trials (CVOTs) in high-risk patients, adding a BB to background LDL-lowering (statins, etc.), TG-lowering (specifically icosapent ethyl, which reduces ASCVD in patients with high TG, although apparently not via TG-lowering), and/or anti-diabetic (sodium glucose transport-2 inhibitors, SGLT2i, and glucagon-like protein-1 receptor agonists, GLP1-RA) treatments, as indicated in a given subject population.