Role of Bempedoic Acid in Clinical Practice

Christie M Ballantyne,Joseph J Saseen,Anne Goldberg,Alberico L Catapano,Kausik K Ray,Harold Bays

doi:10.1007/s10557-021-07147-5

Abstract

Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.

Highlights

Lowering of low-density lipoprotein cholesterol (LDL-C) with statins reduces atherosclerotic cardiovascular disease (ASCVD) risk and associated mortality proportional to the absolute decrease in LDL-C [1]
Among patients in the ASCVD and/or HeFH on statins pool, 51% of whom were taking high-intensity statins; muscle spasms, pain in the extremity, myalgia, and muscle weakness were reported at the same incidence rate in patients treated with bempedoic acid or placebo [33, 34]
Bempedoic acid reduces LDL-C when combined with a statin

Summary

Introduction

Lowering of low-density lipoprotein cholesterol (LDL-C) with statins reduces atherosclerotic cardiovascular disease (ASCVD) risk and associated mortality proportional to the absolute decrease in LDL-C [1]. Some patients may benefit from additional LDL-C-lowering therapies, such as ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, when LDL-C is ≥70 or ≥ 100 mg/dL, despite treatment with maximally tolerated statin [4, 5]. Use of additional and effective add-on treatments in patients for whom statins alone do not sufficiently lower LDL-C levels, or alternative treatments for patients who cannot take statins, may help to reduce the risk of ASCVD. A recent cross-sectional study of almost 6000 patients in 18 countries in the European Union found that combination of a statin with another lipid-lowering agent was low, including those patients who are at high and very high risk for ASCVD [6]. Add-on or alternative treatments to statins include primarily ezetimibe, PCSK9 inhibitors, and/or bile acid sequestrants, mainly because they have been proven to reduce LDL-C levels and cardiovascular events in randomized, placebo-controlled trials [7–9]. Access to PCSK9 inhibitors is often challenging because of the requirement of prior insurance authorization, cost, and patients having LDL-C levels below the payer-specific threshold for monoclonal antibodies [10, 11]

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