Role of Bempedoic Acid in Clinical Practice

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.

Keywords: ATP-citrate lyase; Atherosclerotic cardiovascular disease; Bempedoic acid; High-sensitivity C-reactive protein; Hypercholesterolemia; Low-density lipoprotein cholesterol.

Fig. 1

Mechanism of action and physiologic sites of bempedoic acid metabolism, activation, biologic activity, and clearance. Following oral administration, bempedoic acid is converted to its active metabolite bempedoyl-CoA by ASCVL1 in the liver. Bempedoyl-CoA inhibits the cytoplasmic ACL enzyme, which converts citrate to acetyl-CoA in the cholesterol synthesis pathway, leading to upregulation of LDLR. ASCVL1 is not present in the muscle so is not converted to bempedoyl-CoA. Clearance of bempedoic acid and bempedoyl-CoA is primarily enacted by glucuronidation and subsequent renal elimination. Bempedoic acid is a weak inhibitor of OAT2, resulting in minor increases in plasma uric acid and creatinine. ACL ATP-citrate lyase, ASCVL1 very long-chain acyl-CoA syntheasae-1, HMGR 3-hydroxy-3-methylglutarate-CoA reductase, LDL-C low-density lipoprotein cholesterol, LDLR low-density lipoprotein receptor, OAT2 organic anion transporter-2

Fig. 2

Overview of bempedoic acid phase 3 program [–36]. ^aLow-dose statin therapy = average daily dose of rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, or pitavastatin 2 mg. Average daily doses less than these were considered very low-dose statin therapy. ASCVD atherosclerotic cardiovascular disease, DM diabetes mellitus, HeFH heterozygous familial hypercholesterolemia, HTN hypertension

Fig. 3

Effect of bempedoic acid on LDL-C after 12 weeks of treatment [–36]. CI confidence interval, LDL-C low-density lipoprotein cholesterol

Fig. 4

Effect of bempedoic acid on hsCRP after 12 weeks of treatment [–36]. CI confidence interval, hsCRP high-sensitivity C-reactive protein

Fig. 5

Management of patients receiving bempedoic acid therapy