Bempedoic acid, an inhibitor of ATP citrate lyase for the treatment of hypercholesterolemia: early indications and potential

ABSTRACT

Introduction

The lowering of low-density lipoprotein cholesterol (LDL-C), regardless of the method used, results in a reduction of cardiovascular events. Bempedoic acid is a new and until now, the only approved adenosine triphosphate citrate lyase inhibitor that works through the cholesterol-synthesis pathway (similar to statins) that leads to a safe and effective reduction in LDL-C.

Areas covered

We review clinical phase 2 and 3 studies on bempedoic acid’s lipid-lowering effect and approved indications.

Expert opinion

In the United States, bempedoic acid is currently approved for use in secondary prevention. In primary prevention, its approval is limited to individuals with heterozygous familial hypercholesterolemia (FH). However, its tolerability and safety profile may warrant its use in primary prevention besides FH. Even though its efficacy appears weaker than high-intensity statins, it may be a useful adjunct in individuals who achieve less than desirable LDL-C reductions with statins or who cannot tolerate statins, where bempedoic acid alone or in combination with ezetimibe may be useful alternatives.

KEYWORDS:

• ACL inhibitor
• atherosclerosis
• bempedoic acid
• cardiovascular disease
• dyslipidemia
• LDL-Cholesterol

Article highlights

• Bempedoic acid is a first-in-class, orally-administered, lipid-lowering agent that inhibits ACL, a key enzyme of the hepatic cholesterol biosynthesis pathway. As a prodrug, it becomes activated in the hepatocyte, thus avoiding potential muscle adverse effects associated with statins.

• Recently, bempedoic acid and its fixed-dose combination preparation with ezetimibe have been approved by the FDA as an adjunct therapy to reduce LDL-C in patients with ASCVD or familial hypercholesterolemia. The first new oral cholesterol-lowering therapy approved in over a decade.

• In phase 2 and 3 clinical studies, it has been shown that bempedoic acid monotherapy lowers LDL-C by ~20% on top of statins and in combination with ezetimibe by ~40%. Also, it was shown to be well tolerated by patients with and without a history of statin intolerance. Hence, adding bempedoic acid may allow further intensification of existing treatment regimens in high-risk patients, and it may improve LDL-C goal attainment in statin-intolerant patients, who otherwise have limited options.

• If bempedoic acid’s LDL-C lowering effect translates into a significant reduction of events in the currently ongoing cardiovascular outcome trial, bempedoic acid may become an additional treatment option in cardiovascular disease prevention.

Box 1. Drug summary.

Declaration of interest

KK Ray reports personal fees for consultancy from Abbvie, Amgen, Astra Zeneca, Sanofi, Regeneron MSD, Pfizer, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddys, Lilly, Zuellig Pharma, Bayer, Daiichi Sankyo, The Medicines Company; Esperion and research grant support from Pfizer, Amgen, Sanofi, Regeneron and MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.