Emerging lipid lowering agents targeting LDL cholesterol

ABSTRACT

Atherosclerotic cardiovascular disease (ASCVD) is the main cause of morbidity and mortality in the US. ASCVD is caused by elevated levels of ApoB lipoproteins, which over many years penetrate the arterial subendothelial space leading to plaque growth and eventually rupture causing clinical symptoms. ApoB lipoprotein levels are approximated in clinical practice by LDL-C measurement. LDL-C lowering agents (statins, ezetimibe, and PCSK9 inhibitors) reduce cardiovascular risk in primary and secondary prevention proportionally to LDL-C reduction (23% per 1 mmol/L of LDL). However, for a variety of reasons, many patients do not achieve their recommended LDL-C levels using currently available therapies. This has prompted the development of new LDL-C lowering drugs in the hope to reduce cardiovascular risk, such as bempedoic acid, inclisiran, gemcabene, and evinacumab. Drugs targeting other lipids (triglycerides, HDL-C, lipoprotein (a)), intravascular inflammation or acting by other mechanisms also have a role in atherosclerosis prevention, however, they will not be covered in this review.

Abbreviations

ACLY: (ATP-citrate lyase); ANGPTL: (angiopoietin-like protein 3); ASCVD: (atherosclerotic cardiovascular disease); BPA: (bempedoic acid); CETP (cholesteryl ester transfer protein); CV: (cardiovascular); CVD: (cardiovascular diseases); FH (familial hypercholesterolemia); HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase); HoFH (homozygous FH); LDL-C: (low density lipoprotein cholesterol); LDL-P: (low density lipoprotein particle); LDLr: (low density lipoprotein receptor); NPC1L1: (Niemann-Pick C1-like 1 protein); PCSK9: (proprotein convertase subtilisin/kexin type 9); SREBP-2: (sterol regulatory element binding protein 2)

KEYWORDS:

• LDL
• PCSK9 inhibitors
• inclisiran
• bempedoic acid
• gemcabene
• evinacumab
• ASCVD prevention

Declaration of interest

The contents of the paper and the opinions expressed within are those of the author, and it was the decision of the author to submit the manuscript for publication.

Financial disclosures

C.W. has received consulting fees from Esperion and The Medicines Company.

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