New Biological Therapies for Low-Density Lipoprotein Cholesterol

Area of Science:

• Cardiovascular Medicine
• Genetics
• Pharmacology

Background:

• Low-density lipoprotein cholesterol (LDL-C) reduction is crucial for preventing atherosclerotic cardiovascular disease (ASCVD).
• Monogenic hypocholesterolemia provides insights into genetic targets for lowering LDL-C.
• Pathogenic variants in PCSK9, ANGPTL3, MTTP, and APOB genes are linked to naturally low cholesterol levels.

Purpose of the Study:

• To review the development and clinical application of novel therapeutics targeting key genes involved in lipid metabolism.
• To highlight the impact of proprotein convertase subtilisin kexin type 9 (PCSK9) and angiopoietin-like 3 (ANGPTL3) inhibitors on clinical practice.
• To discuss emerging therapies with the potential for long-term or lifelong reduction of LDL-C.

Main Methods:

• Focused review of existing literature on lipid-lowering therapeutics.
• Discussion of currently approved biologic therapies targeting PCSK9, ANGPTL3, and MTTP.
• Overview of preclinical and clinical trial-stage therapies, including vaccines and gene-editing approaches.

Main Results:

• Several therapies targeting PCSK9 and ANGPTL3 are now in clinical use, including monoclonal antibodies (alirocumab, evolocumab, evinacumab) and small interfering RNA (inclisiran).
• Lomitapide, a microsomal triglyceride transfer protein inhibitor, is also clinically available.
• A diverse range of novel therapies, including vaccines and gene-editing, are under development.

Conclusions:

• Biologic therapies inspired by monogenic hypocholesterolemia are effective tools for managing elevated LDL-C and preventing ASCVD.
• PCSK9 and ANGPTL3 inhibition have significantly impacted cardiovascular disease treatment strategies.
• Future therapies, particularly vaccines and gene editing, hold promise for sustained, long-term control of lipid levels.