The PCSK9 revolution: Current status, controversies, and future directions

Area of Science:

• Cardiovascular Medicine
• Biochemistry
• Pharmacology

Background:

• Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is crucial for cholesterol homeostasis.
• PCSK9 has emerged as a key target for managing atherosclerotic cardiovascular disease (ASCVD).
• Familial hypercholesterolemia (FH) is a rare condition linked to PCSK9.

Purpose of the Study:

• To review the discovery, history, and therapeutic development of PCSK9 inhibitors.
• To provide context on the current status of PCSK9-targeted treatments.
• To highlight knowledge gaps, controversies, and future research directions in PCSK9 therapeutics.

Main Methods:

• Literature review of PCSK9 research and clinical trials.
• Analysis of Food and Drug Administration (FDA)-approved PCSK9 inhibitors.
• Synthesis of current understanding of PCSK9 physiology and function.

Main Results:

• PCSK9 inhibition, primarily via monoclonal antibodies, achieves significant low-density lipoprotein cholesterol (LDL-C) reduction.
• Two large cardiovascular outcome trials demonstrate positive results for PCSK9 inhibition in ASCVD risk reduction.
• Lowering LDL-C is strongly associated with reduced ASCVD risk.

Conclusions:

• PCSK9 inhibitors represent a major advancement in lipid-lowering therapy and ASCVD prevention.
• Despite therapeutic success, gaps remain in understanding PCSK9's full physiological role.
• Future research should address ongoing controversies and explore novel PCSK9-targeting strategies.