PCSK9 inhibitors: clinical evidence and implementation

Area of Science:

• Cardiovascular Medicine
• Genetics
• Pharmacology

Background:

• The gene encoding PCSK9 was identified 15 years ago and linked to familial hypercholesterolemia.
• PCSK9 regulates LDL-receptor recycling, and loss-of-function variants are associated with low LDL cholesterol (LDL-C) and reduced coronary artery disease risk.

Purpose of the Study:

• To evaluate the efficacy and safety of PCSK9 inhibitors in reducing cardiovascular events.
• To assess the impact of PCSK9 inhibition on LDL-C levels, even in patients on maximum statin therapy.

Main Methods:

• Development and clinical study of monoclonal antibodies targeting PCSK9.
• Completion of three large cardiovascular outcome trials for PCSK9 inhibitors.

Main Results:

• PCSK9 inhibitors reduced plasma LDL-C by approximately 60%, surpassing the efficacy of maximum-dose statin therapy.
• Three cardiovascular outcome trials demonstrated significant reductions in major vascular events with PCSK9 inhibitors.
• No major offsetting adverse events were observed, including myalgias, elevated liver enzymes, incident diabetes, or neurocognitive issues.

Conclusions:

• PCSK9 inhibitors offer significant cardiovascular benefits with an excellent safety profile.
• The unprecedentedly low LDL-C levels achieved suggest the adoption of more aggressive LDL-C targets.
• New technologies for PCSK9 inhibition may further revolutionize dyslipidemia treatment.