PCSK9 Inhibitors: Are We on the Verge of a Breakthrough?

Statins are first-line therapy for lowering cholesterol and reducing cardiovascular events. A significant need for new lipid-modifying therapies remains for patients unable to tolerate statins or achieve guideline-based cholesterol targets. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL receptor recycling. Gain-of-function PCSK9 mutations are associated with high low-density lipoprotein cholesterol (LDL-C) levels and increased risk of coronary artery disease, while loss-of-function variants result in low LDL-C and decreased risk of cardiovascular events. PCSK9 monoclonal antibody inhibitors have been developed and lower LDL-C levels up to 70% in clinical trials. These inhibitors are well tolerated, with low serious adverse event rates. Phase III clinical outcome trials with these agents are ongoing and will determine their efficacy in reducing cardiovascular events and address long-term safety concerns.