Epidemiological observations indicate that loss-of-function mutations in PCSK9—a serine protease responsible for binding irreversibly to the LDL–LDL receptor complex in hepatocytes, leading to the lysosomal degradation of the LDL receptor—are associated with a lower risk of cardiovascular disease. This highlights PCSK9 as a therapeutic target. Monoclonal antibodies targeting PCSK9 inhibit its interaction with the LDL receptor, leading to reduced LDL-C levels.
Evolocumab has shown significant reductions in LDL-C levels across various patient populations, including those with hypercholesterolemia, statin intolerance, familial hypercholesterolemia (HeFH), and type 2 diabetes mellitus. The FOURIER trial, involving patients with established atherosclerotic cardiovascular disease (ASCVD), demonstrated a reduction in cardiovascular events with evolocumab compared to placebo.
Alirocumab has consistently shown superior reductions in LDL-C levels compared to ezetimibe and placebo across various patient populations, including those with HeFH, ASCVD, and patients intolerant to statin therapy. The ODYSSEY OUTCOMES trial demonstrated a reduction in major adverse cardiovascular events with alirocumab compared to placebo in patients with recent acute coronary syndrome.
Bococizumab exhibited significant reductions in lipid profile biomarkers in phase III trials. However, concerns regarding immunogenicity led to its discontinuation despite initial positive results in reducing major adverse cardiovascular events in higher-risk patient populations.
Alirocumab and evolocumab are FDA-approved for LDL-C reduction as adjuncts to diet and statin therapy, as well as standalone therapy in patients with clinical ASCVD or HeFH. PCSK9 inhibitors are recommended in specific populations with clinical ASCVD who are unable to achieve target LDL-C levels despite maximally tolerated statin therapy or those who are statin intolerant.
Initial concerns regarding adverse effects of PCSK9 inhibitors have been addressed by recent meta-analyses, demonstrating their overall safety and tolerability comparable to placebo, with the most common adverse effects being injection site reactions, influenza-like illnesses, and myalgias.
Cost-effectiveness analyses have shown that PCSK9 inhibitors meet current thresholds for cost-effectiveness, with ICERs within acceptable ranges per quality-adjusted life year gained, making them valuable additions to lipid-lowering therapies.
© The AtheroPrev Team (2024)
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