evolocumab

Mechanism: PCSK9 normally binds LDL receptors on hepatocytes, promoting their degradation in lysosomes after LDL-receptor mediated endocytosis, thereby reducing the number of LDL receptors available on the cell surface to clear circulating LDL cholesterol. Evolocumab binds circulating PCSK9, preventing it from binding LDL receptors. This allows LDL receptors to be recycled back to the hepatocyte surface rather than degraded, increasing hepatic uptake and clearance of LDL-C from the blood, resulting in LDL-C reductions of 50-70% when added to statin therapy.

Clinical use: Indicated for heterozygous and homozygous familial hypercholesterolemia (HeFH/HoFH), and for secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) who require additional LDL lowering beyond statins/ezetimibe. FOURIER trial demonstrated reduction in major adverse cardiovascular events (MACE) with evolocumab added to statin therapy, though without significant mortality benefit in the trial duration.

Administration: Subcutaneous injection, typically every 2-4 weeks. Other PCSK9 inhibitors include alirocumab (antibody) and inclisiran (siRNA-based, different mechanism - inhibits PCSK9 synthesis rather than blocking the protein directly).

Adverse effects: Generally well tolerated; injection site reactions, nasopharyngitis, and rarely neurocognitive effects have been reported. Unlike statins, PCSK9 inhibitors do not cause significant myalgias or hepatotoxicity.

Boards relevance: Key testable concepts include the PCSK9-LDL receptor pathway, contrast with statin mechanism (HMG-CoA reductase inhibition, which paradoxically increases PCSK9 expression), and the loss-of-function PCSK9 mutations associated with very low LDL and reduced cardiovascular risk (the biologic rationale for this drug class).