“PCSK9 inhibitors are the most exciting thing going on right now in the field of lipids. They are rocking the lipid world,” says MUSC Health cardiologist Pamela B. Morris, M.D., who is the principal investigator for the MUSC Health site of two trials of these inhibitors: GAUSS III, which is testing the efficacy of evolocumab in patients who have been verified as being statin intolerant, and FOURIER (NCT01764633), which is seeking to definitively establish whether the dramatic decreases in LDL-C seen with evolocumab indeed reduce the risk for cardiovascular events long term in patients already receiving statin therapy.
Side effects of PCSK9 inhibitors include minor injection-site reactions and, in a few cases, memory deficit. OSLER showed that these deficits are not attributable to excessively low LDL-C levels.
PCSK9 inhibitors are monoclonal antibodies that must be subcutaneously injected, and it is still being assessed whether better efficacy and patient adherence can be achieved with a smaller dose every two weeks or a larger dose once a month.
If approved, PCSK9 inhibitors will offer a promising new therapy for statin-intolerant patients and for patients who do not reach target LDL-C levels despite taking the highest-tolerated dose of statins.
How They Work: LDL receptors on the surface of liver cells bind to LDL-C and target it for degradation. Depending on the body’s needs, LDL receptors are then either degraded or recycled to clear more LDL-C. PCSK9 binds to the LDL-C/LDL receptor complex and targets the receptors for degradation rather than recycling. Inhibiting PCSK9 ensures that more of the receptors are recycled to the cell surface to clear LDL-C. Indeed, patients with a loss-of-function PCSK9 mutation tend to have very low levels of LDL-C and very low rates of cardiovascular disease, an observation that helped spark interest in PCSK9 inhibitors.
Addendum: On June 9, 2015, the FDA’s independent cardiovascular committee voted 13-3 to recommend approval of the PCSK9 inhibitor alirocumab (Sanofi/Regeneron), backing its use in patients genetically predisposed to severely high LDL but hesitating to recommend it for larger populations. On June 10, 2015, the Endocrinologic and Metabolic Drugs Advisory Committee voted 11-4 to recommend that the FDA approve the PCSK9 inhibitor evolocumab (Amgen) for lowering LDL cholesterol and unanimously supported its use in patients with homozygous familial hypercholesterolemia.