Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases
low-density lipoprotein cholesterol (
LDL-C) concentrations through interference with normal physiologic hepatic
LDL receptor (LDLR) recycling. Inhibiting PCSK9 results in improved LDLR recycling, increased LDLR availability on hepatocyte cell surfaces, and reduced blood
LDL-C levels, making PCSK9 inhibition a novel therapeutic strategy for managing
hypercholesterolemia.
Monoclonal antibodies directed against PCSK9 have been developed for this purpose. A large number of clinical trials have demonstrated that
monoclonal antibodies against PCSK9 yield substantial reductions in
LDL-C when administered as monotherapy or in combination with
statins to patients with nonfamilial and familial forms of
hypercholesterolemia. Data from long-term trials demonstrate that the
LDL-C-lowering effect of
PCSK9 inhibitors is durable. These agents are generally well tolerated, and few patients discontinue treatment due to adverse events. Moreover,
PCSK9 inhibitors do not appear to elicit the hepatic and muscle-related side effects associated with
statin use. The ultimate value of
PCSK9 inhibitors will be measured by their effect on clinical outcomes. Early evidence of a reduction in cardiovascular events after 1 year of treatment was shown in a prospective exploratory analysis of two ongoing long-term open-label extension
evolocumab trials. Similarly, cardiovascular events were reduced in another exploratory analysis after >1 year of
therapy with
alirocumab. For the primary care physician,
PCSK9 inhibitors represent a welcome additional option for lowering
LDL-C in patients with familial forms of
hypercholesterolemia and those with clinical atherosclerotic
cardiovascular disease who are on maximally tolerated
statin therapy.