Klin Farmakol Farm. 2013;27(3-4):114-118

Perspectives of further reduction in cholesterol by means of PCSK9 blockade

Vladimír Bláha

III. interní gerontometabolická klinika, LF UK a FN Hradec Králové

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a newly discovered member of the proprotein convertase family. Expression studies

and human genetics have revealed an important role for PCSK9 in cholesterol metabolism. PCSK9 is regulated by dietary cholesterol

and cellular cholesterol levels putatively via the SREBP (sterol-responsive element-binding protein) transcription factors. Mutations in

PCSK9 are associated with the third locus implicated in ADH (autosomal dominant hypercholesterolemia). PCSK9 clearly plays an important

role in controlling LDLR levels. If the true function of PCSK9 is to degrade the LDLR, inhibitors of PCSK9 may act to increase LDLR

levels, enhance LDL uptake by the liver, and decrease plasma LDL cholesterol levels. Furthermore, such inhibitors would be synergistic

with statin drugs in raising hepatic LDLR levels. PCSK9 inhibition is undoubtedly the most attractive new approach to decrease levels of

atherogenic lipoproteins and to enhance the LDL-C-lowering efficacy of statins. Published phase II data have shown that monoclonal

antibodies are effective and well tolerated at 3 months. The most advanced monoclonal antibodies are currently in phase III to determine

the long-term safety, tolerability and efficacy profile, including the effect on cardiovascular disease.

Keywords: dyslipidemia, hypolipidemic treatment, cardiovascular risk, atherosclerosis

Published: December 1, 2013  Show citation