PCSK9 : une nouvelle cible pour le traitement de l'hypercholestérolémie

PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a secreted protease that modulates cholesterol homeostasis by decreasing LDL receptor (LDLr) expression. PCSK9 gain-of-function mutations are linked to familial autosomal dominant hypercholesterolemia, characterized by elevated plasma concentrations of cholesterol associated to LDL-cholesterol (LDL-C). Conversely, PCSK9 loss-of-function mutations result in low LDL-C levels and protect against coronary heart disease. In the recent years, epidemiological data accumulated, in particular concerning the correlation between plasma PCSK9 concentrations and LDL-C levels. More importantly, new pharmacological strategies aiming for PCSK9 inhibition have arisen during the last year. Notably, phase 2 studies with monoclonal antibodies directed against PCSK9 have led to consistent and promising results in patients with either heterozygous familial hypercholesterolemia or primary hypercholesterolemia with a 50 to 65% reduction of LDL-C levels in association to statin therapy. Phase 3 studies are currently ongoing and will help to position PCSK9 inhibitors in the pharmacological management of hypercholesterolemia.