Physicians' Academy for Cardiovascular Education

PCSK9 inhibition: hope for treating dyslipidemia?

Literature - Lambert G et al. J Lipid Res. 2012 Jul 17

PCSK9 inhibition: hope for treating dyslipidemia?

The PSCK9 decade

Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK.

J Lipid Res. 2012 Jul 17. [Epub]

 

Background

Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a pivotal role in LDL metabolism as it promotes the degradation of the LDL receptor and prevents it from recycling to the membrane. PCSK9 is therefore a novel target for lipid-lowering therapy. Inhibition of PCSK9 acts synergistically with existing treatments such as statins. A lot of research has been done to understand the biology of PCSK9. This article describes the role of PSCK9 in cholesterol metabolism and data on PCSK9 inhibition.

 

Main results

PCSK9 inhibition is an interesting target to further lower LDL-C levels. The mechanism of action is shown in figure 1.


Figure 1.

PCSK9 inhibition. Monoclonal antibodies bound to PCSK9 prevent the association between PCSK9 and the LDL receptor (LDLR). The LDL receptor binds the LDL particle, is internalized, and then the LDL particle is degraded in the lysosome whereas the LDLR is recycled back to the plasma membrane.

Click on image to enlarge


Monoclonal antibodies are in development that inhibit PCSK9, with varying effects on lipid profile. Recently published results with SAR236553/REGN727 are shown in table 1.

Conclusion

PSCK9 inhibition is efficacious in reducing LDL-C levels. It has to be further evaluated whether this also leads to reduction in coronary risk.

References

  1. McKenney, J., M. Koren, D. Kereiakes, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J. Am. Coll. Cardiol. [Epub ahead of print]
  2. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce lowdensity lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. May 25 [Epub ahead of print]
  3. Stein, E. A., S. Mellis, G. D. Yancopoulos, et al. Effect of a monoclonal antibody to PCSK9 on LDL Cholesterol. N. Engl. J.Med. 366: 1108-1118.

Abstract

PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism, by virtue of its pivotal role in the degradation of the LDL receptor. In recent years, both in vitro and in vivo studies have greatly supplemented our understanding of the (patho)physiological role of PCSK9 in human biology. In the current review, we summarize studies published or in print before May 2012 with regards to the physiological role of PCSK9 in cholesterol metabolism. Moreover, we briefly describe the clinical phenotypes encountered in carriers of mutations in the gene encoding PCSK9. Since PCSK9 has emerged as a novel target for LDL-C lowering therapy, methods to inhibit PCSK9 will also be reviewed. Initial data from investigations of PCSK9 inhibition in humans are promising and indicate that PCSK9 inhibition may be a viable new therapeutic option for the treatment of dyslipidemia and associated cardiovascular diseases.

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