PCSK9 inhibition in the management of hyperlipidemia: focus on evolocumab

Abstract

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.

Keywords:

• alirocumab
• monoclonal antibody
• hypercholesterolemia
• hyperlipidemia
• LDL-C

Acknowledgments

The authors thank Meera Kodukulla, PhD, CMPP of Amgen, Inc. (Thousand Oaks, CA, USA) and Laura Evans, PharmD, on behalf of Amgen Inc., for preliminary drafting of the manuscript.

Disclosure

Dr Dirk J Blom has received research grants and clinical trial payments from Amgen, Inc. (Thousand Oaks, CA, USA) and Sanofi-Aventis (Bridgewater, NJ, USA), and speaker’s honoraria from Amgen, Inc. Dr Dirk J Blom has served as an advisory board member for Amgen, Inc. and Sanofi-Aventis. Dr Peter P Toth is a member of the speaker’s bureau Amarin Corporation, (Dublin, Ireland), Kowa Pharmaceuticals America, Inc. (Montgomery, AL, USA), Merck & Co., Inc. (Whitehouse Station, NJ, USA), Sanofi-Aventis, and Novartis International AG (Basel, Switzerland), and a consultant Amgen, Inc., Kowa Pharmaceuticals America, Inc., Merck Co., Inc., Sanofi-Aventis, and Novartis International AG. Drs Ricardo Dent and Rita Castro are employees and stockholders of Amgen, Inc. The authors report no other conflicts of interest in this work.