PCSK9 inhibitors: current status and emerging frontiers in lipid control

ABSTRACT

Introduction

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, imposing substantial healthcare economic burdens. Among the modifiable risk factors, hypercholesterolemia, especially elevated low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in ASCVD development. Novel therapies such as PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors are emerging to address this concern. These inhibitors offer the potential to reduce ASCVD risk by directly targeting LDL-C levels.

Areas covered

The article reviews the structural and functional aspects of PCSK9, highlighting its role in LDL receptor regulation. The pharmacological strategies for PCSK9 inhibition, including monoclonal antibodies, binding peptides, gene silencing, and active immunization, are explored. Clinical evidence from various trials underscores the safety and efficacy of PCSK9 inhibitors in reducing LDL-C levels and potentially improving cardiovascular outcomes. Despite these promising results, challenges such as cost-effectiveness and long-term safety considerations are addressed.

Expert opinion

Among PCSK9 inhibitors, monoclonal antibodies represent a cornerstone. Many trials have showed their efficacy in reducing LDL-C and the risk for major adverse clinical events, revealing long-lasting effects, with special benefits particularly for statin-intolerant and familial hypercholesterolemia patients. However, long-term impacts, high costs, and patient selection necessitate further research.

KEYWORDS:

• PCSK9 inhibitors
• evolocumab
• alirocumab
• inclisiran
• lipid-lowering therapy
• LDL cholesterol

Article highlights

• Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality with a significant economic burden on healthcare systems.

• Hypercholesterolemia, particularly elevated low-density lipoprotein cholesterol (LDL-C), is a key modifiable risk factor for ASCVD.

• PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors are emerging as crucial therapies for lowering LDL-C levels, with evidence supporting their safety and efficacy.

• Monoclonal antibodies, gene silencing, binding peptides, and active immunization are among the innovative pharmacological strategies being explored for PCSK9 inhibition.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A peer reviewer on this manuscript has received research support from Kowa, Nipro and Abbott, and honoraria from Nipro, Abbott, Kowa, Amgen, Sanofi, Astellas, Takeda and Daiichi-Sankyo. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.