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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
PCSK9 inhibition as an emerging lipid lowering therapy: Unanswered questions
Lοukianos S Rallidis1, John Lekakis1
1Second Department of Cardiology, University General Hospital, "Attikon", Athens, Greece.
Insights
New PCSK9 inhibitors offer significant LDL-C reduction beyond statins, potentially lowering cardiovascular risk. These monoclonal antibodies are a promising advancement in managing hypercholesterolemia and preventing cardiovascular events.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Cardiovascular disease (CVD) remains a leading cause of death globally, despite statin use for hypercholesterolemia.
- Statins effectively lower low-density lipoprotein cholesterol (LDL-C), but further reductions are needed to decrease cardiovascular events.
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in LDL clearance.
Purpose of the Study:
- To review the efficacy and safety of PCSK9 inhibitors.
- To evaluate the role of PCSK9 inhibitors in reducing cardiovascular risk.
- To discuss the clinical use of PCSK9 inhibitors as an adjunct to statin therapy.
Main Methods:
- Review of clinical trial data for PCSK9 inhibitors.
- Analysis of LDL-C reduction achieved with PCSK9 inhibitors compared to statins.
- Assessment of safety and efficacy data from phase III clinical trials.
Main Results:
- PCSK9 inhibitors provide an additional mean reduction of approximately 60% in LDL-C levels beyond statin therapy.
- Phase III clinical trials show promising efficacy and safety data for PCSK9 inhibitors.
- These agents have the potential to lower LDL-C levels to unprecedented lows.
Conclusions:
- PCSK9 inhibitors represent a significant advancement in managing hypercholesterolemia.
- They offer a new therapeutic option for patients at high cardiovascular risk who do not achieve sufficient LDL-C lowering with statins.
- Further evaluation of their long-term impact on cardiovascular outcomes is warranted.
Abstract:
Although statins have been used for the treatment of hypercholesterolemia for more than two decades, cardiovascular disease (CVD), which is related at least in part to high levels of low-density lipoprotein cholesterol (LDL-C), is the number one cause of death in Europe and the USA. Several studies have shown that the reduction in cardiovascular (CV) events is proportional to the absolute LDL-C lowering achieved with statins. In the quest for further reduction in LDL-C and CV events, new drugs that mainly support statin action have emerged. Since 2003, with the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), which is a key factor in the LDL clearance pathway, new modalities, mainly in the form of monoclonal antibodies that block this protein (PCSK9 inhibitors), have reached phase III of clinical development with very promising efficacy and safety data. With a mean further reduction of LDL-C levels of ∼60% beyond that achieved with statins, the PCSK9 inhibitors set the bar even lower in terms of LDL-C levels. This review manuscript addresses important questions about the efficacy, safety and clinical use of PCSK9 inhibitors to evaluate the role of these agents in reducing CV risk.
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