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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
PCSK9 inhibitors: clinical evidence and implementation
1TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Hale Building for Transformative Medicine, Boston, MA, USA. msabatine@bwh.harvard.edu.
Abstract:
The gene encoding PCSK9 was first identified and linked to the phenotype of familial hypercholesterolaemia approximately 15 years ago. Soon after, studies uncovered the role of PCSK9 in the regulation of LDL-receptor recycling and identified loss-of-function variants of PCSK9 that were associated with low circulating levels of LDL cholesterol (LDL-C) and a reduced risk of coronary artery disease. With amazing rapidity, monoclonal antibodies against PCSK9 were developed and studied in large clinical programmes. These PCSK9 inhibitors lowered plasma LDL-C levels by approximately 60%, even in patients already receiving maximum-dose statin therapy. In the past year, three cardiovascular outcome trials were completed and showed that PCSK9 inhibitors significantly reduce the risk of major vascular events. Reassuringly, this benefit comes with no major offsetting adverse events, such as an excess of myalgias, elevation of hepatic aminotransferases levels in the plasma, incident diabetes mellitus or neurocognitive adverse events. The clinical benefit of PCSK9 inhibitors seen in these trials occurred in the setting of reducing LDL-C levels to unprecedentedly low levels, suggesting that more aggressive LDL-C targets should be adopted. New technologies to inhibit PCSK9 are now being harnessed and might further revolutionize our treatment of dyslipidaemia.
Insights
PCSK9 inhibitors significantly reduce cardiovascular events and lower LDL cholesterol (LDL-C) without major adverse effects. This breakthrough suggests more aggressive LDL-C targets are beneficial for patients with dyslipidemia.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Pharmacology
Background:
- The gene encoding PCSK9 was identified 15 years ago and linked to familial hypercholesterolemia.
- PCSK9 regulates LDL-receptor recycling, and loss-of-function variants are associated with low LDL cholesterol (LDL-C) and reduced coronary artery disease risk.
Purpose of the Study:
- To evaluate the efficacy and safety of PCSK9 inhibitors in reducing cardiovascular events.
- To assess the impact of PCSK9 inhibition on LDL-C levels, even in patients on maximum statin therapy.
Main Methods:
- Development and clinical study of monoclonal antibodies targeting PCSK9.
- Completion of three large cardiovascular outcome trials for PCSK9 inhibitors.
Main Results:
- PCSK9 inhibitors reduced plasma LDL-C by approximately 60%, surpassing the efficacy of maximum-dose statin therapy.
- Three cardiovascular outcome trials demonstrated significant reductions in major vascular events with PCSK9 inhibitors.
- No major offsetting adverse events were observed, including myalgias, elevated liver enzymes, incident diabetes, or neurocognitive issues.
Conclusions:
- PCSK9 inhibitors offer significant cardiovascular benefits with an excellent safety profile.
- The unprecedentedly low LDL-C levels achieved suggest the adoption of more aggressive LDL-C targets.
- New technologies for PCSK9 inhibition may further revolutionize dyslipidemia treatment.
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