Related Experiment Video
Updated: Nov 8, 2025
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Role of PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia
Brian Tomlinson1, Nivritti Gajanan Patil1, Manson Fok1
1Faculty of Medicine, Macau University of Science and Technology, Macau, China.
Insights
New PCSK9 inhibitors effectively lower LDL-C in familial hypercholesterolemia (FH) patients. These therapies offer improved cardiovascular disease risk management for both heterozygous (HeFH) and homozygous (HoFH) forms of the condition.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Familial hypercholesterolemia (FH) confers a high risk of cardiovascular disease.
- Standard therapies like statins and ezetimibe are often insufficient for achieving lipid targets in FH patients, particularly those with homozygous FH (HoFH).
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a novel therapeutic class for managing hyperlipidemia.
Purpose of the Study:
- To evaluate the efficacy of PCSK9 inhibitors in reducing low-density lipoprotein cholesterol (LDL-C) in patients with FH.
- To compare the effectiveness of PCSK9 monoclonal antibodies and small interfering RNA (siRNA) therapeutics in different FH genotypes.
- To assess the tolerability and potential of PCSK9 inhibition for achieving LDL-C goals in the FH population.
Main Methods:
- Review of clinical data on PCSK9 monoclonal antibodies (alirocumab, evolocumab) and the siRNA therapeutic (inclisiran).
- Analysis of LDL-C reduction percentages and achievement of treatment goals in patients with heterozygous FH (HeFH) and HoFH.
- Assessment of response variability in HoFH based on LDL receptor activity and mutation type.
Main Results:
- Subcutaneous PCSK9 monoclonal antibodies reduced LDL-C by 50-60% in HeFH patients, enabling goal attainment.
- PCSK9 monoclonal antibodies showed a reduced and variable response in HoFH patients, dependent on residual LDL receptor function.
- Inclisiran demonstrated sustained LDL-C reduction (>50%) for at least 6 months in both HeFH and HoFH patients, comparable to monoclonal antibodies.
Conclusions:
- PCSK9 inhibitors, including monoclonal antibodies and inclisiran, provide a significant therapeutic advancement for FH management.
- These agents offer effective LDL-C lowering for the majority of FH patients, including those refractory to conventional therapies.
- PCSK9 inhibition represents a valuable new strategy to mitigate cardiovascular risk in patients with familial hypercholesterolemia.
Abstract:
Patients with familial hypercholesterolemia (FH) are at high or very high risk for cardiovascular disease. Those with heterozygous FH (HeFH) often do not reach low-density lipoprotein cholesterol (LDL-C) targets with statin and ezetimibe therapy, and those with homozygous FH (HoFH) usually require additional lipid-modifying therapies. Drugs that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) offer a novel approach to reduce LDL-C. The monoclonal antibodies, alirocumab and evolocumab, given by subcutaneous injection every 2 or 4 weeks produce reductions in LDL-C of 50% to 60% in patients with HeFH, allowing many of them to achieve their LDL-C goals. Patients with HoFH show a reduced and more variable LDL-C response, which appears to depend on residual LDL receptor activity, and those with receptor-negative mutations may show no response. Inclisiran is a long-acting small interfering RNA therapeutic agent that inhibits the synthesis of PCSK9. Subcutaneous doses of 300 mg can reduce LDL-C by more than 50% for at least 6 months and the responses in HeFH and HoFH patients are similar to those achieved with monoclonal antibodies. These PCSK9 inhibitors are generally well tolerated and they provide a new opportunity for effective treatment for the majority of patients with FH.
More Related Videos
Related Concept Videos
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents
01:26Atherosclerosis III: Management
01:26Coronary Artery Disease IV: Preventive Measures
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
01:29Cholesterol: Significance and Regulation
Considering cholesterol and...
01:28Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...