Related Experiment Video
Updated: Oct 7, 2025
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial
Gabriella Iannuzzo1, Alessio Buonaiuto1, Ilenia Calcaterra1
1Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
Insights
Familial hypercholesterolemia patients with defective or null LDLR mutations respond similarly to PCSK9 inhibitors. However, compound heterozygous or homozygous FH patients show a significantly lower response to this therapy.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Pharmacology
Background:
- Familial hypercholesterolemia (FH) is an inherited condition causing high LDL-C and increased cardiovascular disease risk.
- Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) effectively lower LDL-C and reduce cardiovascular events.
- Understanding the impact of LDL receptor (LDLR) mutations on PCSK9-I response is crucial for personalized treatment.
Purpose of the Study:
- To investigate the relationship between specific LDLR gene mutations and patient response to PCSK9-I therapy.
- To evaluate the efficacy of PCSK9-I in achieving LDL-C targets across different FH genetic subtypes.
Main Methods:
- Prospective evaluation of lipid profiles (TC, LDL-C, HDL-C, TG) in 80 FH patients before and during 36 weeks of PCSK9-I treatment.
- Categorization of patients based on LDLR mutation type: heterozygous defective, heterozygous null, and compound heterozygous/homozygous.
- Assessment of LDL-C target achievement rates according to mutation status.
Main Results:
- Overall LDL-C reduction of 51% from baseline to 36 weeks.
- No significant difference in LDL-C reduction between heterozygous defective and heterozygous null LDLR mutation groups.
- Lower LDL-C target achievement in heterozygous null (36%) and no patients achieving target in compound heterozygous/homozygous groups.
Conclusions:
- PCSK9-I therapy shows comparable efficacy in FH patients with heterozygous defective and heterozygous null LDLR mutations.
- Patients with compound heterozygous or homozygous FH mutations exhibit a significantly diminished response to PCSK9-I.
- Genetic profiling of LDLR mutations can inform treatment strategies for FH.
Background And Aims:
Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy.
Methods And Results:
We evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target.
Conclusions:
After 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations. Registration number for clinical trials: NCT04313270 extension.
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
01:30Coronary Artery Disease I: Introduction