Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study |
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| Institution: | 1. Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy;2. Department of Molecular Medicine e Medical Biotechnologies, Federico II University, Naples, Italy;3. Department of Translational Medical Sciences, Federico II University, Naples, Italy;1. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada;2. Healthy Heart Program Prevention Clinic, St Paul’s Hospital, Vancouver, British Columbia, Canada;3. Centre for Health Evaluation and Outcome Sciences, University of British Columbia, Vancouver, British Columbia, Canada;4. Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada;5. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada;1. Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada;2. Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada;3. Department of Pathology and Laboratory Medicine, Lipoprotein Receptor Biology Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada;4. Departments of Medicine and Biochemistry, Atherogenomics Laboratory, University of Ottawa, Heart Institute, Ottawa, Ontario, Canada;5. Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada;6. Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada;1. Third Department of Internal Medicine, General University Hospital and First Faculty of Medicine, Charles University, U Nemocnice 1, 128 08 Prague 2, Czech Republic;2. Coordination Centre for Familial Hypercholesterolemia and Institute of Nutrition, Slovak Medical University, Limbova 14, 833 03 Bratislava, Slovak Republic;3. Internal Gerontometabolic Department, University Hospital Hradec Kralove, Sokolska 408, 500 05 Hradec Kralove, Czech Republic;4. Department of Clinical Biochemistry and the International Clinical Research Center – Department of Cardiovascular Diseases, St. Anne''s University Hospital Brno, Pekarska 53, 656 91 Brno, Czech Republic;5. Obezita-Ormiga, Koterova 5546, 760 01 Zlin, Czech Republic;6. NEOX Clinical Research, V Jame 1, 110 00 Prague 1, Czech Republic;7. Second Department of Internal Medicine, Faculty of Medicine Masaryk University and St. Anne''s University Hospital Brno, Pekarska 53, 656 91 Brno, Czech Republic;8. Centre for Cardiovascular Surgery and Transplantation, Pekarska 53, 656 91 Brno, Czech Republic;9. Ceitec and Medical Faculty of Masaryk University, Zerotinovo nam. 617/9, 601 77 Brno, Czech Republic;1. Department of Translational Medical Sciences, Federico II University, Naples, Italy;2. Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy;3. Department of Pharmacy, Federico II University, Naples, Italy;4. Unit of Metabolomics and Cellular Biochemistry of Atherothrombosis, Centro Cardiologico Monzino IRCCS, Milan, Italy;5. Department of Molecular Medicine e Medical Biotechnologies, Federico II University, Naples, Italy;1. Department of Cardiology, Government Medical College, Trivandrum, Kerala, India;2. P. D. Hinduja Hospital and MRC, Mumbai, Maharashtra, India |
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| Abstract: | Background and aimsFamilial 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 resultsWe 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.ConclusionsAfter 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. |
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| Keywords: | Familial hypercholesterolemia Proprotein convertase subtilisin/kexin type 9 inhibitors Low-density lipoprotein cholesterol Low-density lipoprotein receptor gene |
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