Diagnosing Resistance to a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor

Letters6 March 2018Diagnosing Resistance to a Proprotein Convertase Subtilisin/Kexin Type 9 InhibitorMichael D. Shapiro, DO, Joshua Miles, BS, Hagai Tavori, PhD, and Sergio Fazio, MD, PhDMichael D. Shapiro, DOOregon Health & Science University, Portland, Oregon (M.D.S., J.M., H.T., S.F.)Search for more papers by this author, Joshua Miles, BSOregon Health & Science University, Portland, Oregon (M.D.S., J.M., H.T., S.F.)Search for more papers by this author, Hagai Tavori, PhDOregon Health & Science University, Portland, Oregon (M.D.S., J.M., H.T., S.F.)Search for more papers by this author, and Sergio Fazio, MD, PhDOregon Health & Science University, Portland, Oregon (M.D.S., J.M., H.T., S.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M17-2485 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) revolutionized the understanding of lipoprotein metabolism (1). Rapid translation of genetic insights led to the development of a new class of therapeutic agents that antagonize plasma PCSK9 and cause remarkable reductions (between 45% and 75%) in low-density lipoprotein (LDL) cholesterol levels. A large randomized controlled trial recently showed that adding a PCSK9 inhibitor in patients with established vascular disease who were already treated with optimized statin therapy caused statistically significant reductions in rates of myocardial infarction and stroke (2). Most patients receiving a PCSK9 inhibitor respond with marked reductions in ...References1. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154-6. [PMID: 12730697] CrossrefMedlineGoogle Scholar2. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-22. [PMID: 28304224] doi:10.1056/NEJMoa1615664 CrossrefMedlineGoogle Scholar3. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63:1278-88. [PMID: 24509273] doi:10.1016/j.jacc.2014.01.006 CrossrefMedlineGoogle Scholar4. Tavori H, Fan D, Blakemore JL, Yancey PG, Ding L, Linton MF, et al. Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation. Circulation. 2013;127:2403-13. [PMID: 23690465] doi:10.1161/CIRCULATIONAHA.113.001592 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: Oregon Health & Science University, Portland, Oregon (M.D.S., J.M., H.T., S.F.)Acknowledgment: The authors thank Paul Ziajka, MD, for contributing plasma samples for 1 of the participants.Grant Support: Partially supported by National Institutes of Health (National Heart, Lung, and Blood Institute) R01 grant HL-132985 (Dr. Fazio).Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-2485.Reproducible Research Statement:Study protocol and statistical code: Not available. Data set: Available from Dr. Shapiro (e-mail, [email protected]edu).This article was published at Annals.org on 28 November 2017. 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