Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis

• Type of Material: Article
• Authors: Patrick r. Lawler, McGill University; Garen Manvelian, Rengeneron Pharmaceuticals; Alida Coppi, Rengeneron Pharmaceuticals; Amy Damask, Rengeneron Genetics Center; Michael N. Cantor, Rengeneron Genetics Center; Manuel A.R. Ferreira, Rengeneron Genetics Center; Charles Paulding, Rengeneron Genetics Center; Milanjana Banerjee, Rengeneron Genetics Center; Dadong Li, Rengeneron Genetics Center; Susan Jorgensen, Rengeneron Pharmaceuticals; Richa Attre, Rengeneron Pharmaceuticals; David J. Carey, Geisinger Medical Center; Kristi Krebs, University of Tartu; Lili Milani, University of Tartu; Kristian Hveem, Norwegian University of Science and Technology; Jan K. Damås, Norwegian University of Science and Technology; Erik Solligård, Norwegian University of Science and Technology; Stegan Stender, Copenhagen University; Anne Tybjærg-Hansen, Copenhagen University; Børge G Nordestgaard, Copenhagen University; tamara Hernandez-Beeftink, Universidad de La Laguna; Tormod Rogne, Norwegian University of Science and Technology; Carlos Flores, Universidad de La Laguna; Jesús Villar, Universitario de Gran Canaria Dr. Negrin; Keith R. Walley, University of British Columbia; Vincent X. Liu, Kaiser Permanente Northern California; Alison E. Fohner, Kaiser Permanente Northern California; Luca A. Lotta, Regeneron Genetics Center; Christos A. Kyratsous, Regeneron Pharmaceuticals; Mark W. Sleeman, Regeneron Pharmaceuticals; Michel Scemama, Sanofi; Richard DelGizzi, Regeneron Pharmaceuticals; Robert Pordy, Regeneron Pharmaceuticals; Julie E. Horowitz, Regeneron Genetics Center; Aris Baras, Regeneron Pharmaceuticals; Greg Martin, Emory University; Philippe Gabriel Steg, Université de Paris; Gregory G. Schwartz, University of Colorado, Aurora; Michael Szarek, University of Colorado, Aurora; Shaun G. Goodman, University of Toronto
• Language: English
• Date: 2023-11-08
• Publisher: Wolters Kluwer Health, Inc.
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1097/CCE.0000000000000997
• Title of Journal or Parent Work: Critical Care Explorations
• Volume: 5
• Issue: 11
• Start Page: e0997
• Grant/Funding Information: This study was funded by Regeneron Pharmaceuticals. The GENetics of SEPsis study was supported by Instituto de Salud Carlos III, Madrid, Spain. The work by Drs. Krebs and Milani was supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) and the Estonian Research Council (Grant No. PRG184).
• Keywords: lipid regulating agents; sepsis; proprotein convertase subtilisin/kexin type 9; endotoxins; septic shock
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Immunology; Health Sciences, Pharmacology

Abstract

OBJECTIVES: Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies—lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN: Genetic and clinical epidemiology, and experimental models. SETTING: Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS: Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS: Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS: Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67–1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32–1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS: PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.