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

Patrick R. Lawler, MD, MPH; Garen Manvelian, PhD; Alida Coppi, PhD; Amy Damask, PhD; Michael N. Cantor, MD; Manuel A. R. Ferreira, PhD; Charles Paulding, PhD; Nilanjana Banerjee, PhD; Dadong Li, PhD; Susan Jorgensen, MS; Richa Attre, PhD; David J. Carey, PhD; Kristi Krebs, PhD; Lili Milani, PhD; Kristian Hveem, MD; Jan K. Damås, PhD; Erik Solligård, PhD; Stefan Stender, MD; Anne Tybjærg-Hansen, MD; Børge G. Nordestgaard, MD; Tamara Hernandez-Beeftink, PhD; Tormod Rogne, MD; Carlos Flores, PhD; Jesús Villar, MD; Keith R. Walley, MD; Vincent X. Liu, MD; Alison E. Fohner, PhD; Luca A. Lotta, MD; Christos A. Kyratsous, PhD; Mark W. Sleeman, PhD; Michel Scemama, MD; Richard DelGizzi, MS; Robert Pordy, MD; Julie E. Horowitz, PhD; Aris Baras, MD; Greg S. Martin, MD; Philippe Gabriel Steg, MD; Gregory G. Schwartz, MD; Michael Szarek, PhD; Shaun G. Goodman, MD

doi:10.1097/CCE.0000000000000997

Critical Care Explorations (Nov 2023)

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

Patrick R. Lawler, MD, MPH,
Garen Manvelian, PhD,
Alida Coppi, PhD,
Amy Damask, PhD,
Michael N. Cantor, MD,
Manuel A. R. Ferreira, PhD,
Charles Paulding, PhD,
Nilanjana Banerjee, PhD,
Dadong Li, PhD,
Susan Jorgensen, MS,
Richa Attre, PhD,
David J. Carey, PhD,
Kristi Krebs, PhD,
Lili Milani, PhD,
Kristian Hveem, MD,
Jan K. Damås, PhD,
Erik Solligård, PhD,
Stefan Stender, MD,
Anne Tybjærg-Hansen, MD,
Børge G. Nordestgaard, MD,
Tamara Hernandez-Beeftink, PhD,
Tormod Rogne, MD,
Carlos Flores, PhD,
Jesús Villar, MD,
Keith R. Walley, MD,
Vincent X. Liu, MD,
Alison E. Fohner, PhD,
Luca A. Lotta, MD,
Christos A. Kyratsous, PhD,
Mark W. Sleeman, PhD,
Michel Scemama, MD,
Richard DelGizzi, MS,
Robert Pordy, MD,
Julie E. Horowitz, PhD,
Aris Baras, MD,
Greg S. Martin, MD,
Philippe Gabriel Steg, MD,
Gregory G. Schwartz, MD,
Michael Szarek, PhD,
Shaun G. Goodman, MD

Affiliations

Patrick R. Lawler, MD, MPH: 1 Department of Medicine, McGill University Health Centre, McGill University, Montreal, QC, Canada.
Garen Manvelian, PhD: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
Alida Coppi, PhD: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
Amy Damask, PhD: 5 Regeneron Genetics Center, Tarrytown, NY.
Michael N. Cantor, MD: 5 Regeneron Genetics Center, Tarrytown, NY.
Manuel A. R. Ferreira, PhD: 5 Regeneron Genetics Center, Tarrytown, NY.
Charles Paulding, PhD: 5 Regeneron Genetics Center, Tarrytown, NY.
Nilanjana Banerjee, PhD: 5 Regeneron Genetics Center, Tarrytown, NY.
Dadong Li, PhD: 5 Regeneron Genetics Center, Tarrytown, NY.
Susan Jorgensen, MS: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
Richa Attre, PhD: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
David J. Carey, PhD: 6 Department of Molecular and Functional Genomics, Geisinger Medical Center, Danville, PA.
Kristi Krebs, PhD: 7 Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Lili Milani, PhD: 7 Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Kristian Hveem, MD: 8 K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Jan K. Damås, PhD: 10 Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Erik Solligård, PhD: 10 Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Stefan Stender, MD: 14 Department of Clinical Biochemistry, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark.
Anne Tybjærg-Hansen, MD: 14 Department of Clinical Biochemistry, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark.
Børge G. Nordestgaard, MD: 15 Department of Clinical Biochemistry, Copenhagen University Hospital – Herlev Gentofte, University of Copenhagen, Copenhagen, Denmark.
Tamara Hernandez-Beeftink, PhD: 16 Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
Tormod Rogne, MD: 10 Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Carlos Flores, PhD: 16 Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
Jesús Villar, MD: 17 Research Unit, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria, Spain.
Keith R. Walley, MD: 24 Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada.
Vincent X. Liu, MD: 25 Kaiser Permanente Northern California, Division of Research, Oakland, CA.
Alison E. Fohner, PhD: 25 Kaiser Permanente Northern California, Division of Research, Oakland, CA.
Luca A. Lotta, MD: 5 Regeneron Genetics Center, Tarrytown, NY.
Christos A. Kyratsous, PhD: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
Mark W. Sleeman, PhD: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
Michel Scemama, MD: 27 Sanofi, Chilly-Mazarin, France.
Richard DelGizzi, MS: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
Robert Pordy, MD: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
Julie E. Horowitz, PhD: 5 Regeneron Genetics Center, Tarrytown, NY.
Aris Baras, MD: 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY.
Greg S. Martin, MD: 28 Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA.
Philippe Gabriel Steg, MD: 30 Université de Paris, INSERM U-1148 F75018 Paris, France and Assistance Publique-Hôpitaux de Paris, Paris, France.
Gregory G. Schwartz, MD: 31 Division of Cardiology, University of Colorado School of Medicine, Aurora, CA.
Michael Szarek, PhD: 31 Division of Cardiology, University of Colorado School of Medicine, Aurora, CA.
Shaun G. Goodman, MD: 3 Division of Cardiology, Department of Medicine, University of Toronto, Toronto, ON, Canada.

DOI: https://doi.org/10.1097/CCE.0000000000000997
Journal volume & issue: Vol. 5, no. 11
p. e0997

Abstract

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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.

Published in Critical Care Explorations

ISSN: 2639-8028 (Online)
Publisher: Wolters Kluwer
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Medical emergencies. Critical care. Intensive care. First aid
Website: https://journals.lww.com/ccejournal/pages/default.aspx

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