TY - JOUR

T1 - Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival from Sepsis

AU - Lawler, Patrick R.

AU - Manvelian, Garen

AU - Coppi, Alida

AU - Damask, Amy

AU - Cantor, Michael N.

AU - Ferreira, Manuel A.R.

AU - Paulding, Charles

AU - Banerjee, Nilanjana

AU - Li, Dadong

AU - Jorgensen, Susan

AU - Attre, Richa

AU - Carey, David J.

AU - Krebs, Kristi

AU - Milani, Lili

AU - Hveem, Kristian

AU - Damås, Jan K.

AU - Solligård, Erik

AU - Stender, Stefan

AU - Tybjærg-Hansen, Anne

AU - Nordestgaard, Børge G.

AU - Hernandez-Beeftink, Tamara

AU - Rogne, Tormod

AU - Flores, Carlos

AU - Villar, Jesús

AU - Walley, Keith R.

AU - Liu, Vincent X.

AU - Fohner, Alison E.

AU - Lotta, Luca A.

AU - Kyratsous, Christos A.

AU - Sleeman, Mark W.

AU - Scemama, Michel

AU - Delgizzi, Richard

AU - Pordy, Robert

AU - Horowitz, Julie E.

AU - Baras, Aris

AU - Martin, Greg S.

AU - Steg, Philippe Gabriel

AU - Schwartz, Gregory G.

AU - Szarek, Michael

AU - Goodman, Shaun G.

N1 - Publisher Copyright: © 2023 The Author(s).

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - endotoxins

KW - lipid regulating agents

KW - proprotein convertase subtilisin/kexin type 9

KW - sepsis

KW - septic shock

U2 - 10.1097/CCE.0000000000000997

DO - 10.1097/CCE.0000000000000997

M3 - Journal article

C2 - 37954898

AN - SCOPUS:85180469123

VL - 5

JO - Critical Care Explorations

JF - Critical Care Explorations

SN - 2639-8028

IS - 11

M1 - E0997

ER -