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

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

doi:10.1097/CCE.0000000000000997

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

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

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.

Originalsprog	Engelsk
Tidsskrift	Critical care explorations
Vol/bind	5
Udgave nummer	11
Sider (fra-til)	e0997
ISSN	2639-8028
DOI	https://doi.org/10.1097/CCE.0000000000000997
Status	Udgivet - nov. 2023

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Lawler, P. R., Manvelian, G., Coppi, A., Damask, A., Cantor, M. N., Ferreira, M. A. R., Paulding, C., Banerjee, N., Li, D., Jorgensen, S., Attre, R., Carey, D. J., Krebs, K., Milani, L., Hveem, K., Damås, J. K., Solligård, E., Stender, S., Tybjærg-Hansen, A., ... Goodman, S. G. (2023). Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis. Critical care explorations, 5(11), e0997. https://doi.org/10.1097/CCE.0000000000000997

Lawler, PR, Manvelian, G, Coppi, A, Damask, A, Cantor, MN, Ferreira, MAR, Paulding, C, Banerjee, N, Li, D, Jorgensen, S, Attre, R, Carey, DJ, Krebs, K, Milani, L, Hveem, K, Damås, JK, Solligård, E, Stender, S , Tybjærg-Hansen, A , Nordestgaard, BG, Hernandez-Beeftink, T, Rogne, T, Flores, C, Villar, J, Walley, KR, Liu, VX, Fohner, AE, Lotta, LA, Kyratsous, CA, Sleeman, MW, Scemama, M, DelGizzi, R, Pordy, R, Horowitz, JE, Baras, A, Martin, GS, Steg, PG, Schwartz, GG, Szarek, M & Goodman, SG 2023, 'Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis', Critical care explorations, bind 5, nr. 11, s. e0997. https://doi.org/10.1097/CCE.0000000000000997

@article{199bebc843eb41938fc7ed509d1afaa7,

title = "Pharmacologic and Genetic Downregulation of Proprotein Convertase Subtilisin/Kexin Type 9 and Survival From Sepsis",

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.",

author = "Lawler, {Patrick R} and Garen Manvelian and Alida Coppi and Amy Damask and Cantor, {Michael N} and Ferreira, {Manuel A R} and Charles Paulding and Nilanjana Banerjee and Dadong Li and Susan Jorgensen and Richa Attre and Carey, {David J} and Kristi Krebs and Lili Milani and Kristian Hveem and Dam{\aa}s, {Jan K} and Erik Sollig{\aa}rd and Stefan Stender and Anne Tybj{\ae}rg-Hansen and Nordestgaard, {B{\o}rge G} and Tamara Hernandez-Beeftink and Tormod Rogne and Carlos Flores and Jes{\'u}s Villar and Walley, {Keith R} and Liu, {Vincent X} and Fohner, {Alison E} and Lotta, {Luca A} and Kyratsous, {Christos A} and Sleeman, {Mark W} and Michel Scemama and Richard DelGizzi and Robert Pordy and Horowitz, {Julie E} and Aris Baras and Martin, {Greg S} and Steg, {Philippe Gabriel} and Schwartz, {Gregory G} and Michael Szarek and Goodman, {Shaun G}",

note = "Copyright {\textcopyright} 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.",

year = "2023",

month = nov,

doi = "10.1097/CCE.0000000000000997",

language = "English",

volume = "5",

pages = "e0997",

journal = "Critical care explorations",

issn = "2639-8028",

publisher = "Lippincott Williams & Wilkins",

number = "11",

}

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

PY - 2023/11

Y1 - 2023/11

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.

UR - http://www.scopus.com/inward/record.url?scp=85180469123&partnerID=8YFLogxK

U2 - 10.1097/CCE.0000000000000997

DO - 10.1097/CCE.0000000000000997

M3 - Journal article

C2 - 37954898

SN - 2639-8028

VL - 5

SP - e0997

JO - Critical care explorations

JF - Critical care explorations

IS - 11

ER -

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

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