Abstract
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 |
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Artikelnummer | E0997 |
Tidsskrift | Critical Care Explorations |
Vol/bind | 5 |
Udgave nummer | 11 |
Antal sider | 12 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
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). The Trøndelag Health Study (HUNT Study) is a collaboration between the HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology), Trøndelag County Council, the Central Norway Regional Health Authority, and the Norwegian Institute of Public Health.
Publisher Copyright:
© 2023 The Author(s).