Trinder M, Wang Y, Madsen CM, et al. - Researchers here examined the hypothesis that HDL levels would be preserved and mortality would be reduced in clinical cohorts and animal models of sepsis by performing genetic or pharmacologic inhibition of cholesteryl ester transfer protein (CETP). Using Cox proportional hazard models adjusted for age and gender, they investigated how a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for reduced CETP function affected 28-day sepsis survival in the UK Biobank (n = 5,949), Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR; n = 882), Copenhagen General Population Study (n = 2,068), Copenhagen City Heart Study (n = 493), Early Infection (n = 200), St. Paul's Intensive Care Unit 2 (n = 203), and Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock studies (n = 632). The effect of the CETP inhibitor anacetrapib were then examined in adult, female APOE*3-Leiden mice with or with human CETP expression using the cecal-ligation and puncture model of sepsis. Findings from clinical genetics and humanized mouse models support that inhibition of CETP may lead to preservation of HDL levels and improvement in outcomes in individuals with sepsis.