Anacetrapib
Genetic and drug-based CETP inhibition preserves HDL and improves survival in sepsis, in humans and humanized mice (Circulation 2021)
Original title: Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis
Since CETP activity partly explains the drastic fall in HDL cholesterol seen during sepsis, this study tested whether inhibiting CETP could preserve HDL and reduce sepsis mortality. Meta-analysis across seven cohorts, including UK Biobank and the Copenhagen studies, found the CETP gain-of-function variant rs1800777 significantly associated with increased 28-day sepsis mortality (hazard ratio 1.44, 95% CI 1.22-1.70, P less than 0.0001), while a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in UK Biobank (hazard ratio 0.77, 95% CI 0.59-1.00 per 1 mmol/L HDL-C increase) and iSPAAR (hazard ratio 0.60, 95% CI 0.37-0.98). In APOE*3-Leiden mice expressing human CETP, anacetrapib treatment preserved HDL-C and apoA-I and increased sepsis survival (70.6% versus 35.3%, log-rank P equals 0.03), with no survival effect in mice lacking CETP expression (50.0% versus 42.9%, log-rank P equals 0.87), together indicating CETP inhibition may improve sepsis outcomes by preserving HDL.
Original abstract
Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.
Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), 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). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis.
Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87).
Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.
anacetrapibgeneticsinfectionmechanisms
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.