Mendelian randomization finds genetically proxied CETP inhibition reduces sepsis-related critical care admission and death (World J Emerg Med 2025)

Original title: Exploring lipid-modifying therapies for sepsis through the modulation of circulating inflammatory cytokines: a Mendelian randomization study

World J Emerg Med · 1 May 2025 · 7

Li Q, Qu Y, Xue J, Kang H, Lyu C

To test whether lipid-modifying drugs causally affect sepsis outcomes, researchers first validated causal associations between HDL cholesterol, LDL cholesterol and sepsis using two-sample Mendelian randomization, then used drug-target Mendelian randomization to assess genetically proxied lipid-modifying therapies against sepsis risk, sepsis-related critical care admission, and sepsis-related death, followed by analysis of 36 circulating inflammatory cytokines and enrichment analyses. Genetically proxied CETP inhibitors were significantly associated with reduced sepsis-related critical care admission (odds ratio 0.84, 95% CI 0.74 to 0.95, P equals 0.008) and reduced sepsis-related death (odds ratio 0.68, 95% CI 0.52 to 0.88, P equals 0.004), and were strongly associated with levels of 15 circulating inflammatory cytokines. The authors conclude CETP inhibition causally reduces the risk of severe sepsis outcomes, likely through modulation of inflammatory cytokine pathways.

Original abstract

Background: Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain. Therefore, systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines, which may play critical roles in the pathogenesis of sepsis. This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.

Methods: First, a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and sepsis. A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetically proxied lipid-modifying therapies on the risk of sepsis, sepsis-related critical care admission, and sepsis-related death. The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines. Finally, enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.

Results: Genetically proxied cholesteryl ester transfer protein (CETP) inhibitors were significantly associated with sepsis-related critical care admission (OR=0.84, 95% CI [0.74, 0.95], P=0.008,) and sepsis-related death (OR=0.68, 95% CI [0.52, 0.88], P=0.004). The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines. Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.

Conclusion: This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death. These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines, influencing the inflammatory response pathway.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.