Genetics
Genetic CETP inhibition doesn't touch particle-size-defined LDL-C the way statins do, but lowers remnant, VLDL and HDL-triglyceride content instead (PLoS Biol 2019)
Original title: Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition
CETP inhibition reduces vascular event risk, but its effect on LDL cholesterol has been confusing. This study used a genetic variant lowering CETP expression (rs247617) to mimic CETP inhibition, and one lowering HMGCR expression (rs12916) to mimic statins, in 65,427 European-ancestry participants with NMR lipoprotein subclass profiling, and separately checked observational associations with incident CHD in three cohorts (616 cases, 13,564 controls). Genetic CETP and HMGCR inhibition gave near-identical associations with Friedewald-estimated LDL cholesterol, but HMGCR inhibition lowered cholesterol consistently across all apoB-containing lipoproteins, while CETP inhibition acted more strongly on remnant and VLDL cholesterol, with no effect on LDL cholesterol defined by particle size (18 to 26 nm). CETP inhibition was also strongly associated with a lower proportion of triglycerides within HDL particles, and higher HDL triglyceride content was independently associated with higher CHD risk in the observational cohorts. CETP inhibition appears to lower CHD risk mainly through remnant and VLDL cholesterol rather than particle-size-defined LDL-C, meaning standard lipid panels mask this heterogeneity.
Original abstract
Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.