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.