Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation.
Level 5 - mechanism / opinion, no new human data
Narrative review evaluating clinical trial outcomes, genetic data, and mechanistic pathways without a systematic review protocol.
PubMed 27454452 · doi:10.1097/MOL.0000000000000332
What was done
This narrative review synthesized human genetic findings, prospective epidemiological studies, and results from cardiovascular outcome trials of three pharmacological cholesteryl ester transfer protein (CETP) inhibitors (torcetrapib, dalcetrapib, and evacetrapib) to re-evaluate the physiological and clinical role of CETP in reverse cholesterol transport and atherosclerosis.
What was found
The abstract reports no numerical data. It notes that large outcome trials for torcetrapib, dalcetrapib, and evacetrapib were stopped early due to futility or increased mortality, despite increasing HDL cholesterol and lowering LDL cholesterol (except for dalcetrapib). It highlights that genetic CETP deficiency is sometimes associated with atherosclerotic cardiovascular disease, and prospective epidemiological studies indicate atheroprotective roles for CETP. Mechanistically, CETP inhibition was reported to generate small dense LDL, promote dysfunctional HDL, and downregulate hepatic scavenger receptor class B type I (SR-BI), thereby impairing reverse cholesterol delivery to the liver.
Why it matters
It provides a mechanistic explanation for why raising HDL-C via CETP inhibition failed to prevent cardiovascular events, suggesting future drug development should focus on enhancing reverse cholesterol transport rather than inhibiting it.
Limits
As an unsystematic narrative review, it is vulnerable to selection bias. The abstract provides no quantitative effect sizes, pooled estimates, or specific cohort statistics. Mechanistic hypotheses regarding dysfunctional HDL and SR-BI downregulation require further direct clinical validation.
Cited by
- supports In humans, LDL performs the majority of reverse cholesterol transport by receiving cholesterol transferred from HDLs and transporting it back to the liver.