A CETP inhibitor is a member of a class of drugs that inhibit
cholesterylester transfer protein
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low ...
(CETP).
They are intended to reduce the risk of
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
(a
cardiovascular disease
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
) by improving blood lipid levels. At least three medications within this class have failed to demonstrate a beneficial effect.
Types
These drugs have generally failed in clinical trials, either causing a marked increase in deaths (
torcetrapib), or having no meaningful clinical improvement despite HDL increases (
dalcetrapib,
evacetrapib).
Failed:
*
Torcetrapib: failed in 2006 due to excess deaths in Phase III clinical trials.
*
Dalcetrapib: development halted in May 2012 when Phase III trials failed to show clinically meaningful efficacy.
*
Evacetrapib: development discontinued in 2015 due to insufficient efficacy.
Others:
*
Anacetrapib: In 2017, the REVEAL trial based on more than 30,000 participants showed a modest benefit of the addition of anacetrapib to statin therapy.
halted the development of the drug in 2017, concluding it wasn't sufficiently effective to be a competitive product.
*
Obicetrapib (TA-8995, AMG-899): Phase II results were reported in 2015 and Phase III trials beginning in 2023.
Mechanism
Drugs in this class substantially increase
HDL cholesterol, lower
LDL cholesterol
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall dens ...
, and enhance
reverse cholesterol transport.
CETP inhibitors inhibit
cholesterylester transfer protein
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low ...
(CETP), which normally transfers cholesterol from
HDL cholesterol to
very low density or
low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels and reduces LDL levels.
CETP inhibitors do not reduce rates of mortality, heart attack, or stroke in patients already taking a statin.
Pharmacogenomics
In 2015, a pharmacogenomic sub-study of the dal-OUTCOMES clinical trial on 5,749 individuals identified a genetic variant in the ADCY9 gene which modulates response to
dalcetrapib. In patients with the rs1967309 'AA' genotype, there was a significant reduction in the rate of cardiovascular events in the dalcetrapib arm whereas non-carriers were at increased risk. Beginning in 2015, the efficacy of dalcetrapib in the genetic sub-population was being investigated in the dal-GenE trial.
Chemical structures
References
{{Lipid modifying agents