Effects of CETPi cholesterol drugs may depend on genetic variants

A new study, presented at the 2017 European Society of Cardiology Congress, assessed the efficacy of new lipid-lowering drugs called cholesteryl ester transfer protein inhibitors (CETPis) and found that it may depend on genetic variants.
CETPis are drugs used for preventing unbalanced cholesterol levels and atherosclerotic plaques (fatty deposits) from forming in the arteries of those at higher risk for cardiovascular disease (CVD), such as people with type 2 diabetes.
They work by inhibiting the protein CETP, which plays a role in the transport of esters of cholesterol, or dietary lipids, between molecules called lipoproteins that carry cholesterol in the blood.
They are two important kinds of lipoproteins: the low-density lipoprotein (LDL), dubbed atherogenic (promoting atherosclerosis) and the healthful kind, high-density lipoprotein (HDL).
The protein CETP promotes the transfer of dietary lipids from HDLs to, in part, LDLs. In contrast, a deficiency in CETP triggered by CETPis is thought to lead to increased HDL levels and decreased LDL levels.
Some CETPis that have gone through phase II and phase III clinical trials have showed mixed results. For example, the CETPi Dalcetrapib elevates HDL but did not reduce LDL.
Researchers have recently reported at the latest ESC meeting that CETPis are not as effective as statins in reducing cholesterol precisely for that reason, because they have a lower LDL-lowering capacity than statins.
However, there is a debate as to whether focusing on reducing LDL by any mean for lowering CVD risk is effective or if depends on how LDL cholesterol is lowered.
Results from one of the most recent CETP trial, ACCELERATE, show that, despite reducing cholesterol by 39 per cent, the CETP evacetrapib failed to cut the risk of CVD death, myocardial infarction or stroke.
The new data, published online in the journal JAMA, now suggest that the action of CETPis may depend on genetic variants that researchers have tested for in hundreds of thousands of participants from 48 different studies.
They have found that genetic variants that mimic the effect of CETPis were associated with higher HDL cholesterol, lower LDL cholesterol, lower apoB – which is a component of lipoproteins involved in atherosclerosis – and a lower risk of CVD.
The second surprising finding is that other variants with discordant effects on LDL cholesterol and apoB were associated with a lower CVD risk that was more proportional to the change in apoB than a change in LDL cholesterol.
Overall, further trials are needed but these most findings suggest that it might be the change in apoB and gene variants that influence CVD risks, which would explain why certain CETPis do not reduce CVD despite significantly lowering LDL.

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