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Review asks why targeting HDL for cardiovascular protection has not delivered clinical benefit (J Cardiovasc Pharmacol 2013)
Original title: Why targeting HDL should work as a therapeutic tool, but has not
This review examines why raising HDL cholesterol has not translated into reduced cardiovascular risk despite a strong inverse epidemiological association between plasma HDL cholesterol and cardiovascular disease. It describes reverse cholesterol transport, in which ATP-binding cassette transporter A1 packages cellular cholesterol into nascent HDL with apolipoprotein A-I for hepatic uptake, and identifies CETP inhibition, which blocks the transfer of cholesteryl ester from HDL to triglyceride-rich particles, as the most widely pursued pharmacological approach to raising HDL cholesterol. While CETP inhibition reliably raises plasma HDL cholesterol, the review notes that clinical benefit has not been demonstrated, likely due to off-target effects, prompting a shift toward cholesterol efflux capacity and apolipoprotein A-I function as better predictors of cardiovascular risk than HDL cholesterol concentration alone.
Original abstract
Atherosclerosis is one of the most common causes of death and disability in the United States today despite the availability of statins, which reduce hyperlipidemia, a risk factor that predisposes individuals to this disease. Epidemiology of human populations has overwhelmingly demonstrated an inverse correlation between the concentration of plasma high-density lipoprotein (HDL) cholesterol (HDL-C) and the likelihood of developing cardiovascular disease (CVD). Decades of observations and mechanistic studies suggest that one protective function of HDL is its central role in reverse cholesterol transport. In this pathway, the ATP-binding cassette transporter A1 releases intracellular cholesterol, which is packaged with apolipoprotein A-I (apoA-I) into nascent HDL particles and released from the plasma membrane. Further lipidation and maturation of HDL occur in plasma with the eventual uptake by the liver where cholesterol is removed. It is generally accepted that CVD risk can be reduced if plasma HDL-C levels are elevated. Several different pharmacological approaches have been tried; the most popular approach targets the movement of cholesteryl ester from HDL to triglyceride-rich particles by cholesteryl ester transfer protein. Inhibition of cholesteryl ester transfer protein increases plasma HDL-C concentration; however, beneficial effects have yet to be demonstrated, likely the result of off-target effects. These revelations have led to a reevaluation of how elevating HDL concentration could decrease risk. A recent, landmark study showed that the inherent cholesterol efflux capacity of an individual's plasma was a better predictor of CVD status than overall HDL-C concentration. Even more provocative are recent studies showing that apoA-I, the principle protein component of HDL modulates cellular inflammation and oxidation. The following will review all these potential routes explaining how HDL apoA-I can reduce the risk of CVD.
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Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.