The class
A review argues CETP inhibitor trial failures show HDL-C elevation alone is insufficient, motivating apoA-I-targeted therapies instead (Drugs 2010)
Original title: Therapeutic interventions to enhance apolipoprotein A-I-mediated cardioprotection
High-density lipoprotein (HDL) primarily functions to facilitate reverse cholesterol transport (RCT) and inhibit atheroma formation, and epidemiologic and interventional evidence has suggested HDL is cardioprotective, but raising HDL concentration does not necessarily increase RCT, particularly when the increase results from inhibiting HDL cholesterol flux rather than boosting production. This review notes that recent phase III trials using a cholesteryl ester transfer protein (CETP) inhibitor to raise HDL cholesterol in hypoalphalipoproteinaemia showed this approach insufficient to combat atherosclerosis or reduce cardiovascular risk. A more desirable approach, the review argues, is enhancing de novo hepatic and intestinal HDL production, and knowledge of the apolipoprotein A-I gene promoter has fueled development of pharmacological agents that selectively regulate its transcription, de-repress its expression, or deliver recombinant apolipoprotein A-I or mimetics.
Original abstract
The principal function of high-density lipoprotein (HDL) is to facilitate the reverse cholesterol transport (RCT) and inhibition of atheroma formation. Epidemiological studies and interventional trials have suggested that HDL has cardioprotective properties. However, increasing HDL concentration may not necessarily increase RCT, especially if the increase in HDL levels is the result of inhibiting HDL cholesterol (HDL-C) flux. The results of recent phase III clinical trials utilizing a cholesterol ester transfer protein (CETP) inhibitor to increase HDL-C levels in hypoalphalipoproteinaemia have shown that this approach of elevating HDL-C levels is insufficient to combat atherosclerosis and reduce the risk of cardiovascular disease. Although there are several interventions that increase HDL-C by preventing its turnover in the circulation, a more desirable approach is to enhance de novo production of HDL in the liver and/or small intestine. To this end, our acquired knowledge of the apolipoprotein-I (apo A-I) gene promoter as well as the signalling pathways that modulate its expression, has fuelled the development of novel therapeutic strategies to increase HDL-C flux. Promising pharmacological agents that selectively regulate transcription of the apo A-I gene, therapeutic strategies to de-repress apo A-I gene expression, and infusion of recombinant apo A-I or apo A-I mimetics are under development and may be clinically beneficial in the near future.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.