The class
Review argues CETP inhibitor failures show over-reliance on HDL cholesterol as an efficacy marker (Clin Lipidol 2013)
Original title: Monogenic causes of elevated HDL cholesterol and implications for development of new therapeutics
This review examines three monogenic causes of elevated HDL cholesterol, CETP, LIPG (endothelial lipase), and APOC3, and their implications for drug development. Identification of these genes and analysis of rare variants within them substantially advanced understanding of HDL metabolism, but the authors argue the failure of two CETP inhibitors illustrates a possible over-reliance on HDL cholesterol itself as a marker of therapeutic efficacy, rather than proof the target was wrong. In contrast, the endothelial lipase and apoC-III cases show the value of population-wide genetic studies of rare variants for gaining direct evidence on cardiovascular endpoints. The authors conclude single-gene studies of HDL-related drug targets should focus on cardiovascular endpoints, not just lipid-profile changes.
Original abstract
Identification of the CETP, LIPG (encoding endothelial lipase) and APOC3 genes, and ana lysis of rare genetic variants in them, have allowed researchers to increase understanding of HDL metabolism significantly. However, development of cardiovascular risk-reducing therapeutics targeting the proteins encoded by these genes has been less straightforward. The failure of two CETP inhibitors is complex but illustrates a possible over-reliance on HDL cholesterol as a marker of therapeutic efficacy. The case of endothelial lipase exemplifies the importance of utilizing population-wide genetic studies of rare variants in potential therapeutic targets to gain information on cardiovascular disease end points. Similar population-wide studies of cardiovascular end points make apoC-III a potentially attractive target for lipid-related drug discovery. These three cases illustrate the positives and negatives of single-gene studies relating to HDL-related cardiovascular drug discovery; such studies should focus not only on HDL cholesterol and other components of the lipid profile, but also on the effect genetic variants have on cardiovascular end points.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.