Dalcetrapib
Beyond failed HDL trials: a review argues the dal-GenE genomic-test approach to dalcetrapib and ADCY9 is the key to actionable HDL therapy (J Cardiovasc Pharmacol 2021)
Original title: Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition
A review argues that decades of unsuccessful attempts to raise HDL as a strategy for atherosclerotic cardiovascular disease reflect the complexity of HDL metabolism and the heterogeneity of human genetics, since earlier HDL trial failures were confounded by other lipid changes and unsuccessful when isolating HDL elevation alone. The authors present dal-GenE (NCT02525939) as the first large cardiovascular outcomes trial to use a genomic test to select the subpopulation most likely to benefit, testing the CETP inhibitor dalcetrapib specifically in patients with a particular ADCY9 polymorphism. Both the CETP drug target and the ADCY9 diagnostic marker are grounded in inherited variation and an evolving understanding of inborn cardiovascular risk. The authors propose that selectively treating genetically defined subpopulations, rather than treating HDL as a universal target, may resolve the long-standing puzzle of why raising HDL has not translated into cardiovascular benefit.
Original abstract
Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.