Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition

J Cardiovasc Pharmacol. 2021 Oct 1;78(4):496-500. doi: 10.1097/FJC.0000000000001093.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenylyl Cyclases / genetics*
  • Adenylyl Cyclases / metabolism
  • Amides / therapeutic use*
  • Anticholesteremic Agents / therapeutic use*
  • Atherosclerosis / blood
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / genetics
  • Biomarkers / blood
  • Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
  • Cholesterol Ester Transfer Proteins / metabolism
  • Clinical Decision-Making
  • Clinical Trials as Topic
  • Esters / therapeutic use*
  • Humans
  • Lipoproteins, HDL / blood*
  • Pharmacogenetics
  • Pharmacogenomic Testing
  • Pharmacogenomic Variants*
  • Polymorphism, Single Nucleotide*
  • Predictive Value of Tests
  • Research Design
  • Sulfhydryl Compounds / therapeutic use*
  • Treatment Failure
  • Up-Regulation


  • Amides
  • Anticholesteremic Agents
  • Biomarkers
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Esters
  • Lipoproteins, HDL
  • Sulfhydryl Compounds
  • dalcetrapib
  • Adenylyl Cyclases
  • adenylate cyclase 9

Associated data