Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol...

Area of Science:

• Cardiovascular Medicine
• Genetics
• Pharmacology

Background:

• Despite effective low-density lipoprotein cholesterol (LDL-C) lowering therapies, significant cardiovascular disease burden persists.
• Previous attempts to increase high-density lipoprotein (HDL) cholesterol for cardiovascular benefit have been largely unsuccessful, possibly due to metabolic complexity and genetic heterogeneity.
• Residual cardiovascular risk necessitates novel therapeutic strategies beyond LDL-C reduction.

Purpose of the Study:

• To evaluate the efficacy of a cholesterol ester transfer protein (CETP) inhibitor, dalcetrapib, in a cardiovascular outcomes study (dal-GenE).
• To identify a target population likely to benefit from dalcetrapib using a selective genomic test targeting the ADCY9 polymorphism.
• To explore the role of HDL-C as an actionable risk factor through precision medicine.

Main Methods:

• The dal-GenE study (NCT02525939) employed a selective genomic approach to identify participants.
• A cholesterol ester transfer protein inhibitor, dalcetrapib, was administered to the selected subpopulation.
• The study design integrated genetic risk factors and HDL metabolism insights.

Main Results:

• The study focused on a genetically defined subpopulation, investigating the impact of dalcetrapib.
• The ADCY9 polymorphism was a key factor in participant selection, linked to inborn risk.
• The findings aim to clarify the role of HDL-C and CETP inhibition in cardiovascular risk management.

Conclusions:

• Selective treatment of subpopulations based on genetic markers may be crucial for unlocking HDL-C's potential as a therapeutic target.
• Understanding genetic heterogeneity is key to overcoming challenges in HDL-based cardiovascular therapies.
• Precision medicine approaches hold promise for managing residual cardiovascular risk.