High-density lipoprotein cholesterol targeting for novel drug discovery: where have we gone wrong?

Area of Science:

• Cardiovascular Medicine
• Biochemistry
• Pharmacology

Background:

• Lowering low-density lipoprotein-cholesterol (LDL-C) effectively reduces cardiovascular risk, but residual risk persists in statin-treated patients.
• High-density lipoprotein cholesterol (HDL-C) is an independent inverse predictor of cardiovascular risk, making it a potential therapeutic target.
• Previous clinical trial failures (CETP inhibitors, niacin) created doubt regarding HDL's therapeutic benefits.

Purpose of the Study:

• To explore the potential of HDL-C as a therapeutic target for residual cardiovascular risk.
• To investigate the diverse cardioprotective functions of HDL and its subpopulations.
• To highlight the need for validated measures of HDL functionality.

Main Methods:

• Review of experimental studies identifying HDL's cardioprotective functions.
• Analysis of epidemiological data on HDL-C and cardiovascular risk.
• Discussion of challenges in translating HDL research into clinical practice.

Main Results:

• HDL exhibits multiple cardioprotective functions: enhancing reverse cholesterol transport, improving endothelial function, and possessing antioxidant, anti-inflammatory, and anti-thrombotic properties.
• HDL is heterogeneous, with varying atheroprotective functions among subpopulations.
• Increased HDL-C levels do not consistently correlate with enhanced HDL functionality.

Conclusions:

• HDL-C remains a potential therapeutic target, but its functional capacity is key.
• Current understanding of HDL subpopulations and their functions requires further investigation.
• Development of validated assays for HDL function is essential for advancing HDL-based therapies.