Advances in the Study of the Antiatherogenic Function and Novel Therapies for HDL

Area of Science:

• Cardiovascular Medicine
• Lipid Metabolism
• Pharmacology

Background:

• The long-held hypothesis that increasing high-density lipoprotein cholesterol (HDL-C) levels reduces cardiovascular disease (CVD) risk is increasingly challenged.
• Recent clinical trials of HDL-C-raising drugs have failed to demonstrate a clear association with reduced CVD risk.
• Genetic studies suggest that steady-state HDL-C concentrations may not fully reflect the antiatherogenic capacity of HDL.

Purpose of the Study:

• To review current HDL therapeutics and explore newer strategies beyond simply raising plasma HDL-C levels.
• To highlight the need for efficient biomarkers predicting atherosclerosis (AS) risk.
• To examine the role of HDL composition, structure, and function in cardiovascular risk.

Main Methods:

• Review of recent clinical trial data on HDL-C-raising drugs.
• Analysis of genetic and biochemical studies on HDL function.
• Examination of the reverse cholesterol transport (RCT) pathway as a key mechanism of HDL's antiatherogenic effect.

Main Results:

• Current evidence indicates that simply increasing HDL-C levels does not translate to reduced CVD risk.
• HDL's antiatherogenic properties are linked to its composition, structure, and function, particularly the reverse cholesterol transport (RCT) process.
• Disappointing outcomes from clinical trials targeting HDL necessitate a re-evaluation of therapeutic approaches.

Conclusions:

• Therapeutic strategies solely focused on increasing plasma HDL-C levels are unlikely to be effective for CVD prevention.
• Future research should focus on understanding and targeting HDL's functional capabilities, such as RCT.
• Development of novel biomarkers reflecting HDL's functional status is crucial for identifying patients at risk for atherosclerosis and guiding new therapeutic development.