HDL particle functionality as a primary pharmacological target for HDL-based therapies

Area of Science:

• Cardiovascular Medicine
• Lipid Metabolism
• Pharmacology

Background:

• Coronary heart disease (CHD) prevalence is increasing globally.
• High-density lipoprotein (HDL) cholesterol is a traditional target for CHD treatment.
• Current HDL-targeting drugs have shown limited success in clinical trials.

Purpose of the Study:

• To review the limitations of targeting HDL cholesterol (HDL-C) levels for CHD treatment.
• To highlight the heterogeneity of HDL particles and their functional implications.
• To propose HDL particle functionality as a more effective therapeutic target for CHD.

Main Methods:

• Review of epidemiological studies on HDL and CHD.
• Analysis of recent clinical trial data for HDL-targeting therapies.
• Discussion of HDL particle composition and function.

Main Results:

• Pharmacological elevation of HDL-C levels has not consistently translated to atheroprotection.
• HDL is a heterogeneous particle mixture with varying atheroprotective and proatherogenic functions.
• Existing therapeutic strategies targeting HDL-C levels do not account for HDL's functional diversity.

Conclusions:

• HDL-C levels are an inadequate surrogate for HDL's atheroprotective capacity.
• HDL particle functionality, rather than mere quantity, should guide pharmaceutical development.
• A shift towards targeting HDL function is necessary for developing effective HDL-based CHD treatments.