HDL-targeted therapies: progress, failures and future

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Pharmacology

Background:

• Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular outcomes.
• HDL's anti-atherogenic properties have led to the hypothesis that increasing HDL-C is a viable therapeutic strategy.
• Recent clinical trials of HDL-C-raising agents have yielded disappointing results, challenging the established HDL hypothesis.

Purpose of the Study:

• To critically examine the HDL hypothesis in molecular and mechanistic detail.
• To evaluate the effectiveness of non-selective HDL-C elevation as a therapeutic approach.
• To identify gaps in understanding HDL biology and explore novel therapeutic targets.

Main Methods:

• Review of existing literature on HDL cholesterol, particle subpopulations, and reverse cholesterol transport.
• Analysis of molecular and mechanistic aspects of HDL's atheroprotective functions.
• Examination of recent pharmacological interventions targeting HDL-C.

Main Results:

• The relationship between HDL-C concentration, particle number, and subpopulations is complex.
• The direct link between elevated HDL-C and cardiovascular benefit is questionable.
• Current understanding of HDL biology is incomplete, hindering effective therapeutic translation.

Conclusions:

• Simply increasing HDL-C levels may not be sufficient to confer cardiovascular protection.
• Further research into the diverse functions of HDL particle subpopulations is necessary.
• New therapeutic strategies should target specific HDL functionalities rather than total HDL-C.