Should low high-density lipoprotein cholesterol (HDL-C) be treated?

Area of Science:

• Cardiovascular Medicine
• Lipidology
• Translational Science

Background:

• Low serum high-density lipoprotein cholesterol (HDL-C) is a significant predictor of cardiovascular disease (CVD) risk globally.
• The
• HDL hypothesis
• postulates that raising HDL-C levels will reduce cardiovascular events.
• Despite decades of research, clinical evidence supporting this hypothesis remains limited.

Purpose of the Study:

• To review the evidence linking HDL-C levels to cardiovascular risk.
• To examine the proposed atheroprotective mechanisms of HDL particles.
• To evaluate the findings of therapeutic interventions aimed at increasing HDL-C.

Main Methods:

• Review of observational studies and randomized controlled trials (RCTs).
• Analysis of meta-analyses and post hoc trial data.
• Exploration of the HDL proteome and lipidome for mechanistic insights.

Main Results:

• Four recent prospective trials (ILLUMINATE, dal-OUTCOMES, AIM-HIGH, HPS2-THRIVE) failed to demonstrate that raising HDL-C reduces cardiovascular events.
• Some post hoc analyses suggest potential benefits of HDL-C-raising therapies, especially with concurrent LDL-C reduction.
• The biological plausibility for HDL's atheroprotective role exists due to its complex composition.

Conclusions:

• The assumption that raising HDL-C directly reduces cardiovascular event risk is questioned by recent trial outcomes.
• HDL-C should not currently be considered a direct target for therapy.
• Further research into HDL particle function and novel therapeutic strategies is warranted.