HDL as a Treatment Target: Should We Abandon This Idea?

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Pharmacology

Background:

• High-density lipoproteins (HDL) are recognized for their antiatherogenic properties, including reverse cholesterol transport (RCT), anti-inflammatory, and antioxidant functions.
• HDL has been a long-standing therapeutic target for atherosclerotic cardiovascular diseases (ASCVD).

Purpose of the Study:

• To review the current status of HDL as a therapeutic target for ASCVD.
• To discuss the implications of recent clinical trial outcomes on HDL-based therapies.
• To explore future directions for HDL-based therapeutic strategies beyond ASCVD.

Main Methods:

• Review of existing literature on HDL function and therapeutic interventions.
• Analysis of outcomes from major clinical trials involving HDL-modulating drugs and reconstituted HDL infusions.
• Discussion of emerging research on optimizing HDL properties for therapeutic applications.

Main Results:

• Previous attempts to increase HDL levels or infuse reconstituted HDL have not yielded convincing cardiovascular benefits.
• Two pivotal clinical trials (CETP inhibitor Obicetrapib and reconstituted HDL infusion) are pending, which may determine the future of HDL as a direct therapeutic target.
• The efficacy of HDL as a therapeutic agent may depend on optimizing its beneficial properties.

Conclusions:

• The role of HDL as a direct therapeutic target for ASCVD is uncertain pending results of ongoing trials.
• Future therapeutic strategies may focus on enhancing HDL's beneficial functions rather than solely increasing its levels.
• HDL may hold therapeutic promise beyond cardiovascular diseases by optimizing its multifaceted properties.