Implications of torcetrapib failure for the future of HDL therapy: is HDL-cholesterol the right target?

Area of Science:

• Cardiovascular Disease Research
• Lipid Metabolism and Atherosclerosis

Background:

• High-density lipoprotein (HDL) cholesterol is inversely correlated with cardiovascular risk, making it an attractive therapeutic target.
• Previous drug failures (e.g., torcetrapib) and confounding factors raise questions about HDL-C as a sole therapeutic target.
• HDL-C levels do not fully represent HDL particle function, necessitating better assessment tools.

Purpose of the Study:

• To highlight the limitations of HDL-C as a sole measure of HDL's role in cardiovascular disease.
• To emphasize the need for biomarkers that reflect HDL particle functionality.
• To advocate for research into novel therapeutics targeting HDL metabolism and function.

Main Methods:

• Review of existing literature on HDL-C, cardiovascular risk, and therapeutic interventions.
• Analysis of the limitations of current HDL-C measurements in assessing cardiovascular risk.
• Discussion of the need for functional HDL biomarkers.

Main Results:

• HDL-C is an integrative but non-functional measure of HDL particle size and number.
• Existing data on HDL dyslipidemias and therapeutic outcomes are inconsistent.
• Functional biomarkers are crucial for assessing cardiovascular risk and monitoring HDL-related treatments.

Conclusions:

• HDL-C alone is an inadequate target for anti-atherogenic therapy.
• Functional HDL biomarkers are essential for accurate cardiovascular risk assessment.
• Future research should focus on developing therapeutics that enhance HDL metabolism and function to combat atherosclerosis.