Objective:

To explore the complexities of HDL in relation to cardiovascular disease (CVD) and its implications for treatment.

Approach:

• Clinical Trials: High-dose niacin and cholesteryl ester transfer protein inhibitors raised HDL-C levels but did not reduce CVD risk.
• Mendelian Randomization Studies: Studies showed no causal association between genetic variants affecting HDL levels and CVD.
• Preclinical Studies: Demonstrated HDL's direct vascular protective and antidiabetic actions across various cell types.
• Lipid Marker Studies: Research indicated that combining HDL with other lipid markers improves cardiovascular risk prediction.
• Metabolic Context Analysis: Study of individuals with normal BMI showed insulin resistance may exist in non-obese populations.
• Genetic Analysis: Exome sequencing identified rare genetic variants contributing to low HDL-C syndrome.
• Therapeutic Review: Combination of PCSK9 inhibitors and statins showed greater cardiovascular benefits than statin monotherapy.

Key Findings:

• HDL-C levels alone do not reliably predict cardiovascular risk.
• Lipid-related composite indices may better capture cardiovascular risk than HDL-C alone.
• Insulin resistance can occur in individuals with normal BMI, affecting HDL-related risk interpretation.
• HDL exhibits genetic and biological complexity, influencing its role in CVD.

Interpretation:

Limitations:

• The studies reviewed may not encompass all aspects of HDL's role in CVD.
• Potential confounding factors in observational studies may affect results.

Conclusion:

This editorial emphasizes the importance of understanding HDL beyond traditional metrics.