High-Density Lipoprotein and Cardiovascular Disease-Where do We Stand?

Area of Science:

• Cardiovascular Medicine
• Biochemistry
• Genetics

Background:

• High-density lipoprotein cholesterol (HDL-C) levels are consistently associated with atherosclerotic cardiovascular disease (ASCVD) risk.
• Animal studies and biological mechanisms suggest HDL particles may be protective against atherosclerosis.
• A strong association does not confirm causality, prompting further investigation into HDL-C's role.

Purpose of the Study:

• To critically evaluate the causal role of HDL-C in atherosclerotic cardiovascular disease (ASCVD).
• To reconcile observational data with genetic and clinical trial findings regarding HDL-C and ASCVD.
• To assess the therapeutic potential of targeting HDL-C for ASCVD prevention.

Main Methods:

• Review of epidemiological studies demonstrating the association between HDL-C and ASCVD.
• Analysis of Mendelian randomization studies investigating the causal relationship between HDL-C and ASCVD.
• Examination of results from clinical trials testing HDL-C-raising therapies for ASCVD outcomes.

Main Results:

• Observational studies show a strong, consistent association between higher HDL-C levels and lower ASCVD risk.
• Mendelian randomization data challenge the causal role of HDL-C in ASCVD.
• Clinical trials of drugs designed to increase HDL-C have largely failed to demonstrate a reduction in ASCVD events.

Conclusions:

• The observed association between HDL-C and ASCVD may not reflect a direct causal relationship.
• Targeting HDL-C levels alone may not be an effective strategy for preventing or treating ASCVD.
• Further research is needed to understand the complex biology of HDL and its role in cardiovascular health.