Should we take high-density lipoprotein cholesterol levels at face value?

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Atherosclerosis Research

Background:

• High-density lipoprotein (HDL) cholesterol levels inversely correlate with cardiovascular disease (CVD).
• Targeting increased HDL to prevent atherosclerosis has yielded mixed and often negative results.
• The mechanism of HDL elevation significantly impacts cardiovascular outcomes.

Purpose of the Study:

• To investigate the differential impact of HDL-C raising mechanisms on cardiovascular outcomes.
• To explore the role of reverse cholesterol transport (RCT) independent of HDL-C levels.
• To re-evaluate therapeutic strategies for atherosclerosis prevention.

Main Methods:

• Review of clinical trial data and observational studies.
• Analysis of outcomes based on HDL-C elevation secondary to synthesis versus reduced catabolism.
• Examination of genetic studies, such as individuals with apolipoprotein A-I Milano.

Main Results:

• HDL-C increases from greater synthesis (e.g., fibrates) show beneficial cardiovascular effects.
• HDL-C increases from reduced catabolism (e.g., CETP inhibitors) are linked to adverse cardiovascular events.
• Individuals with apolipoprotein A-I Milano have low HDL-C but increased RCT and low CVD incidence.

Conclusions:

• The mechanism of HDL-C elevation is critical for cardiovascular outcomes, not just the level.
• Improving reverse cholesterol transport may be more important than raising HDL-C levels.
• Clinical practice should maintain HDL-C targets, but research should focus on enhancing RCT through novel methods.