HDL and ASCVD: is high HDL-C protective, harmful, or simply misleading?

Area of Science:

• Cardiovascular Medicine
• Lipid Metabolism
• Atherosclerosis Research

Background:

• High-density lipoprotein cholesterol (HDL-C) is traditionally viewed as protective against atherosclerotic cardiovascular disease (ASCVD).
• However, HDL-C may be an imperfect surrogate for the actual function of HDL particles.
• Recent evidence questions the consistent atheroprotective role of high HDL-C levels.

Purpose of the Study:

• To evaluate whether high HDL-C is protective, harmful, or misleading regarding ASCVD risk.
• To review recent mechanistic, epidemiologic, genetic, and clinical trial data.
• To assess the role of HDL quantity versus quality in ASCVD.

Main Methods:

• Review of recent cohort studies examining HDL-C associations with mortality and ASCVD.
• Analysis of Mendelian randomization studies to assess causality.
• Evaluation of randomized controlled trials for HDL-C-raising therapies.
• Examination of emerging research on HDL function and CETP inhibition.

Main Results:

• Very high HDL-C levels are not consistently protective and can be associated with increased mortality.
• Mendelian randomization studies do not support HDL-C as a causal protective factor.
• Randomized trials of HDL-C-raising strategies have largely failed to reduce ASCVD events.
• Attention is shifting towards HDL quality metrics like cholesterol efflux capacity.

Conclusions:

• HDL biology is important, but HDL-C alone is not a reliable marker for atheroprotection or a therapeutic target.
• Very high HDL-C should not overshadow established cardiovascular risk factors.
• Future research must prioritize functional HDL metrics and mechanism-aligned trials to improve ASCVD risk reduction.