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

PURPOSE OF REVIEW: This review examines whether high high-density lipoprotein cholesterol (HDL-C) is protective, harmful, or simply misleading in relation to atherosclerotic cardiovascular disease (ASCVD), with emphasis on recent mechanistic, epidemiologic, genetic, and trial evidence. RECENT FINDINGS: HDL is biologically important and multifunctional, but HDL-C is an imperfect surrogate for HDL function. Recent cohort studies show nonlinear associations, with very high HDL-C not consistently protective and in some settings associated with increased mortality. Mendelian randomization studies do not support HDL-C as a causal protective factor, and randomized trials of HDL-C-raising strategies have generally failed to reduce ASCVD events. These findings have shifted attention from HDL quantity to HDL quality, including cholesterol efflux capacity, particle characteristics, and pathway-specific biology. At the same time, modern cholesteryl ester transfer protein (CETP) inhibition has renewed interest in whether benefit, if any, relates to Apolipoprotein B-lowering rather than HDL-C elevation itself. SUMMARY: HDL biology remains highly relevant, but HDL-C alone should not be interpreted as a reliable marker of atheroprotection or as a therapeutic target. Very high HDL-C should not be used to downplay established causal risk factors. Future research should prioritize functional HDL metrics, deeper phenotyping, and mechanism-aligned trials to determine whether improving HDL quality, rather than simply raising HDL-C, can reduce ASCVD risk.