Beyond quantity: The nonlinear association between HDL cholesterol and coronary atherosclerosis

This letter provides a critical perspective on the recent study by Laukkanen et al. examining the association between high-density lipoprotein cholesterol (HDL-C) levels and coronary atherosclerosis. While the authors' demonstration of a nonlinear, inverse relationship is noteworthy, our analysis highlights fundamental limitations in interpreting HDL-C as a causal risk factor. We emphasize that the observed plateau effect at higher HDL-C levels aligns with evidence from Mendelian randomization studies and failed trials of HDL-C-raising therapies, which collectively question the "more is better" paradigm. Substantial methodological limitations are addressed, including the reliance on static HDL-C measurements that fail to capture HDL's functional heterogeneity. Furthermore, we discuss how residual confounding by metabolic syndrome components may partly explain the association at low HDL-C levels. We conclude that the field must transition from quantifying HDL cholesterol to assessing its functionality, as this shift is essential for advancing our understanding of HDL's role in cardiovascular disease.