Epidemiology
High Lp(a) erases the mortality benefit of high HDL-C, especially in men, cohort of 97,396 (Coron Artery Dis 2026)
Original title: High lipoprotein(a) attenuates the mortality benefit of elevated high-density lipoprotein cholesterol with sex-specific variation: a retrospective cohort study
Retrospective cohort of 97,396 patients with measured Lp(a) and HDL-C, stratified by Lp(a) (50 mg/dL or more vs below) and HDL-C category (low below 40, optimal 40-60, high above 60 mg/dL), followed a median 5.9 years (7794 deaths). Versus the optimal-HDL-C/low-Lp(a) reference, high HDL-C with low Lp(a) had the lowest mortality (adjusted HR 0.85, 95% CI 0.80-0.91), while low HDL-C with high Lp(a) had the highest (adjusted HR 1.55, 95% CI 1.41-1.71); high HDL-C's protective effect became non-significant when Lp(a) was elevated (adjusted HR 0.98, 95% CI 0.89-1.08). Sex-stratified analysis showed women with high HDL-C and high Lp(a) retained a protective effect (adjusted HR 0.82, 95% CI 0.72-0.93), while men with the same combination had increased risk (adjusted HR 1.22, 95% CI 1.05-1.42). The authors conclude elevated Lp(a) blunts HDL-C's protective association with mortality, more so in men than women.
Original abstract
Background: Elevated lipoprotein(a) [Lp(a)] and low high-density lipoprotein-cholesterol (HDL-C) are established cardiovascular (CV) risk factors, but their combined impact on mortality and sex differences remains unclear.
Methods: This retrospective study analyzed 97 396 patients with measured Lp(a) and HDL-C. Groups were stratified by Lp(a) (≥50 vs. <50 mg/dl) and HDL-C [low (<40), optimal (40-60), high (>60 mg/dl)]. Mortality was assessed using the Kaplan-Meier curve and Cox models.
Results: Over a median of 5.9 years, 7794 deaths occurred. Compared to optimal HDL-C/low Lp(a) (reference), high HDL-C/low Lp(a) had the lowest mortality [adjusted hazard ratio (aHR): 0.85; 95% confidence interval (CI): 0.80-0.91], while low HDL-C/high Lp(a) had the highest risk (aHR: 1.55; 1.41-1.71). High HDL-C protective effect was insignificant with elevated Lp(a) (aHR: 0.98; 0.89-1.08). Sex-stratified analyses revealed divergent effects: women with high HDL-C/high Lp(a) retained the HDL-C protective effect (aHR: 0.82; 0.72-0.93), whereas men faced increased risk (aHR: 1.22; 1.05-1.42).
Conclusion: Elevated Lp(a) enhances mortality risk despite elevated HDL-C levels, with sex-specific differences: women retain mortality benefits from high HDL-C despite elevated Lp(a), whereas men with concurrent elevations in HDL-C and Lp(a) experienced mortality risks comparable to those with low HDL-C. Findings underscore sex-specific CV risk stratification incorporating HDL-C and Lp(a), challenging the HDL-C universal protective role.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.