Association Between Very High HDL-C Levels And Mortality: A Systematic Review And Meta-analysis

Background Recent research has raised questions about the assumed cardiovascular (CV) benefits of high-density lipoprotein cholesterol (HDL-C) and the potential for adverse outcomes with extremely high levels. Objective We conducted a meta-analysis to investigate the association between very high HDL-C levels (≥80 mg/dL) and mortality outcomes in individuals without coronary artery disease (CAD). Methods We systematically searched PubMed, Embase, and Cochrane databases for studies comparing very high HDL-C levels to normal levels (40-60 mg/dL) in CAD-free individuals. We assessed heterogeneity using I2 statistics with a random-effects model. Results Our analysis included 1,004,584 individuals from 8 studies, of whom 133,646 (13.3%) had very high HDL-C levels. All-cause mortality did not significantly differ between groups (p=0.55), nor did cancer mortality (p=0.45). Cardiovascular mortality showed no change in those with very high HDL-C (HR 1.05; 95% CI 0.94-1.17; p=0.37). Fatal and non-fatal coronary heart disease events were less frequent in the very high HDL-C group (HR 0.79; 95% CI 0.73–0.86; p<0.00001). Subgroup dose-response analysis revealed that very high HDL-C levels increased cardiovascular death in women above 116 mg/dL (HR 1.47; 95% CI 1.01-2.15) and in men above 94 mg/dL (HR 1.29; 95% CI 1.01-1.65) (p_nonlinearity <0.01). Conclusions These findings suggest that very high HDL-C levels are not protective against cardiovascular mortality and may, in fact, increase CV mortality risk specially in men.