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 (hazard ratio [HR] 1.05; 95% confidence interval [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 CV mortality and may, in fact, increase CV mortality risk especially in men.