Association between very high HDL-C levels and mortality: A systematic review and meta-analysis.
Level 2 - randomized trial
Systematic review and meta-analysis of observational cohort studies
PubMed 39278774 · doi:10.1016/j.jacl.2024.06.002
What was done
Authors conducted a systematic review and meta-analysis of PubMed, Embase, and Cochrane databases evaluating the association between very high HDL-C (≥80 mg/dL) compared to normal levels (40–60 mg/dL) and mortality outcomes in individuals without coronary artery disease (CAD). Eight studies including 1,004,584 individuals (133,646 with very high HDL-C) were pooled using random-effects models and non-linear dose-response analyses.
What was found
All-cause mortality (p = 0.55) and cancer mortality (p = 0.45) did not differ significantly between groups. Cardiovascular mortality showed no overall difference (HR 1.05; 95% CI 0.94–1.17; p = 0.37), while 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). However, dose-response analysis showed non-linear increases in cardiovascular death above extreme thresholds: HR 1.47 (95% CI 1.01–2.15) for women above 116 mg/dL and HR 1.29 (95% CI 1.01–1.65) for men above 94 mg/dL (p_nonlinearity < 0.01).
Why it matters
These findings challenge the assumption that higher HDL cholesterol is uniformly cardioprotective, identifying sex-specific threshold effects beyond which cardiovascular mortality risk increases.
Limits
The analysis relies entirely on observational cohort data, leaving potential for residual confounding by alcohol consumption, genetics, or systemic disease. Specific HDL particle subfractions and functional properties were not evaluated.
Cited by
- supports HDL cholesterol levels exceeding 100 mg/dL are frequently dysfunctional or ineffective as cardiovascular bioindicators.