The change of paradigm: high HDL-c levels could not mean a long lifespan

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Abstract Background It is known that a low HDL-c level is associated with a high risk of overall mortality. Consequently, it was presumed that achieving higher levels of high-density lipoprotein cholesterol (HDL-c) would reduce the risk or even extend the lifespan. However, clinical trials with medical intervention failed to find clinical benefits. Aim We aimed to investigate the association between (HDL-c) levels and overall mortality using a prospective cohort from Portugal. Methods A prospective sub-study (2001-2022) was performed in a cohort of 1718 participants without coronary artery disease (CAD) of the control arm of the ongoing GENEMACOR study. The participants <65 years were followed during a mean follow-up of 7.0±5.7 years. All demographic, biochemical, and clinical data were collected. Participants were stratified into six levels of HDL-c. Kaplan-Meier estimated differences in the survival probability of each HDL-c level. Cox proportional analysis models (unadjusted and adjusted) were used to assess the association between HDL-c levels and overall mortality. Results The HDL-c levels with the lowest overall mortality rate were 60 to 70 mg/dl, set as the reference level. Total HDL-c strata were associated with overall mortality with a U-shaped relationship: in the control group, the first level (<40 mg/dl) was independently associated with increased risk of overall mortality (HR of 3.533; 95% CI: 1.738-7.178; p<0.0001). This risk drops and falls to the reference level (the lower risk) and rises again to an HR of 3.875 (95% CI: 1.472-10.201; p=0.006) in the very high HDL-c levels (≥80 mg/dl). Conclusions Our results, based on a large Portuguese cohort, suggest that very high HDL-c levels in the normal population may not represent a good prognosis, especially in women. Future research may confirm these findings and investigate the underlying mechanisms.