Association of high-density lipoprotein cholesterol with non-fatal cardiac and non-cardiac events: a CANHEART substudy

Background — Emerging evidence has questioned the role of high-density lipoprotein cholesterol (HDL-C) as an independent and modifiable risk factor for cardiovascular disease. We sought to understand the relationship between HDL-C levels and subsequent non-fatal clinical events.

Methods — Individuals without prior cardiovascular disease or cancer were identified. Outcomes of interest were classified as non-fatal cardiovascular, cancer and infectious. Sex-stratified, multivariable, cause-specific Cox proportional hazards models were created. The reference level HDL-C for both women and men was 51-60 mg/dL.

Results — Our cohort consisted of 631 762 individuals. For cardiovascular events, there was a consistent inverse relationship, with higher adjusted HRs for the lower HDL-C strata in both men and women. This relationship was also seen in the composite of non-cardiovascular outcomes. In women, the HR in the <30 mg/dL HDL-C category was 2.10 (95% CI 1.66 to 2.57) and 1.86 (95% CI 1.27 to 2.72) for cardiovascular and non-cardiovascular outcomes, respectively; in contrast, in the >90 mg/dL group, it was 0.87 (95% CI 0.74 to 1.02) and 0.81 (95% CI 0.63 to 1.06). For men, HRs were 2.02 (95% CI 1.79 to 2.28) and 1.84 (95% CI 1.47 to 2.31) in the <30 mg/dL HDL-C category for cardiovascular and non-cardiovascular outcomes, respectively, compared with 0.73 (95% CI 0.53 to 1.00) and 1.07 (95% CI 0.67 to 1.70) in the >90 mg/dL group.

Conclusions — We found an inverse relationship between HDL-C and a wide spectrum of non-fatal outcomes, suggesting that HDL-C is a heavily confounded factor that may be a marker of poor overall health, rather than an independent and modifiable risk factor.