High HDL-C Level Associated with Higher Mortality Risk in Patients with CAD

Arshed A. Quyyumi, MD

New data suggest that patients with coronary artery disease (CAD) with very high high-density lipoprotein cholesterol (HDL-C) levels may have an increased risk of all-cause and cardiovascular death.

Findings from the multicenter, cohort study show high HDL-C levels were paradoxically associated with higher mortality risk in 2 high-risk cohorts with CAD in 2 countries, independent of common polymorphisms associated with higher levels.

“Our study addresses an important knowledge gap as current risk calculators used in the general population input high HDL-C level as a protective factor, whereas at very high levels, this protective effect does not appear to hold true and, in fact, may confer increased risk,” wrote study author Arshed A. Quyyumi, MD, Division of Cardiology, Department of Medicine, Emory University School of Medicine.

The Study

Investigators sought to investigate the association between very high HDL-C levels and all-cause and cardiovascular mortality risk in 2 independent groups of patients with CAD in the UK Biobank (UKB) and the Emory Cardiovascular Biobank (EmCAB).

Patients in the UKB and EmCAB were followed prospectively for a median of 8.9 years and 6.7 years, respectively. In the UKB, individuals aged 40 to 72 years with a history of CAD at enrollment were included from the general population in the UK between 2006 and 2010. The EmCAB is an ongoing prospective cohort of adults ≥18 years undergoing left heart catheterization for suspected or confirmed CAD at 3 Emory Healthcare sites in Atlanta, Georgia.

All-cause death was considered the primary outcome in the study, while the secondary outcome was cardiovascular death.

Investigators excluded patients without confirmed CAD from the study. They used analysis of variance, Mann-Whitney U test, and x² tests to compare baseline characteristics between 5 categories of HDL-C:

• 30 mg/dL or less
• 30 - 40 mg/dL
• 40 to 60 mg/dL
• 60 to 80 mg/dL
• ≥80 mg/dL

A total of 14,478 participants (mean age, 62.1 years; 11,034 men [76.2%]) from the UKB were included in the study and 5467 participants (mean age, 63.8 years; 3632 men [66.4%]) from the EmCAB were included in the study.

The Findings

In patients with HDL-C levels ≥80 mg/dL in the UKB, all-cause death was reported in 43 of 255 participants (16.9%) and cardiovascular deaths were reported in 22 of 255 participants (8.6%). Meanwhile, in the EmCAB in patients with HDL-C levels ≥80mg/dL, all-cause and cardiovascular deaths were observed in 27 of 90 participants (30%) and 15 of 90 participants (16.7%), respectively.

Within a median follow-up of 8.9 years in the UKB and 6.7 years in the EmCAB, data show a U-shaped association with outcomes was found with higher risk in those with both low and very high HDL-C levels, compared with those with midrange values.

Following adjustment in UKB, the highest HDL-C group had an increased risk of both all-cause death (HR, 1.96; 95% CI, 1.42 - 2.71; P <.001) and cardiovascular death (HR, 1.71; 95% CI, 1.09 - 2.68; P = .02) compared to those with HDL-C levels in the range of 40 to 60 mg/dL.

From the fully adjusted models in the EmCAB, the group with the lowest HDL-C levels had a higher risk of all-cause (HR, 1.22; 95% CI, 1.03 - 1.45; P = .02) and cardiovascular death (HR, 1.35; 95% CI, 1.06 - 1.72; P = .01). Meanwhile, the highest group had a significant or near-significant higher risk of all-cause death (HR, 1.63; 95% CI, 1.09 - 2.43; P = .02) and cardiovascular death (HR, 1.57; 95% CI, 0.95 - 2.61; P = .08).

Additionally, sensitivity analyses demonstrated that the risk of all-cause mortality in the very high HDL-C group was higher among men than women in the UKB (HR, 2.63; 95% CI, 1.75 - 3.95; P <.001 vs HR, 1.39; 95% CI, 0.82 - 2.35; P = .23).

“Future studies are warranted to investigate the association of very high HDL-C level with other cause-specific outcomes,” Quyyumi concluded.

The study, “Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations,” was published in JAMA Cardiology.