Previous studies have demonstrated lower cardiovascular risk with higher high-density lipoprotein cholesterol (HDL-C) levels; however, recent data in the general population have revealed a heightened risk of adverse outcomes with very high HDL-C concentrations.

In a recent publication in the Journal of the American Medical Association (JAMA) Cardiology, researchers investigated the correlation between very high HDL-C levels (>80 mg/dL) and mortality in patients with coronary artery disease (CAD), and the association of known HDL-C genotypes with high HDL-C level outcomes.

The prospective, multicenter, cohort study was conducted from 2006 to the present in the UK and from 2003 to the present in Atlanta, Georgia. It recruited patients with CAD from the UK Biobank (UKB) and the Emory Cardiovascular Biobank (EmCAB), respectively. Patients without confirmed CAD were excluded from the study. The primary outcome was all-cause death; the secondary outcome was cardiovascular (CV) death. A total of 14,478 participants (mean age, 62 years; 76.2% men) from the UKB and 5,467 participants (mean age, 64 years; 66.4% men) from the EmCAB were included in the study.

During an average follow-up of 8.9 years in the UKB and 6.7 years in the EmCAB, the researchers observed a U-shaped association between HDL level, all-cause death, and CV death, with elevated risk among patients with low and very high HDL versus patients with midrange values.

For the UK Biobank analysis, compared with patients with an HDL between 40 mg/dL and 60 mg/dL, patients with an HDL of at least 80 mg/dL were nearly twice as likely to die of any cause during follow-up, with a hazard ratio (HR) of 1.96 (95% CI, 1.42-2.71; P <.001) and 71% more likely to die of CV causes, with an HR of 1.71 (95% CI, 1.09-2.68; P = .02). Results persisted after adjustment for other CV risk factors, including hypertension, diabetes, and smoking.

Findings were comparable for patients in the EmCAB, with findings for the UKB persisting after further adjustment for genetic risk score.

In sensitivity analyses, all-cause death risk among patients from the UK Biobank with very high HDL was greater among men (HR = 2.63; 95% CI, 1.75-3.95; P <.001) compared with women (HR = 1.39; 95% CI, 0.82-2.35; P = .23).

The authors concluded that findings from this cohort study imply that very high HDL-C levels are paradoxically correlated with greater mortality risk in individuals with CAD, and this correlation was independent of the common polymorphisms associated with high HDL-C levels.

In a follow-up editorial in JAMA Cardiology, Drs. Sadiya Khan and Gregg Fonarow wrote, "Although the present findings may be related to residual confounding, high HDL-C levels should not automatically be assumed to be protective. Clinicians should use HDL-C levels as a surrogate marker with very low and very high levels as a red flag to target for more intensive primary and secondary prevention, as the maxim for HDL-C as 'good' cholesterol only holds for HDL-C levels of 80 mg/dL or less."

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