HDL-Cholesterol: Is the H for Harmful not Happy Cholesterol?

Question:  What is the association between a "very high" high-density lipoprotein cholesterol (HDL-C) level and outcomes in patients with coronary artery disease (CAD)? Is HDL-C a "happy" finding or is HDL-C a "harmful" finding? Is there a difference between men and women?

Importance  Previous studies over decades have shown lower cardiovascular risk with higher HDL-C levels. However, recent data in the general population have shown increased risk of adverse outcomes at very high HDL-C concentrations. This is confusing and more data is needed to clarify the importance of a a "very high" HDL-C in men and women. 

Objective  To study the association between very high HDL-C levels (>80 mg/dL) and mortality in patients with coronary artery disease (CAD).

Design, Setting, and Participants  This prospective, multicenter, cohort study, conducted in nearly 20,000 subjects from 2006 to present in the UK and from 2003 to present in Atlanta, Georgia, recruited patients with CAD from the UK Biobank (UKB) and the Emory Cardiovascular Biobank (EmCAB), respectively. 

Exposure  Vey high HDL-C levels (>80 mg/dL) were measured

Main Outcomes and Measures  The primary outcome was all-cause death. The secondary outcome was cardiovascular death.

Results  A total of 14 478 participants (mean age, 62.1 years; 11 034 men [76.2%]) from the UKB and 5467 participants (mean age, 63.8 years; 3632 men [66.4%]) from the EmCAB were included in the study. Over a median follow-up of 8.9 years in the UKB and 6.7 years in the EmCAB, a U-shaped association with outcomes was observed with higher risk in those with both low and very high HDL-C levels compared with those with midrange values.

Very high HDL-C levels (>80 mg/dL) were associated with increased risk of all-cause death that was nearly twice as high as those with mid range HDL-C levels. The risk of cardiovascular death was 70% higher compared with those with HDL-C levels in the range of 40 to 60 mg/dL.

The risk of all-cause mortality in the very high HDL-C group was higher among men than women in the UKB study and mean with a very high HDL-C of >80 mg/dL had nearly 3 times the risk of death of any cause during the period study.

Conclusions and Relevance  Results of this study suggest that very high HDL-C levels >80 mg/dl are paradoxically associated with higher mortality risk in individuals with CAD. The risk of death observed was much higher in men with very high HDL-C than women with very high HDL-C. Low HDL-C was still a risk for death and the "sweet spot" of 40-60 mg/dl had the lowest risk. 

Clinical Importance: This suprising study follows others indicating that a very high HDL-C is NOT reassuring and may be a risk for cardiac issues and death. All risk factors like diet, LDL-cholesterol, blood sugar, blood pressure, fitness, dental health, stress, and sleep should be optimized in these, and all, patients. 

Dr. Joel Kahn

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