Very high HDL ‘red flag’ for all-cause, CV death risk in adults with CAD
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In adults with CAD, those with HDL of 80 mg/dL or greater are nearly twice as likely to die of any cause compared with those with HDL between 40 mg/dL and 60 mg/dL, according to an analysis of two large biobank databases.
In an analysis of data from nearly 20,000 patients, researchers also found the higher risk for all-cause and CV death associated with very high HDL, typically considered protective, was independent of traditional CV risk factors and alcohol use.
“Very high HDL levels are associated with increased risk for adverse outcomes, not lower risk, as previously thought,” Arshed A. Quyyumi, MD, FRCP, professor of medicine, director of the Emory Clinical Cardiovascular Research Institute and the Bruce Logue Chair for Cardiovascular Research at Emory University School of Medicine, told Healio. “This is true not only in the general population but also in people with known coronary artery disease. The higher risk with very high HDL levels is particularly seen in men, although women also have higher risk at very high HDL levels.”
Prospective biobank data
In a prospective study, Quyyumi and colleagues analyzed data from patients with confirmed CAD and high HDL, defined as at least 80 mg/dL, using UK Biobank (2006-present; n = 14,478; mean age, 62 years; 76.2% men) and Emory Cardiovascular Biobank (2003-present; n = 5,467; mean age, 64 years; 66.4% men) data. Patients without confirmed CAD were excluded. The primary outcome was all-cause death; secondary outcome was CV death.
The findings were published in JAMA Cardiology.
During a median follow-up of 8.9 years in the UK Biobank and 6.7 years in the Emory Cardiovascular Biobank, researchers observed a U-shaped association between HDL level, all-cause death and CV death, with higher risk among patients with low and very high HDL vs. 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 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 similar for patients in the Emory Cardiovascular Biobank, with findings for the UK Biobank 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).
“Physicians have to be cognizant of the fact that, at levels of HDL above 80 mg/dL, they must be more aggressive with risk reduction and not believe that that the patient is at ‘low risk’ because of high levels of ‘good cholesterol,’” Quyyumi told Healio. “We need to understand what the mechanisms underlying this increased risk are. What are the functional changes in HDL that lead to this higher risk?”
Very high HDL as ‘red flag’
In a related editorial, Sadiya S. Khan, MD, MSc, assistant professor of preventive medicine (epidemiology) and medicine (cardiology) at Northwestern University Feinberg School of Medicine, and Gregg C. Fonarow, MD, FACC, FAHA, FHFSA, director of the Ahmanson-UCLA Cardiomyopathy Center, co-director of the UCLA Preventive Cardiology Program, co-chief of the division of cardiology at UCLA and the Eliot Corday Chair in Cardiovascular Medicine and Science, wrote that emerging data from healthy populations suggest a “paradoxical association” may be present, with higher mortality observed among people with very high HDL.
“Although the present findings may be related to residual confounding, high HDL-C levels should not automatically be assumed to be protective,” Khan and Fonarow wrote. “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.”
Previous analyses have suggested very high HDL may be a risk factor for all-cause death. As Healio previously reported, patients with HDL levels greater than 60 mg/dL in the Emory Cardiovascular Biobank had a nearly 50% increased risk for all-cause mortality, CV mortality and MI compared with those with HDL levels of 41 mg/dL to 60 mg/dL.
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For more information:
Arshed A. Quyyumi, MD, FRCP, can be reached at aquyyum@emory.edu; Twitter: @EmoryCCRI.
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