A new study suggests that .
Investigators studied close to 10,000 patients with CAD in two separate cohorts. After adjusting for an array of covariates, they found that individuals with HDL-C levels greater than 80 mg/dL had a 96% higher risk for all-cause mortality and a 71% higher risk for cardiovascular mortality than those with HDL-C levels between 40 and 60 mg/dL.
A U-shaped association was found, with higher risk for all-cause and cardiovascular mortality in patients with both very low and very high, compared with midrange, HDL-C values.
“Very high HDL levels are associated with increased risk of adverse outcomes, not lower risk, as previously thought. This is true not only in the general population, but also in people with known coronary artery disease,” senior author Arshed A. Quyyumi, MD, professor of medicine, division of cardiology, Emory University, Atlanta, told this news organization.
“Physicians have to be cognizant of the fact that, at levels of HDL-C above 80 mg/dL, they [should be] more aggressive with risk reduction and not believe that the patient is at ‘low risk’ because of high levels of ‘good’ cholesterol,” said Dr. Quyyumi, director of the Emory Clinical Cardiovascular Research Institute.
The study was published online in JAMA Cardiology.
Inverse association?
HDL-C levels have “historically been inversely associated with increased cardiovascular disease (CVD) risk; however, recent studies have questioned the efficacy of therapies designed to increase HDL-C levels,” the authors wrote. Moreover, genetic variants associated with HDL-C have not been found to be linked to CVD risk.
Whether “very high HDL-C levels in patients with coronary artery disease (CAD) are associated with mortality risk remains unknown,” they wrote. In this study, the researchers investigated not only the potential risk of elevated HDL-C levels in these patients, but also the association of known HDL-C genetic variants with this risk.
To do so, they analyzed data from a subset of patients with CAD in two independent study groups: the UK Biobank (UKB; n = 14,478; mean [standard deviation] age, 61.2 [5.8] years; 76.2% male; 93.8% White) and the Emory Cardiovascular Biobank (EmCAB; n = 5,467; mean age, 63.8 [12.3] years; 66.4% male; 73.2% White). Participants were followed prospectively for a median of 8.9 (interquartile range, 8.0-9.7) years and 6.7 (IQR, 4.0-10.8) years, respectively.
Additional data collected included medical and medication history and demographic characteristics, which were used as covariates, as well as genomic information.
Of the UKB cohort, 12.4% and 7.9% sustained all-cause or cardiovascular death, respectively, during the follow-up period, and 1.8% of participants had an HDL-C level above 80 mg/dL.
Among these participants with very high HDL-C levels, 16.9% and 8.6% had all-cause or cardiovascular death, respectively. Compared with the reference category (HDL-C level of 40-60 mg/dL), those with low HDL-C levels (≤ 30 mg/dL) had an expected higher risk for both all-cause and cardiovascular mortality, even after adjustment for covariates (hazard ratio, 1.33; 95% confidence interval, 1.07-1.64 and HR, 1.42; 95% CI, 1.09-1.85, respectively; P = .009).
“Importantly,” the authors stated, “compared with the reference category, individuals with very high HDL-C levels (>80 mg/dL) also had a higher risk of all-cause death (HR, 1.58 [1.16-2.14], P = .004).”
Although cardiovascular death rates were not significantly greater in unadjusted analyses, after adjustment, the highest HDL-C group had an increased risk for all-cause and cardiovascular death (HR, 1.96; 95% CI, 1.42-2.71; P < .001 and HR, 1.71; 95% CI, 1.09-2.68, respectively; P = .02).
Compared with females, males with HDL-C levels above 80 mg/dL had a higher risk for all-cause and cardiovascular death.
Similar findings were obtained in the EmCAB patients, 1.6% of whom had HDL-C levels above 80 mg/dL. During the follow-up period, 26.9% and 13.8% of participants sustained all-cause and cardiovascular death, respectively. Of those with HDL-C levels above 80 mg/dL, 30.0% and 16.7% experienced all-cause and cardiovascular death, respectively.
Compared with those with HDL-C levels of 40-60 mg/dL, those in the lowest (≤30 mg/dL) and highest (>80 mg/dL) groups had a “significant or near-significant greater risk for all-cause death in both unadjusted and fully adjusted models.
“Using adjusted HR curves, a U-shaped association between HDL-C and adverse events was evident with higher mortality at both very high and low HDL-C levels,” the authors noted.
Compared with patients without diabetes, those with diabetes and an HDL-C level above 80 mg/dL had a higher risk for all-cause and cardiovascular death, and patients younger than 65 years had a higher risk for cardiovascular death than patients 65 years and older.
The researchers found a “positive linear association” between the HDL-C genetic risk score (GRS) and HDL levels, wherein a 1-SD higher HDL-C GRS was associated with a 3.03 mg/dL higher HDL-C level (2.83-3.22; P < .001; R 2 = 0.06).
The HDL-C GRS was not associated with the risk for all-cause or cardiovascular death in unadjusted models, and after the HDL-C GRS was added to the fully adjusted models, the association with HDL-C level above 80 mg/dL was not attenuated, “indicating that HDL-C genetic variations in the GRS do not contribute substantially to the risk.”
“Potential mechanisms through which very high HDL-C might cause adverse cardiovascular outcomes in patients with CAD need to be studied,” Dr. Quyyumi said. “Whether the functional capacity of the HDL particle is altered when the level is very high remains unknown. Whether it is more able to oxidize and thus shift from being protective to harmful also needs to be investigated.”