Very High HDL-C: Too Much of a Good Thing?

Batya Swift Yasgur MA, LSW

May 26, 2022

A new study suggests that very high levels of high-density lipoprotein cholesterol (HDL-C) may be associated with higher mortality risk in patients with coronary artery disease (CAD).

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 School of Medicine, Atlanta, told | Medscape Cardiology.

"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 Quyyumi, who is the director of the Emory Clinical Cardiovascular Research Institute.

The study was published online May 18 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 write. 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 write. 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 [SD] age, 61.2 [5.8] years; 76.2% male; 93.8% White) and the Emory Cardiovascular Biobank (EmCAB; n = 5467; mean age, 63.8 [12.3] years; 66.4% male; 73.2% White). Participants were followed prospectively for a median of 8.9 (IQR, 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 [HR], 1.33; 95% CI, 1.07 - 1.64 and HR, 1.42; 95% CI, 1.09 - 1.85, respectively; P = .009).

"Importantly," the authors state, "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.

Risk for All-Cause and Cardiovascular Death With HDL-C >80 vs 40 – 60 mg/dL by Sex
  Men Women
Type of Death R (95% CI) Value HR (95% CI) P Value
All-cause 2.63 (1.75–3.95) <.001 1.39 (0.82–2.35) .23
Cardiovascular 2.50 (1.47–4.27) <.001 0.89 (0.39–2.07) .79

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.

Risk for Death With Low and High Levels of HDL vs 40 - 60 mg/dL in Unadjusted and Adjusted Models
  Unadjusted HR (95% CI) Value Adjusted HR (95% CI) P Value
Type of Death HDL ≤30 mg/dL HDL >80 mg/dL HDL ≤30 mg/dL HDL >80 mg/dL
All-cause 1.26 (1.09–1.46) .002 1.43 (0.97–2.10) .07 1.22 (1.03–1.45)  .02 1.63 (1.09–2.43) .02
Cardiovascular 1.37 (1.13–1.68) .002 1.46 (0.88 - 2.44) .14 1.35 (1.06–1.72) .01 1.57 (0.95–2.61) .08

"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 note.

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," Quyyumi commented. "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."

Red Flag

Commenting for | Medscape Cardiology, Sadiya Sana Khan, MD, MSc, assistant professor of Medicine (cardiology) and Preventive Medicine (epidemiology), Northwestern University Feinberg School of Medicine, Chicago, said: "I think the most important point [of the study] is to identify people with very high HDL-C. This can serve as a reminder to discuss heart-healthy lifestyles and discussion of statin therapy if needed, based on LDL-C."

In an accompanying editorial coauthored with Gregg Fonarow, MD, Ahmanson-UCLA Cardiomyopathy Center, David Geffen School of Medicine, University of California, Los Angeles, the pair writes: "Although the present findings may be related to residual confounding, high HDL-C levels should not automatically be assumed to be protective."

They advise clinicians to "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."

This study was supported in part by grants from the National Institutes of Health, the American Heart Association, and the Abraham J. & Phyllis Katz Foundation. Quyyumi and coauthors report no relevant financial relationships. Khan reports receiving grants from the American Heart Association and the National Institutes of Health outside the submitted work. Fonarow reports receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck, and Novartis outside the submitted work. No other disclosures were reported.

JAMA Cardiology. Published online May 18, 2022. Abstract, Editorial


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