Too much good stuff?

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

Investigators studied about 10,000 patients with CAD in two separate cohorts. After adjusting a number of covariates, they found that people with HDL-C levels above 80 mg / dL had a 96% higher risk of death from all causes and 71% higher risk of death from cardiovascular disease than people with HDL-C levels. Between 40 and 60 mg / dl.

A U-shaped compound was found in both patients with very low and very high HDL-C values ​​for all causes and a high risk for cardiovascular death compared to moderate, HDL-C values.

“Very high HDL levels are associated with an increased risk of side effects, not a lower risk than previously thought. This applies not only to the general population, but also to people with known coronary artery disease,” said senior author Arshed A. Quyyumi MD. , A professor of cardiology at Emory University School of Medicine in Atlanta theheart.org | Medscape Cardiology.

“Doctors need to know that HDL-C levels are above 80 mg / dL. [should be] “Be more aggressive in reducing the risk and don’t believe that the patient is‘ at low risk ’due to high levels of‘ good ’cholesterol,” said Kuyumi, director of the Emory Clinical Cardiovascular Research Institute.

The investigation was posted online on May 18 JAMA Cardiology.

Reverse association?

HDL-C levels “have historically been associated with an increased risk of cardiovascular disease (CVD); however, recent studies have questioned the effectiveness of therapy aimed at increasing HDL-C levels,” the authors write. In addition, genetic variants associated with HDL-C have not been found to be associated with CVD risk.

“It remains unclear whether very high HDL-C levels in patients with coronary artery disease (CAD) are associated with a risk of death,” they write. In this study, the researchers examined 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 this, they analyzed data from a set of patients with CAD in two independent study groups: UK Biobank (UKB; n = 14,478; average [SD] age, 61.2 [5.8] years; 76.2% of men; 93.8% White) and Emory Cardiovascular Biobank (EmCAB; n = 5467; mean age, 63.8% [12.3] years; 66.4% of men; 73.2% white). Participants followed the prospect for the median of 8.9 (IQR, 8.0 – 9.7) years and 6.7 (IQR, 4.0 – 10.8) years, respectively.

Additional data collected include medical and drug history and demographic characteristics used as covariates, as well as genomic information.

In the UKB cohort, 12.4% and 7.9%, respectively, in the following period had all causes or cardiovascular mortality, respectively, and 1.8% of the participants had HDL-C levels above 80 mg / dL.

Among these participants with very high HDL-C levels, 16.9% and 8.6%, respectively, had either all-cause or cardiovascular death. Compared to the reference category (HDL-C levels 40–60 mg / dl), low HDL-C levels (≤30 mg / dl) were associated with all causes and a higher risk of cardiovascular death than expected. for covariates (risk ratio [HR], 1.33; 95% CI, 1.07 – 1.64 and RH, 1.42; 95% CI, 1.09 – 1.85, respectively; P = .009).

“Importantly,” the authors note, “compared with the reference category, people with very high HDL-C levels (> 80 mg / dl) had a higher risk of death from all causes (HR, 1.58). [1.16 – 2.14], P = .004). “

Although the cardiovascular mortality rate was not significantly higher in the unregulated assays, after adjustment, the highest HDL-C group had a higher risk of cardiovascular death for all reasons and (HR, 1.96; 95% CI, 1.42). – 2.71; P <.001 and HR, 1.71; 95% CI, 1.09 to 2.68, respectively; P = .02).

Compared to women, men with HDL-C levels above 80 mg / dL had a higher risk of death from all causes and cardiovascular disease.

Sexual HDL-C> 80 versus 40 – 60 mg / dL for all causes and risk of cardiovascular death
men women
Type of death R (95% CI) P Price RH (95% CI) P Price
all because 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 results were obtained in EmCAB patients, whose 1.6% had HDL-C levels above 80 mg / dL. In the following period, 26.9% and 13.8% of the participants died of all causes and cardiovascular deaths, respectively. 30.0% and 16.7% of those with HDL-C levels above 80 mg / dL died of all causes and cardiovascular death, respectively.

Compared with those with HDL-C levels of 40–60 mg / dl, the lowest (≤30 mg / dl) and highest (> 80 mg / dl) groups had “significant or almost no significant risk for all. leads to death in unadjusted and fully adjusted models.

Danger of death with low and high levels of HDL against 40 – 60 mg / dL in unstructured and unadjusted models
Uncorrected HR (95% CI) P Price Adjusted HR (95% CI) PPrice
Type of death HDL ≤30 mg / dl HDL> 80 mg / dl HDL ≤30 mg / dl HDL> 80 mg / dl
all because 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 the corrected HR curves, the U-shaped relationship between HDL-C and adverse events was evident with very high mortality at very high and low HDL-C levels,” the authors note.

Compared with non-diabetic patients, those with diabetes and HDL-C levels above 80 mg / dL had a higher risk of cardiovascular death from all causes, and patients younger than 65 years had a higher risk of cardiovascular death than those with 65 years. The risk of death was high. a leader.

The researchers found a “positive linear relationship” between HDL-C genetic risk score (GRS) and HDL levels, where 1-SD higher HDL-C GRS was associated with a 3.03 mg / dL higher HDL-C level (2.83 -). 3.22; P<.001; Р two = 0.06).

HDL-C GRS was not associated with all causes or risk of cardiovascular death in unregulated models, and when HDL-C GRS was added to fully adjusted models, HDL-C levels were above 80 mg / dL. “HDL-C genetic variations in GRS do not contribute significantly to risk,” he said.

“Potential mechanisms that may lead to adverse effects on the cardiovascular system in patients with very high HDL-C CAD should be investigated,” Kuyumi said. “It remains unclear whether the HDL particle’s functional capacity will change when the level is too high.

Red flag

to comment theheart.org | Medscape CardiologySadia Sana Khan, MD, MSc, Assistant Professor of Medicine (Cardiology) and Preventive Medicine (Epidemiology), Feinberg School of Medicine, Northwestern University, Chicago: “I think it’s the most important point. [of the study] is to identify people with very high HDL-C. It can serve as a reminder to discuss your LDL-C-based, heart-healthy lifestyle and discuss statin therapy if needed.

In this article, Greg Fonarow, MD Ahmanson-UCLA Center for Cardiomyopathy, David Geffen School of Medicine, University of California, Los Angeles, co-authored an editorial with the rest of the editorial: “Findings may be associated with high LC levels. should not be taken. “

They recommend clinics use HDL-C levels as a surrogate marker, and very low and very high levels as red flags for intensive primary and secondary prevention because only “good” cholesterol is stored for HDL-C. HDL-C levels are 80 mg / dL or less.

This study was partially supported by grants from the National Institutes of Health, the American Heart Association, and the Abraham J. & Phyllis Katz Foundation. Quyyumi and co-authors report on the relevant financial relationships. In addition to his work, Khan said he has received grants from the American Heart Association and the National Institutes of Health. In addition to the case, Fonarov said he had received individual payments from Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Edwards, Janssen, Medtronic, Merck and Novartis. No other revelations were made.

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

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