‘Our understanding continues to evolve’: HDL cholesterol as a biomarker or risk-enhancer
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Key takeaways:
- Low HDL is linked with heart disease risk but raising it does not reduce heart-related events.
- Because HDL does not have a causal role in heart disease, it may best be considered a biomarker or risk-enhancing factor, a speaker said.
PHILADELPHIA — HDL cholesterol has not been shown to have a causal role in atherosclerotic cardiovascular disease, nor has lowering it reduced CV outcomes, but it may serve as a marker for CVD risk, according to a speaker.
ASCVD risk is elevated when HDL is lower than 40 mg/dL in men or 50 mg/dL in women, a pattern that persists even when LDL cholesterol is well-controlled. For that reason, it has been an “integral” component of ASCVD risk scores, including the American Heart Association’s PREVENT calculator, Laurence S. Sperling, MD, FACC, FACP, FAHA, MASPC, the Katz Professor in Preventive Cardiology and professor of global health at Emory University, said during a presentation at the Heart in Diabetes CME Conference.
However, while low HDL has a strong link to elevated ASCVD risk, “an interesting and somewhat complex story” is that both low and very high HDL raise risk for mortality, Sperling said. In one cohort study, an HDL level greater than 80 mg/dL was associated with a 96% higher risk for all-cause mortality and a 71% higher risk for CV mortality compared with an HDL level of 55 mg/dL, independent of common polymorphisms associated with high HDL, according to Sperling.
He said another study showed that HDL had a U-shaped association with coronary artery calcium score, and that HDL above 100 mg/dL was linked with a CAC score of more than 100.
“Our understanding of HDL continues to evolve,” Sperling said. “It’s more a risk marker than a causative factor” and very high HDL cholesterol appears to be more predictive in men than in women.
Therapies to raise HDL have not been shown to reduce CV events, but the AEGIS II trial tested the hypothesis that improving HDL function, which previous research suggested was more important than the HDL number itself, would improve CV outcomes.
As Healio previously reported, in the main results if AEGIS II, administering a novel formulation of human apolipoprotein A-I (CSL112, CSL Behring), which was designed to boost levels of apolipoprotein A-I and increase cholesterol efflux capacity, did not improve rates of MI, stroke or CV death at 90 days, 180 days or 1 year compared with placebo in patients with acute MI. However, compared with placebo, CSL112 did improve rates of MI, stroke or CV death in patients with an LDL of 100 mg/dL or more at baseline, but had no effect on patients with a baseline LDL below 100 mg/dL.
Sperling said the results of AEGIS II led the authors of an accompanying editorial published in The New England Journal of Medicine to state that until better assays are developed, new targets are identified and the appropriate patient population is refined, “perhaps it is time to shelve HDL therapeutics and put them on the ‘injured reserve list’ of preventive therapies for cardiovascular disease.”
Because HDL appears to play a role in CV health, but not a causal one, it may be best used as a biomarker or a risk-enhancing factor to help identify people who need preventive therapies, Sperling said during the presentation.
“We should think of HDL as ‘guilty by association’: a biomarker,” he said. “We should use it as we think about its association with other risk factors” including obesity, metabolic syndrome, diabetes and tobacco use. “For those with very low HDL or very high HDL, we might want to think of it as a risk-enhancing factor.”
References:
- Ballantyne CM, et al. N Engl J Med. 2024;doi:10.1056/NEJMe2403036.
- Gibson CM, et al. Late breakers. Presented at: National Lipid Association Scientific Sessions; May 30-June 2, 2024; Las Vegas (hybrid meeting).
- Gibson CM, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2400969.
- Liu C, et al. JAMA Cardiol. 2022;doi:10.1001/jamacardio.2022.0912.
- Razavi AC, et al. Curr Cardiol Rep. 2023;doi:0.1007/s11886-023-01987-3.
- Sandesara PB, et al. Circ Cardiovasc Imaging. 2020;doi:10.1161/CIRCIMAGING.120.010473.
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Sperling LS. Session 3 – Dyslipidemia today and tomorrow. Presented at: Heart in Diabetes CME Conference; June 7-9, 2024; Philadelphia.
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