HDL Cholesterol and Large HDL Particles Not Cardioprotective When Adjusted for apoA-1 and apoB

February 05, 2008

February 5, 2008 (Amsterdam, the Netherlands) – "Remarkable" new data from two previously published studies suggest that high levels of plasma HDL cholesterol and large HDL particles are associated with an increased risk of coronary artery disease [1].

The findings, from the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) and European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk studies, showed that when apolipoprotein A1 (apoA-1) and apolipoprotein B (apoB) values were kept constant in regression analyses, increased HDL-cholesterol levels and HDL particle size conferred a risk of major coronary events. ApoA-1, on the other hand, did not turn into a significant risk factor at high plasma concentrations.

Investigators, led by Dr Wim van der Steeg (Academic Medical Center, Amsterdam, the Netherlands), say the findings have clinical and scientific implications, especially as they relate to risk assessment and novel treatment strategies. "On the basis of these data," the group writes, "interventions that primarily raise plasma HDL cholesterol but do not or hardly change apoA-1 levels may not be expected to have potent beneficial effects on atherosclerosis."

The results of the study are published in the February 4, 2008 issue of the Journal of the American College of Cardiology.

Can HDL Cholesterol Become Proatherogenic?

Since the spectacular bust of torcetrapib, a novel cholesterol-ester-transfer protein (CETP) inhibitor that raised HDL-cholesterol levels but increased the risk of mortality and cardiovascular events, in December 2006, there have been questions as to why the HDL-raising drug failed to provide the expected benefit. According to the authors, including lipid expert Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), one possible explanation for the unexpected outcome with torcetrapib might be structural changes of the HDL particle induced by CETP inhibition.

With these concerns in mind, that high levels of HDL cholesterol might actually be harmful, post hoc analyses of the IDEAL data, a randomized, open-label, blinded-end-point trial evaluating simvastatin 20 mg and atorvastatin 80 mg in secondary prevention, and the EPIC-Norfolk case-control study, were performed to assess the relationship between HDL-cholesterol levels, HDL particle size, and coronary heart disease.

The findings, which were first presented last year in Helsinki, Finland, at the European Atherosclerosis Society annual meeting and reported by heartwire at that time, showed that without adjustment for apoA-1 and apoB, HDL cholesterol was significantly and inversely related with risk of major coronary events in IDEAL and EPIC-Norfolk, as was HDL particle size in EPIC-Norfolk. When the regression models, however, were adjusted for apoA-1 and apoB, the risk estimates for HDL cholesterol became significantly positively related to occurrence of events. ApoA-1 was negatively related to the risk of coronary events in both studies.

Risk Estimates for Major Coronary Event by HDL Cholesterol in IDEAL

HDL Cholesterol (mg/dL) Subgroup Relative Risk Estimate (95% CI): Adjusted for Age, Gender, and Smoking Relative Risk Estimate (95% CI): Adjusted for apoA-1 and apoB
<40 1.00 1.00
40–59 0.91 (0.76–1.09) 1.10 (0.88–1.37)
50–59 0.77 (0.62–0.95) 1.12 (0.81–1.55)
60–69 0.71 (0.51–0.99) 1.25 (0.76–2.04)
70–79 1.03 (0.65–1.63) 2.19 (1.12–4.28)
>80 0.96 (0.51–1.82) 2.49 (1.04–5.95)

Risk Estimates for Major Coronary Events by HDL Particle Size in EPIC-Norfolk

HDL Particle Size (nm) Subgroup Relative Risk Estimate (95% CI): Adjusted for Age, Gender, and Smoking Relative Risk Estimate (95% CI): Adjusted for apoA-1 and apoB
<8.60 1.00 1.00
8.60–9.05 0.98 (0.78–1.23) 1.34 (1.05–1.72)
9.05–9.53 0.64 (0.49–0.84) 1.20 (0.87–1.64)
9.53–9.85 0.83 (0.60–1.22) 1.99 (1.25–3.16)
9.85–10.07 0.78 (0.41–1.47) 2.32 (1.12–4.77)
>10.07 1.01 (0.44–2.34) 3.49 (1.37–8.89)

In the paper, van der Steeg and colleagues state there is no clear biological explanation as to how HDL cholesterol can become proatherogenic. When HDL cholesterol particles become very large, the antiatherogenic capacity might be affected, resulting in less functional or possibly even dysfunctional HDL cholesterol, the group notes. In addition, because apoA-1, unlike HDL cholesterol, did not "switch" toward a positive relationship at higher levels, the finding supports apoA-1 as the active component of HDL particles, "possibly defining the atheroprotective capacity of this lipoprotein fraction," they add.

In terms of clinical utility, although these findings need to be confirmed in other comparable data sets, apoA-1, given the uniform lower risk with higher levels, might be a valuable alternative risk marker. Novel biomarkers that provide information about HDL functionality would also be useful, suggest van der Steeg and colleagues.

"Given the present results," they write, "it can be hypothesized that strategies primarily raising plasma apoA-1 levels with small molecular compounds, infusion of small lipid-poor apoA-1 particles, or apoA-1 gene therapy will have a more pronounced effect on atherogenesis."

HDL as a Goal is Fraught with Danger

In an editorial accompanying the published study [2], Dr Jacques Genest (McGill University, Montreal, QC) said the findings have important clinical implications, as the data suggest that naturally occurring high levels of HDL might not protect against heart disease and that HDL cholesterol "as a therapeutic goal may be fraught with dangers."

He writes that while the findings must be replicated in other clinical and epidemiologic studies, there are a number of questions that remain. The first is whether raising HDL-cholesterol levels is beneficial in terms of cardiovascular health. So far, he notes, there are no data showing unequivocally that raising HDL cholesterol by pharmacologic means reduces cardiovascular risk. Other questions--does the means by which this increase is achieved matter? is HDL or apoA-1 the appropriate measurement for therapeutic targets? and is HDL cholesterol simply a marker of cardiovascular health?--must also be answered, writes Genest.

Flashback to the 2007 American Heart Association

Final results of the torcetrapib ILLUMINATE and ILLUSTRATE trials were presented in November at the American Heart Association (AHA) 2007 Scientific Sessions and published simultaneously online in the New England Journal of Medicine [3]. The study showed that the HDL-increasing drug stimulates aldosterone, which possibly accounted for its adverse outcomes.

At the meeting, lead ILLUMINATE investigator Dr Philip Barter (Heart Research Institute, Sydney, Australia) commented: "There have been concerns voiced that the HDL produced by CETP inhibitors may be dysfunctional in some way. But our results, along with new data from the ILLUSTRATE study, are not consistent with that idea. Rather, they are supportive of other in vitro studies that suggest the HDL formed by these drugs is functional." He added, "The observation that torcetrapib increases aldosterone levels is very exciting. If this off-target toxicity were not there, the clinical outcome results might have been very different."

Others were more skeptical. Dr Raymond Gibbons (Mayo Clinic, Rochester, MN) told heartwire : "I've heard all this hype about these findings over the past few days, but now that I've heard the presentation and read the paper, I don't understand what the fuss is about. I can't see the good news here. These new data have not ruled out CETP inhibition as the cause of the adverse outcomes with torcetrapib."

  1. Van der Steeg WA, Holme I, Boekholdt M, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A1: significance for cardiovascular risk. J Am Coll Cardiol 2008; 51:634-42.

  2. Genest J. The yin and yang of high-density lipoprotein cholesterol. J Am Coll Cardiol 2008; 51:643-44.

  3. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357:2109-2122. Abstract

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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