IDEAL: High levels of HDL cholesterol a poor marker of cardioprotection when adjusted for apoA-1 and apoB

June 13, 2007

Helsinki, Finland - An analysis of the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study suggests that high levels of HDL cholesterol, when adjusted for apolipoprotein A1 (apoA-1) and other lipoprotein variables, might be an adverse risk factor for cardiovascular disease and a poor marker of cardioprotection [1].

Presenting the findings from the analysis at the European Atherosclerosis Society (EAS) 76th Congress in Helsinki, Finland, investigators showed that increased levels of HDL cholesterol, when adjusted for apoB and apoA-1, were associated with an increased risk of major cardiac events, particularly at levels greater than 70 mg/dL.

"Epidemiologic data suggest that HDL cholesterol is an independent, inverse predictor of coronary heart disease risk," lead investigator Dr Ingar Holme (Ullevål University Hospital, Oslo, Norway) explained during the late-breaking plenary session. "But recent findings from the torcetrapib trials have suggested that high HDL-cholesterol levels might have an adverse effect on CHD risk. On this basis, we looked at the relationship between high HDL-cholesterol levels and coronary-event rates."

Legacy of torcetrapib spurs analysis

As previously reported by heart wire , torcetrapib was a high-profile cholesteryl-ester-transfer protein (CETP) inhibitor designed to increase HDL cholesterol and decrease, to a small degree, LDL-cholesterol levels, a typically antiatherogenic profile. The much-anticipated and heavily hyped drug was stopped in development in early 2007 when investigators showed it increased the risk of death and cardiovascular events.

With these concerns in mind, that high levels of HDL cholesterol might actually be harmful, the IDEAL investigators performed a post hoc analysis of their data to assess the relationship between HDL-cholesterol levels and coronary heart disease events. Special emphasis was placed on HDL-cholesterol levels >70 mg/dL, especially when apoA-1 and apoB were kept constant. The group also wanted to evaluate the predictive ability of increased apoA-1 on major cardiac-event risk, again when HDL cholesterol and apoB were constant.

IDEAL, in a nutshell

The IDEAL study, previously reported by heartwire , was a prospective, randomized, open-label, blinded-end-point evaluation trial conducted in 8888 patients aged 80 years or younger with a history of acute MI. The primary end point of coronary death, acute MI, or cardiac arrest with resuscitation occurred in 463 patients (10.4%) in the simvastatin group and in 411 patients (9.3%) in the atorvastatin group and was not statistically significantly different between the two study arms. The composite secondary end point of a major cardiovascular event, defined as major coronary events and stroke, was significantly reduced in patients treated with atorvastatin. Similarly, there were reductions in the risk of nonfatal MI, any CHD event, and any cardiovascular event.

As presented earlier at the EAS meeting, Holme noted that the incidence of major cardiovascular events in the IDEAL study declined with increasing HDL-cholesterol levels. However, he said that there was wide variation in the highest quintile, including patients with an HDL-cholesterol level >54.1 mg/dL, and investigators were interested in the relationship with coronary events at this high level. After adjustment for various lipoproteins, the risk of major cardiac events was shown to increase with increasing levels of HDL cholesterol.

Relationship of HDL cholesterol to major cardiac events

Adjustment variable Hazard ratio per each 12-mg/dL increase in HDL cholesterol p
None 0.92 0.043
LDL cholesterol 0.91 0.021
ApoA-1 1.05 0.59
ApoA-1, LDL cholesterol 1.11 0.26
ApoA-1, apoB 1.21 0.038
ApoA-1, LDL cholesterol, apoB 1.26 0.020
One standard-deviation increase in HDL cholesterol=12 mg/dL

Relationship of apoA-1 to risk of major cardiac events

Adjustment variable Hazard ratio per each 0.22-g/L increase in apoA-1 p
None 0.90 0.012
HDL cholesterol 0.86 0.108
HDL cholesterol, apoB 0.74 0.002
One standard-deviation increase in apoA-1=0.22 g/L

"If we adjust for LDL cholesterol, not much happens," said Holme. "However, once we start to adjust for apoA-1, this benefit is turned in the direction of risk. If we also adjust for LDL cholesterol and apoB, a better predictor of risk than LDL cholesterol, then the risk of major cardiac events starts to become significant." He said that by adjusting for apoA-1 statistically and increasing HDL cholesterol, the analysis reflects the effects of increasing HDL particle size.

Increased levels of apoA-1, on the other hand, whether or not adjustments were made for HDL cholesterol and apoB, were associated with decreased risk, said Holme.

"When adjusting for apoA-1 and other lipoprotein variables, a high level of HDL cholesterol might be a poor marker of cardioprotection," said Holme. "In contrast, apoA-1 may be associated with decreased major cardiac events across the whole range, whether or not adjustments for HDL cholesterol and apoB are made."

Holme noted that there are limitations with the analysis, the post hoc nature of the study being one of them. Adjustments for lifestyle, concomitant medications, or other considerations were not made either, he noted, adding that these are observational findings from the combined treatment groups and not from the randomized comparisons.

Why no clinical benefit with the CETP inhibitor?

A second study, by Dr Wim van der Steeg (Academic Medical Center, Amsterdam, the Netherlands), also suggests that very large HDL particles do not confer protection against cardiovascular disease, at least when levels of apoA-1 and apoB are kept constant [2].

Presenting the results during the same late-breaking plenary session, van der Steeg, who works with lipid expert Dr John Kastelein (Academic Medical Center), said the hypothesis of the present study was that an increase in HDL particle size, induced by CETP inhibitors like torcetrapib, might affect its antiatherogenic capacity and might result in less functional and possibly even dysfunctional HDL cholesterol.

In this case-control study, investigators studied 858 cases of fatal and nonfatal MI in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Population Study and 1491 matched controls. HDL particle size was measured by nuclear magnetic resonance spectroscopy. The focus of the analysis was the relationship between HDL particle size and cardiovascular events, particularly with very large HDL particles.

After adjustment for classical cardiovascular risk factors, as well as for apoA-1 and apoB, very large HDL particles, those >9.5 nm, were associated with an increased cardiovascular risk. Very high levels of HDL cholesterol also showed a trend toward increased cardiovascular risk. Very high levels of apoA-1, following an adjustment for classic cardiovascular risk factors as well as HDL cholesterol and apoB, were not associated with an increased risk, the group found.


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