Raising high density lipoprotein: need to take account of functionality?

Are very high levels of high-density lipoprotein (HDL) cholesterol and very large HDL particles associated with increased coronary risk? These are the findings from an analysis of data from the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering) trial and EPIC (European Prospective Information into Cancer and Nutrition) Norfolk Cohort, discussed by HDL Forum Editor Professor Kerry-Anne Rye. The analysis was published in the Journal of the American College of Cardiology on 5 February 2008.

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

An extensive evidence-base from population studies supports an inverse association between low HDL cholesterol and CHD risk. Evidence supporting this association has been elegantly argued in a recent consensus paper, lead authored by Professor John Chapman, a member of the HDL Forum Editorial Board.1 On the basis of these studies, the level of HDL cholesterol was identified as a cardiovascular risk factor in US and European guidelines.2,3

On the basis of this epidemiological evidence, it was postulated that raising HDL cholesterol levels should prevent CHD. The VA-HIT (Veterans Affairs HDL Intervention Trial) in 2,531 men with known CHD, low HDL cholesterol (mean baseline HDL-C 32 mg/dl [0.83 mmol/l]) and average LDL cholesterol levels demonstrated the benefit of increasing HDL-C in terms of reducing coronary risk.4 In multivariate regression analyses, the increase in HDL cholesterol was the only treatment effect that predicted clinical benefit.5 Furthermore, two studies using surrogate measures of clinical outcomes – HATS (HDL Atherosclerosis Treatment Study)6 [LINK TO RESOURCES slides] and ARBITER2 (ARterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol study) [LINK TO RESOURCES slides] have shown the benefit of raising HDL cholesterol levels on atherosclerosis progression.7

However, data from the analysis by Van der Steeg and co-workers suggests that this relationship may be more complex. Importantly, the functional capacity of HDL particles may play a key role.

The analysis included data from 8,654 subjects with a history of myocardial infarction in the IDEAL study (total subjects 8,888), a secondary prevention trial comparing high- to conventional-dose statin therapy, and 858 cases and 1,491 control subjects in the EPIC-Norfolk cohort (total 1,133 cases and 2,237 controls) (Table 1).

Table 1. Composition of analysis populations


 IDEALEPIC
Total N88883370
Included in analysis85642349
Cases + controls 858 + 1,491
No. with major coronary events679225 + 1 matching control
633 + 2 matching controls

Levels of HDL cholesterol and apolipoprotein A-I were comparable in subjects in each study. However, levels of total and LDL cholesterol and apolipoprotein B were lower in IDEAL than in EPIC-Norfolk as all patients in IDEAL were receiving statins, whereas none of the subjects in the EPIC-Norfolk cohort were on lipid-lowering therapy (Table 2).

Table 2. Mean baseline lipid levels of analysis populations


 IDEALEPIC
N85642349
HDL cholesterol (mg/dL)46.550.9
ApoA-I (g/l)1.391.60
Total cholesterol (mg/dL)163243.9
LDL cholesterol (mg/dL)91.7160.4
ApoB (g/l)0.941.32

The researchers categorised patients into 6 subgroups for HDL cholesterol levels (both studies) and HDL particle size (EPIC-Norfolk only). The HDL cholesterol subgroups were: <40, 40-49, 50-59, 60-69, 70-79 and >80 mg/dL. In the IDEAL cohort, these subgroups contained 30.2%, 34.4%, 24.0%, 7.6%, 2.5% and 1.3% of subjects.

In the IDEAL study data, unadjusted analyses showed that HDL cholesterol was inversely associated with coronary risk up to a level of 70 mg/dL (p=0.06). After adjusting for levels of apolipoprotein A-I (apoA-I), the main apolipoprotein in HDL, and apoB (the main apolipoprotein in LDL), patients in the categories above 70 mg/dL were at significantly increased coronary risk compared with patients with ‘low’ HDL cholesterol levels (<40 mg/dL) (Table 3). Similarly, in the EPIC-Norfolk data there was a significant inverse trend between HDL cholesterol and coronary risk (p<0.0001), which was abolished when adjusted for apoA-I and apoB levels (Table 3).

As noted by the authors, these results were only evident when the data were divided into six categories of HDL cholesterol, and not if the data were divided into quartiles.

ApoA-I, even when corrected for HDL cholesterol and apoB levels, remained a significant protective coronary risk factor.

Table 3. Risk estimates for major coronary events by HDL cholesterol level, unadjusted and adjusted for apoA-I and apoB levels – IDEAL study data


 UnadjustedAdjusted for apoA-I and apoB
HDL cholesterol (mg/dL)  
<401.001.00
40-490.911.10
50-590.77*1.12
60-690.71*1.25
70-791.032.19*
<800.962.49*
*p<0.05  

Information on HDL particle size was only available in the EPIC-Norfolk cohort. Coronary risk was increased by between nearly 2-fold and 3.5-fold in subjects with larger HDL particles (Table 4).

Table 4. Risk estimates for major coronary events by HDL particle size, adjusted for apoA-I and apoB levels – IDEAL study data


 Adjusted for apoA-I and apoB
HDL particle size (mm) 
<8.601.00
8.60-9.051.34*
0.05-9.531.20
9.53-9.851.99**
9.85-10.072.32*
<10.07 3.49**
* p<0.05; **p<0.01 

The authors of the analysis acknowledged limitations with their study, notably in that the two cohorts differed in their scope, aim and characteristics. According to Professor JJP Kastelein from the Academic Medical Center, Amsterdam, The Netherlands :'Comparable analyses in other datasets with robust statistical power are urgently needed to validate these remarkable findings.'

In an accompanying editorial, Dr Jacques Genest, from McGill University, Montreal, Quebec, Canada discussed these findings.

Genest J. The yin and yang of high-density lipoprotein cholesterol. J Am Coll Cardiol 2005;51:643-4.

Experimental studies show that HDL is potentially anti-atherogenic via a number of different functions. A key function is the role of HDL in reverse cholesterol transport, the process in which cholesterol is transported from the vasculature to the liver for excretion from the body. It has been suggested that very large cholesterol-enriched HDL may lose some of their anti-atherogenic functions, and become donors rather than acceptors of cholesterol. Dr Genest suggested that the provocative findings of Van der Steeg and co-workers suggest that raising small or nascent HDL particles may be more important than the production of larger cholesterol-enriched HDL particles. He also highlighted the need for developing better analytical techniques for measuring HDL function.

The HDL fraction of human plasma consists of multiple, discrete subpopulations of particles that vary in size, composition and function. While there is a large body of epidemiological evidence indicating that high HDL levels protect against coronary heart disease, little is known about which HDL subpopulations are responsible for this beneficial effect. This issue is explored in the recently reported combined analysis of the IDEAL and EPIC-Norfolk studies, which indicates that high HDL cholesterol levels and very large HDL, but not apoA-I levels, are associated with increased cardiovascular risk. While this could be interpreted in terms of high HDL levels being detrimental, such a conclusion is in direct conflict with a huge amount of other data which indicate that high HDL levels are cardioprotective.

In the interest of maintaining a perspective on the combined IDEAL and EPIC-Norfolk observations, it should be pointed out that, although the total number of subjects in the study was quite high, the positive association of high HDL cholesterol levels and cardiovascular risk was restricted to only a small subset of individuals. Furthermore, this relationship did not extend to apoA-I, which remained inversely associated with cardiovascular risk at all levels. This suggests that the HDL which were not cardioprotective were most likely large particles that were markedly enriched in cholesterol and relatively depleted of apoA-I. Particles of this type are quite uncommon. This result raises questions about what other apolipoproteins may have been associated with these particles, and whether they may have had a detrimental influence HDL function.

Irrespective of these questions, one of the most important points to emerge from this investigation is that apoA-I levels may be a more reliable marker of cardiovascular risk than the more commonly measured HDL cholesterol.

References

1. Chapman MJ, Assmann G, Fruchart J-C et al. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid – a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 2004;20:1253-68.
2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
3. Ryden L, Standl E, Bartnik M et al on behalf of the Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular disease: executive summary. Eur Heart J 2007;28:88-136.
4. Rubins HB, Robins SJ, Collins D et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-8.
5. Robins SJ, Collins D, Wittes JT et al. Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial. JAMA 2001;285:1585-91
6. Brown BG, Zhao XQ, Chait A et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.
7. Taylor AJ, Sullenberger LE, Lee HJ et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol (ARBITER) 2. A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004;110:3512-7

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