In recent years, whether measurements of apolipoproteins are better than lipoproteins for risk prediction of cardiovascular disorders, and whether the apolipoprotein B/A1 ratio should be the preferred lipid measurement in the future has been debated. In today's Lancet, new fuel to this discussion has been added by the INTERHEART study, a large international case–control study about risk factors for myocardial infarction with more than 9000 patients.1 The investigators found that the apolipoprotein B/A1 ratio was better than any other conventional lipid measure, including other ratios, with a population attributable risk of 54% for the apolipoprotein B/A1 ratio compared with 37% for the best conventional lipid measure (LDL-cholesterol/HDL-cholesterol, p<0·0001).

The unique size of INTERHEART allows subgroup analyses with good power. The superiority of the apolipoprotein B/A1 ratio was valid in different ethnic groups across the globe, in both men and women, and in young and elderly people. This last subgroup analysis is important, because conventional lipid measures tend to lose predictive power in elderly patients.2 Furthermore, whether some lipid measures do equally well in countries with a lower lipid burden as in developed countries with a traditionally higher lipid intake is not obvious. Thus the INTERHEART data strongly support increased use of the apolipoprotein B/A1 ratio, but prospective data are also needed to clarify this matter because lipid measurements in case–control studies might be affected by the disease state or treatment initiated before sampling of blood.

The largest prospective study so far in this specialty is the AMORIS study. In this cohort of over 175000 individuals who attended a health-screening programme in Stockholm, Sweden, more than 1000 deaths from myocardial infarction occurred during a 5-year follow-up.3 A later publication from the same cohort presented risk factors for more than 1000 cases of fatal stroke during a 10-year follow-up.4 With either myocardial infarction or stroke as endpoints, the apolipoprotein B/A1 ratio was better than traditional lipids for risk prediction. Drawbacks of the AMORIS study include lack of risk factors other than biochemical markers and a non-standardised lipid assay. This study, nevertheless, provides firm evidence of the usefulness of the apolipoprotein B/A1 ratio in the prospective setting.

Also, from a pathophysiological standpoint, the apolipoprotein B/A1 ratio is better than traditional lipids in its relation to endothelial dysfunction,5 atherosclerosis development,6 and the interplay between the degree of lipid lowering and event reduction during statin treatment.7 These factors further suggest increased use of the apolipoprotein B/A1 ratio.

Several small prospective or case–control studies, usually including 200–300 events, have compared apolipoproteins with conventional lipid variables.8–12 However, results from these studies have been conflicting. Some showed a superiority of the apolipoprotein B/A1 over conventional lipid measurements or that apolipoprotein B/A1 is a substantial predictor independently of conventional lipids, whereas others did not substantiate such a viewpoint. Among the negative studies is a report from the Framingham Heart Study with the most rigorous statistical tests for the evaluation of new biomarkers, including discrimination, calibration, and reclassification.12

In combination, the largest trials (INTERHEART and AMORIS) point out an advantage of the apolipoprotein B/A1 ratio over traditional lipid variables for risk prediction, although divergent results have been obtained in smaller studies. Apolipoproteins can be measured in a standardised and automatic manner at a cost close to assay of traditional lipid variables and also in the non-fasting state. Although wide-scale introduction of apolipoprotein assay in clinical practice would possibly improve risk prediction to some degree, the most important task is to ascertain that lipids are evaluated at all. Physicians and patients have taken decades to learn to measure lipids and treat hyperlipidaemia, and it will be a demanding but not impossible task of education to substitute traditional lipid measurements by the possibly somewhat better apolipoproteins.

References

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