The current analysis of more than 300 000 people has demonstrated that lipid assessment in vascular disease can be simplified by measurement of either cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride. This conclusion derives from several findings. First, HRs with non-HDL-C and HDL-C were nearly identical to those seen with apo B and apo AI. This finding suggests that current discussions about whether to measure cholesterol levels or apolipoproteins in vascular risk assessment should hinge more on practical considerations (eg, cost, availability, and standardization of assays) than on major differences in strength of epidemiological associations. Second, HRs for vascular disease with lipid levels were at least as strong in participants who did not fast as in those who fasted. Third, HRs were similar with non-HDL-C as with directly measured LDL-C. Finally, in contrast with previous findings based on much less data, triglyceride concentration was not independently related with CHD risk after controlling for HDL-C, non-HDL-C, and other standard risk factors, including null findings in women and under nonfasting conditions.21,22
Hence, for population-wide assessment of vascular risk, triglyceride measurement provides no additional information about vascular risk given knowledge of HDL-C and total cholesterol levels, although there may be separate reasons to measure triglyceride concentration (eg, prevention of pancreatitis).
Concentrations of HDL-C and non-HDL-C were each strongly associated— in opposite directions—with CHD risk in an approximately log-linear manner. In contrast with the null triglyceride findings after adjustment, HDL-C and non-HDL-C were largely independent from each other on a multiplicative scale, as well as from triglyceride concentration and other risk factors. Hence, whereas prevailing therapeutic strategies focus on lowering of LDL-C (or, approximately analogously, non-HDL-C), the current findings suggest that therapy directed at HDL-C as well as non-HDL-C may generate substantial additional benefit. For example, CHD risk is approximately two-thirds lower in people with 15 mg/dL higher HDL-C and 80 mg/dL lower non-HDL-C, which are alterations that are attainable with, say, extended-release niacin plus a potent statin.19,20
Long-term randomized trials of such lipid-modifying regimens are therefore needed to test this epidemiologically expected risk reduction.23-25
Because associations of higher non-HDL-C concentration with CHD are similar at both higher and lower HDL-C concentrations, the absolute benefits of lowering LDL-C are likely to be greater if HDL-C concentration is low (or when absolute risk is high for some other reason). While the current findings can-not confirm or refute causality for either triglyceride or HDL-C concentration, they encourage large CHD studies of therapies and genotypes that specifically affect each of these lipid measures to help judge etiological relevance.23-29
Observational analyses focused on etiology should ideally allow for the possibility of disparate associations of different non-HDL-C components with vascular risk, which requires information on each type of low-, intermediate-, and very-low-density lipoprotein cholesterol (such information was not available in most studies contributing to the current analysis).
Hemorrhagic stroke was unrelated to any of the lipids studied here. Only proatherogenic lipids appeared to be associated with risk of ischemic stroke, albeit modestly. Indeed, the current study found an HR for CHD with non-HDL-C about 4 times greater than that for ischemic stroke. Because statin medications reduce risk of both CHD and ischemic stroke to a similar extent,10
the quantitative discrepancy observed between epidemiological associations of non-HDL-C with CHD and ischemic stroke is striking.30
To characterize this risk in more detail, stud ies are needed that can subtype the diverse etiologies for ischemic stroke.31
Given the essentially null associations observed between HDL-C concentration and stroke risk, considerable loss of statistical power may result from inclusion of stroke in primary outcomes of HDL-C-raising trials 23,25,29
(unless similar effects are observed to those in the previous trials of statin).
There was some heterogeneity in the findings, but the broad consistency of results across 68 studies in 21 countries supports their generalizability. Confounding was minimized by adjustment of HRs for long-term average levels of risk factors based on more than 89 000 serial measurements. As the logarithm of triglyceride concentration had a regression dilution ratio comparable with those of other lipid measures, such variability cannot account for the different HRs for CHD that were seen with the different lipid measures. The current prospective data contrast sharply with those of some large retrospective case-control studies that reported that apolipoproteins have much stronger associations with CHD risk than cholesterol levels.32,33
Case-control studies of acute MI may be liable to distortion of lipid levels by recent infarction, a potential bias that is minimized by prospective analyses of participants without cardiovascular disease at baseline.32,33
It remains unclear whether some residual artifact explains the apparent flattening of associations seen in the present analyses with CHD at very high HDL-C or at very low non-HDL-C concentration (whereas, by contrast, randomized statin trials indicate that LDL-C lowering below 80 mg/dL continues to lower CHD risk 10,34