Contrary to previous suggestions of steep threshold effects, the current analysis of 126 634 individuals has demonstrated broadly continuous associations of Lp(a) concentration with the risk of CHD. Because these associations were only slightly reduced after adjustment for long-term average levels of lipids and other established risk factors, it increases the likelihood that Lp(a) is an independent risk factor for CHD. Lipoprotein(a) concentration is, however, a relatively modest coronary risk factor, being only about one-quarter as strong overall as non–HDL cholesterol, although Lp(a) may become proportionally more important to CHD at very high concentrations owing to its potentially curvilinear risk relationship. Because associations of higher Lp(a) concentration with CHD are similar at different levels of non-HDL cholesterol, the absolute benefits of cholesterol lowering should be greater if Lp(a) concentration is high (or when absolute risk is high for some other reason).
Whereas previous literature-based reviews of Lp(a) have focused only on CHD,8-10
the current individual participant meta-analysis also investigated stroke subtypes and cause-specific mortality, including nonvascular deaths. Although current data in relation to Lp(a) concentration and stroke were somewhat sparser and less distinct than those for CHD, findings were broadly similar to those for CHD. In contrast, Lp(a) concentration was unrelated to the aggregate of nonvascular mortality, including cancer and noncancer deaths. Hence, Lp(a) appears to be more specifically associated with vascular outcomes than are a number of systemic markers of inflammation that have been strongly associated with both vascular and nonvascular outcomes.66,74,75
As a subsidiary finding, the current analyses convincingly demonstrate that Lp(a) concentration is more consistent within individuals over several years than are levels of total cholesterol, HDL cholesterol, or systolic blood pressure.
Recent large studies have reported highly significant associations of variants in or near the LPA
gene (a locus known to strongly influence circulating Lp[a] concentration)76-78 with CHD risk.79,80
Together with the current findings of continuous, independent, and specific associations of Lp(a) concentration with vascular outcomes, available data are consistent with the existence of a causal relationship and increase priority for investigation of Lp(a) as a potential therapeutic target. Because the current findings show that Lp(a) concentration is a relatively modest risk factor for CHD, however, interventions capable of much more powerful and specific Lp(a) lowering than currently available may be required to demonstrate any vascular benefits in randomized trials.
Substantial modification of Lp(a) concentration has been difficult to achieve without pharmacological agents.81
Niacin and certain inhibitors of cholesteryl ester transfer protein can reduce Lp(a) by about 20% and about 40%, respectively.82
Contradictory findings have been reported about the effect of statins on Lp(a) concentration,83,84
and it remains uncertain whether statin use attenuates the CHD risk associated with Lp(a) concentration.2,85,86
Large randomized trials of niacin and cholesteryl ester transfer protein inhibitors in the secondary prevention of CHD are in progress.87
Such studies may not, however, enable causal inferences because, in addition to Lp(a) lowering, these agents increase HDL cholesterol and decrease LDL cholesterol and triglyceride concentrations. Similar considerations may apply to mipomersen, an antisense oligonucleotide directed at human apo B100
now in phase 2 clinical trials that has been shown to reduce circulating Lp(a) concentration by 70% in transgenic mice, as well as reducing LDL cholesterol, apo B100
, and oxidized phospholipids.88,89
Even though the first epidemiological study of Lp(a) and CHD was reported in 1972,90
the investigation of this lipoprotein as a potential cardiovascular risk factor has been hampered by the lack of consistent approaches to its measurement. International reference material for Lp(a) laboratory standardization emerged only in 200091
and was accepted by the World Health Organization in 2003.92
Even with methods that use the same standard, however, there is significant variability in measured Lp(a) concentration if assays are sensitive to variation in numbers of repeat domains in apo(a).93,94
Hence, in 2003 an expert panel recommended use of assay systems not sensitive to apo(a) isoforms (eFigure 2B
Population differences can also contribute to variation in Lp(a) concentration, particularly since values differ substantially between individuals and are highly heritable.1,78,95
Nevertheless, pooled analyses of individual data from prospective studies should remain informative, provided that, as in the current study, analyses compare cases and noncases only within each study and explore potential diversity across groups of studies using similar assay methods.
Despite considerable scope for such diversity, it is notable that there is relatively moderate heterogeneity in RRs among the studies based in 15 different Western countries contributing to the current findings, an observation that supports the ability to generalize these data to such populations. Because more than 90% of the participants in the current study were of European continental ancestry, however, further studies are needed in non-white racial groups, particularly in black and South Asian populations, which have different Lp(a) concentrations.96,97
The RRs in the current analysis were not strongly different between studies using assays sensitive and insensitive to apo(a) isoforms (although there was, of course, some heterogeneity within each of these groups of studies). Although the findings did not differ appreciably in subgroups defined by the laboratory and population features recorded, further studies are needed that can explore in greater depth such potential sources of heterogeneity and joint effects with other lipid markers. For example, large studies are needed to assess whether Lp(a) particles with smaller-sized apo(a) isoforms confer even higher RRs for CHD55,98
(such assessment was not possible in the current study because it lacked concomitant data on apo[a] isoforms). Similarly, larger studies are needed to assess proposed synergy in the promotion of vascular disease through oxidative damage (again, this was not possible in the current study because the data set lacked concomitant information on oxidized LDL and lipoprotein-associated phospholipase A2