Lp(a) Is a Causal Factor for CVD, But a Modest One

July 21, 2009

July 21, 2009 (Cambridge, United Kingdom) — A new pooled analysis of 36 prospective studies shows there is a continuous association between blood concentration of lipoprotein (a)--Lp(a)--and the risk of MI and stroke [1]. Importantly, this association "is independent from the influence of known risk factors and in particular from LDL cholesterol," author Dr John Danesh (University of Cambridge, UK) told heartwire .

"Taken together with recent findings from a large genetic study, our findings suggest that Lp(a) is a causative risk factor for cardiovascular disease, albeit a comparatively modest one," he comments. And what this new research adds that is particularly important, says Danesh, "is quantification of the size of this risk--the magnitude of association of Lp(a) is about one-quarter that of LDL cholesterol, which is a useful benchmark."

Danesh and colleagues from the Emerging Risk Factors Collaboration report their findings in the July 22/29, 2009 issue of the Journal of the American Medical Association. The results also demonstrate that the association is continuous, "not a curved relationship as previously suspected, but broadly a straight line," he notes, "and the association appears to be exclusive to vascular disease, rather than nonvascular outcomes, and that may be consistent with a causal association and is another interesting finding."

Considerable Scientific Interest, But Clinical Implications Unclear

The objective of the study by the Emerging Risk Factors Collaboration was to assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes in long-term prospective studies that recorded Lp(a) concentrations and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009.

The individual records of 126 634 participants were examined. During 1.3 million person-years of follow-up and under a wide range of circumstances, the results show continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes, say the researchers.

Risk Ratios for Vascular and Nonvascular Outcomes Per 3.5-Fold (One Standard Deviation) Higher Usual Lp(a) Level, Adjusted for Cardiovascular Risk Factors

Outcome Studies, n Individuals, n Cases, n Risk ratioa
Nonfatal MI and coronary death 30 106 645 8362 1.13
Coronary death b 24 72 683 2159 1.14
Nonfatal MI b 26 102 221 6045 1.12
Ischemic stroke 13 69 539 1684 1.10
Unclassified stroke 12 48 407 680 1.01
Hemorrhagic stroke 9 56 165 285 1.06
Nonvascular death 25 102 268 7268 1.01
Other nonvascular death 22 100 378 3745 1.00
a. Risk ratios adjusted for age, usual levels of systolic BP, smoking status, history of diabetes, body-mass index, and total cholesterol and stratified, where appropriate, by sex and study group

b. Subtotals do not add to the total number of CHD outcomes because some nested case-control studies did not subdivide outcomes into coronary death or nonfatal MI

Danesh told heartwire there is "almost half a century of research on Lp(a), and it was all but dismissed as a risk factor in the mid-1990s, because some relatively small studies reported a lack of association with coronary risk. But the recent emergence of larger studies that have used modern methods to measure Lp(a), plus these large pooled analyses--like the current study--together with the large genetics studies have created a resurgence of interest in Lp(a), and it now looks to be a likely causative risk factor."

This is "of considerable scientific interest, to have a possible addition to the handful of established risk factors for cardiovascular disease," he says, but the clinical implications of this finding "remain somewhat limited. It's not clear whether these modest associations will be strong enough to add to current methods of risk prediction."

No Role Yet for Measuring Lp(a)

Danesh says he believes the overt enthusiasm of some for Lp(a) following the recent Danish genetics study--as reported by heartwire --was because this showed there was likely to be a causal association, "but they couldn't quantify that association very well, whereas now our study quantifies the association and puts it in context."

He does not believe that measuring Lp(a) at the current time would be of any benefit: "We don't have a good idea of what that knowledge would add in terms of predicting risk and therefore in terms of taking action about risk, because it's a relatively modest association." Equally, it's not clear whether lowering concentrations of Lp(a) reverses cardiovascular risk, he observes.

One of the problems in demonstrating any potential benefit is that the only agent available that is capable of considerably reducing Lp(a) levels--niacin--also reduces LDL cholesterol and triglycerides and increases HDL cholesterol.

"Even if this agent is shown to have a substantial protective effect against CVD, it's not going to be possible to disentangle its effects on lowering Lp(a) vs its other effects," Danesh states. This does not mean niacin trials should not be conducted, though, he says, noting that there are several ongoing, including the UK HPS-2 Thrive secondary-protection study.

"But unless there is an agent that is developed or emerges that has much more profound and specific Lp(a)-lowering effects, it's going to be difficult to make specific causal inferences. The way ahead is to try to develop agents that are more specific to Lp(a) and more profound because, remember, the risk is rather modest," he concludes.

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