New Data Show That Lp(a) Is a Causal Factor for MI, Researchers Say

June 10, 2009

June 10, 2009 (Copenhagen, Denmark)— A new study examining genetic data from three different trials shows unequivocally that lipoprotein (a) (Lp[a]) is a causal factor for MI, say the researchers [1]. Dr Pia R Kamstrup (Copenhagen University Hospital, Denmark) and colleagues report their findings in the June 10, 2009 issue of the Journal of the American Medical Association.

"This is a big thing. Here we show, really convincingly for the first time and beyond any doubt, that elevated Lp(a) is a causal factor for MI," senior author Dr Borge G Nordestgaard (Copenhagen University Hospital) told heartwire . Theresults indicate that the 10% of the population studied with the highest levels of Lp(a) had a two- to threefold higher relative risk of MI compared with those who had the lowest levels of Lp(a), he noted.

In the future, this lipoprotein will be taken much more seriously.

In an accompanying editorial [2], Drs George Thanassoulis and Christopher J O'Donnell (National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA) concur: "Taken in the context of previous observational studies of Lp(a), the study by Kamstrup et al adds the strongest evidence to date that lifelong increased Lp(a) plasma levels are causally related to MI. This is an important biological finding that elevates the status of Lp(a) . . . from putative risk marker to confirmed causal factor, and that stimulates renewed interest in the biology of Lp(a) and its role in cardiovascular disease."

Nordestgaard added: "The implication of this is that, in the future, this lipoprotein will be taken much more seriously." He stressed, however, that a very large, randomized controlled intervention trial will be needed to examine whether lowering Lp(a) can reduce MI. Such a trial could be done, he said, as there is a medication that lowers both LDL and Lp(a), niacin, although he acknowledges it has some undesirable side effects.

Exciting Research, But Is It Ready for Primetime?

Experts contacted by heartwire said the new researchis exciting, but they had somewhat differing opinions as to its immediate utility. Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) commented: "The data are intriguing and improve the likelihood that Lp(a) plays a biologic role in atherosclerosis. [They] do not, however, provide evidence that measuring Lp(a) adds to global risk prediction or that lowering Lp(a) improves clinical outcomes. This should stimulate clinical trials and new drug development--we currently have no well-tolerated drugs that effectively lower Lp(a) and have been shown to reduce vascular event rates."

But European Atherosclerosis Society director Dr M John Chapman (Hôpital de la Pitié, Paris, France) said: "This study is exceedingly scientifically and clinically sound, absolutely conclusive, and of tremendous importance. It means that from now on, when patients come into our specialized lipid clinic, we will systematically screen them for their Lp(a) levels."

This study . . . means that from now on, when patients come into our clinic  . . . we will systematically screen them for their Lp(a) levels.

Dr Steven R Jones (Johns Hopkins University Hospital, Baltimore, MD) told heartwire : "Lp(a) is helpful in people who have an otherwise unexplained risk, but I don't know if we are at the point where we would measure it in everybody."

And genetics expert Dr Eric Topol (Scripps Translational Research Institute, La Jolla, CA) told heartwire :"This study is the most convincing to date, using the natural Mendelian 'experiment' that increased Lp(a) levels do in fact track with a higher risk. The quantification of the risk is a significant contribution in what has been a somewhat controversial area."

Nature's Randomized Trial Adds Lp(A) to LDL as a Causal Factor

The study by Kamstrup et al is a Mendelian randomization study, examining the population distribution of a particular polymorphism in the LPA gene, the kringle IV type 2 (KIV-2) size polymorphism. The number of KIV-2 repeats correlates inversely with levels of Lp(a), the researchers explain.

Using data from the Copenhagen City Heart Study (CCHS), a prospective general-population study of 8637 individuals with 16 years of follow-up and 599 MI events; the Copenhagen General Population Study (CGPS), a cross-sectional general-population study of almost 30 000 individuals from 2003 to 2006 with 994 MI events; and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study from 1991 to 2004, with 2461 participants and 1231 MI events; they assessed whether the genetic data were consistent with high levels of Lp(a) being causally associated with increased risk of MI.

"The increase in risk of MI associated with genetically elevated levels of Lp(a) was consistently seen in three large independent studies," Kamstrup et al say. "These findings are consistent with a causal association of elevated Lp(a) levels with increased MI risk." Nordestgaard told heartwire : "This is nature's randomized trial. We have shown that there are now two lipoprotein causal factors--high LDL and high Lp(a)."

Multivariate Adjusted Risk of MI by Quartiles of KIV-2 Repeats in the CCHS

CCHS: Quartiles of KIV-2 repeatsa

Participants, n

Events, n

Multivariate adjusted HRb

Quartile 1












4 (reference)



1.0 (Reference)

a. Quartile 1 is the lowest number of KIV-2 repeats, representing the highest Lp(a) levels

b. Adjusted for age, sex, total cholesterol (corrected for the Lp[a] contribution), triglycerides, body-mass index, hypertension, diabetes mellitus, smoking, and use of lipid-lowering therapy and for women also for menopause and hormone therapy

Multivariate Adjusted Risk of MI by Quartiles of KIV-2 Repeats in the CGPS and CIHDS

Quartiles of KIV-2 repeatsa

Controls, n

Cases, n

Multivariate adjusted ORb

CGPS quartile














4 (reference)



1.0 (reference)

CIHDS quartile














4 (reference)



1.0 (reference)

a. Quartile 1 is the lowest number of KIV-2 repeats, representing the highest Lp(a) levels

b. Adjusted for age, sex and diabetes mellitus

Nordestgaard added that the magnitude of risk associated with high Lp(a) levels is "comparable" to that observed with high LDL levels. But Chapman says that "this is pushing it a little bit too far; let's stay prudent."

"Every time you double the concentration of Lp(a), this study indicates that you increase the cardiovascular risk by 20%," Chapman said. "If you double someone's level of LDL, they would experience about a 40% to 45% increased risk. So in other words, Lp(a) has about half the risk power of LDL, but nonetheless it is very powerful. There is no longer any doubt that this is a significant cardiovascular risk factor in virtually any individual with an Lp(a) level higher than 40 to 50 mg/dL."

But What Are The Clinical Implications, If Any?

In their editorial, Thanassoulis and O'Donnell say that although the study provides evidence suggesting the potential benefit of reducing Lp(a) early in life, clinicians may well wonder: "How will these results affect current approaches for prediction, prevention, and treatment of my patients?"

"At present, the clinical implications remain quite limited," they note. "These results do not provide the necessary evidence that genetic testing of the LPA locus or measurements of plasma Lp(a) have a role in cardiovascular risk stratification or decisions regarding lipid-lowering therapy."

Jones agrees to an extent: "This is an excellent study, but there is uncertainty about its routine application, about how to extend what came out of this paper into clinical practice." For example, he says the way Lp(a) was measured in this study--by using Lp(a) mass--is not the way that Lp(a) is conventionally assessed in clinics, which is by measuring the number of particles. "This is no one's fault, it's just inadvertent." Also, there are currently no assays that measure KIV-2 repeats--as used in this study--available for clinical use, he says.

Nordestgaard suggests there is a role for Lp(a) in those at medium risk of cardiovascular events, in whom it is currently uncertain whether statins would be of benefit. "If these people have high LP(a) and elevated LDL, you're better off lowering one of them as much as possible."

Chapman explained that, generally, Lp(a) will need to be measured only once throughout life, "because the level virtually doesn't change." And he says that epidemiologic studies have demonstrated that people with high LDL and concomitantly high Lp(a) have accelerated atherosclerosis and a significant increase in cardiovascular risk. Also, if such patients have an MI, the MI "would be of greater severity than in a patient with low Lp(a)," he says, suggesting that more aggressive therapy is warranted in such patients.

Jones says he currently measures Lp(a) when he sees a patient who has a family member with an early heart attack, "but the question remains, what is the optimum therapy for those with high Lp(a)?" Jones says he does use niacin. "In some people it reduces levels dramatically, but in some only modestly. But the problem is there are no data showing that if you give niacin and lower Lp(a) levels you reduce risk. But then again, niacin is a very good drug, there is no downside, you're not going to make things worse."

Niacin Trial Warranted

Everyone seems to agree that a randomized controlled trial demonstrating reductions in MI with targeted Lp(a)-lowering therapy is needed. Nordestgaard said: "This trial could be started tomorrow, but it would need to be a big one, with 5000 to 10 000 people. If I were to design the study, I would chose participants with low LDL but high Lp(a), and then it wouldn't be unethical to do a placebo-controlled trial with niacin. That would be the best trial to move the science forward."

Jones says this might prove difficult, as higher LDL tends to be tied to higher Lp(a). He says that a primary-prevention trial should be possible comparing niacin with placebo, even in people with higher LDL levels, "but you would need a large cohort." Or a secondary-prevention study could compare use of niacin with a statin, he noted.

Nordestgaard says a number of proprietary formulations of niacin are available that attempt to reduce the nuisance side effect of flushing.

Dr Christie M Ballantyne (Baylor College of Medicine, Houston, Texas) told heartwire these new data "may be relevant to niacin-based therapies," and he noted that there are two ongoing trials with niacin products, the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study, using extended-release niacin (Niaspan, Abbott), and HPS 2-Thrive, which is testing Merck's niacin/laropiprant combination.

In addition, "there are two thyromimetic compounds in development that lower Lp(a)," Ballantyne says.

Nordestgaard has been a consultant for BG Medicine, Abbott, and AstraZeneca and has received lecture honoraria from Merck, AstraZeneca, Pfizer, Sanofi-Aventis, and Boehringer Ingelheim. Kamstrup has been a consultant for Abbott. Disclosures for the coauthors are listed in the paper. Chapman has received education or clinical grant/research support and/or served as consultant/member for AstraZeneca, Merck Sharp & Dohme, Kowa, and Danone. Jones reports being a consultant for Abbott and AstraZeneca and receiving a grant from Atherotech.