Do I Need to Care About Lp(a)?

Christopher Labos, MD CM, MSc, FRCPC


July 08, 2019

Christopher Labos

For the clinician who does not regularly wade into the cholesterol debate, it might be tempting to simply ignore lipoprotein(a) [Lp(a)]. After all, staying up to date with the cholesterol guidelines is no simple task. Targets for low-density lipoprotein cholesterol (LDL-C) keep falling; alternative targets, such as apolipoprotein B and non–high-density lipoprotein cholesterol (HDL-C), keep popping up[1]; and traditional paradigms, such as HDL-C being the "good" cholesterol, have not survived rigorous testing.

So in the wake of this ever-shifting cholesterol landscape, should one take the time to worry about, let alone routinely measure, a new cholesterol component?

That's actually a trick question, because Lp(a) is not new. It was first discovered in 1963 but has received little attention compared with the other cholesterol components, such as LDL-C, HDL-C, or triglycerides.[2] Its low profile among both physicians and the general public is surprising, given that high Lp(a) levels are fairly common worldwide and about 1 in 5 adults has an elevated Lp(a) level.[3]

What Is Lp(a)?

Lp(a) is similar to its more well-known atherogenic cousin LDL. It is a low-density lipoprotein, though it is slightly larger than an LDL particle and contains two apolipoprotein(a) molecules and one apolipoprotein B molecule.[4] Its exact role in the pathogenesis of cardiovascular disease is still somewhat unclear, and it probably acts via multiple mechanisms. Lp(a) is structurally similar to plasminogen, the protein that dissolves blood clots, and so it acts as competitive inhibitor against fibrinolysis.[5] However, it may also contribute directly to atheroma plaque buildup[6] and aortic valve calcification.[7]

"One way I see it [is] as a second source of atherogenic particles, that you don't actually know is there unless you measure it," says George Thanassoulis, MD, director of preventive and genomic cardiology at McGill University Health Center, who has researched Lp(a).

There is actually no shortage of data linking Lp(a) to the development of cardiovascular disease. A 2009 patient-level meta-analysis of primary prevention studies analyzed data from over 120,000 patients.[8] The authors found a significant association between rising Lp(a) and cardiovascular disease, with increased risk starting at an Lp(a) level of about 30 mg/dL and rising precipitously thereafter.

Another meta-analysis that included patients with established cardiovascular disease showed similar results.[9] It too found higher rates of cardiovascular events starting at Lp(a) levels greater than 30 mg/dL or 50 mg/dL in patients receiving statin therapy.

Causal, or a Marker of Increased Risk?

Clearly, individuals with higher Lp(a) have an increased risk for heart disease, but this type of data can't explain whether Lp(a) is causative or merely a biomarker of increased risk. We have been down this road before with C-reactive protein (CRP). Elevated CRP was associated with increased cardiovascular risk, but ultimately seemed to be more a marker of high risk factor burden than directly causal in and of itself.[10]

One way to tease apart these different possibilities is with Mendelian randomization studies. These exploit a particularly useful quirk of genetic inheritance. At conception, an embryo is equally likely to receive either allele A or allele B of a gene, essentially mimicking the random allocation of a randomized clinical trial. As long as the gene in question doesn't have any pleiotropic effects, (ie, it doesn't also affect an important confounder, such as blood pressure or diabetes risk), people with allele A or allele B should be similar in every other respect. Therefore, any difference in outcomes between the two groups can be attributed to their genetic difference.


When you have a risk factor with a clear genetic contribution, Mendelian randomization can be a useful to test for causality. Fortuitously, Lp(a) is just such a risk factor because Lp(a) levels are largely genetically determined by polymorphisms in the LPA gene.[11] Two studies[12,13] demonstrated that genetically elevated Lp(a) levels were associated with an increased risk for cardiovascular events and strongly support the idea that it is causal in the pathogenesis of cardiovascular disease.

Similar genetic studies have also shown that genetically elevated Lp(a) levels are associated with aortic valve disease. Genome-wide association studies first identified that Lp(a) was associated with aortic stenosis and aortic valve replacement,[14] and subsequent imaging studies confirmed that higher Lp(a) levels are associated with worsening progression of aortic stenosis, suggesting it has a direct causal effect.[7]

What to Do With a High Lp(a) Level?

Given the number of studies and wealth of data surrounding Lp(a) levels, one might be surprised that we do not use it for risk prediction.[15] There are unfortunately no clinical trials to guide treatment decisions. Despite the evidence suggesting that high Lp(a) levels increase cardiovascular risk, there is to date no evidence that lowering Lp(a) levels actually reduces that risk.

Thanassoulis points out that even in the absence of such data, that doesn't mean there's nothing you can do about an elevated Lp(a) level. "The way I practice is if someone were found to have high Lp(a), I would aggressively control their risk factors with both lifestyle and potentially lipid lowering as needed," he advised.

There is some evidence suggesting that optimizing risk factors may help. One study showed that the excess risk conferred by Lp(a) was attenuated with lower LDL-C levels,[16] which suggests that aggressive LDL-C lowering may help mitigate Lp(a) risk. Another report from the Women's Health Study[17] (a randomized trial of low-dose aspirin) found that carriers of the risk allele benefited greatly from aspirin in terms of cardiovascular disease reduction (hazard ratio, 0.44; 95% confidence interval, 0.20-0.94), whereas noncarriers did not. Given recent evidence questioning the value of routine aspirin for primary prevention,[18] Lp(a) might therefore be one way to identify the high-risk patients most likely to benefit.

But the value of lowering Lp(a) itself remains unproven, and there are not many options if one wishes to do so. Neither statins nor ezetimibe have much of an effect on Lp(a) levels.[19] Bezafibrate is the lone medication in the fibrate class that reduces Lp(a), but it is not approved for use in the United States.[20]

The one US Food and Drug Administration-approved cholesterol medication that lowers Lp(a) levels is nicotinic acid, or niacin.[21] Though once very popular, enthusiasm for niacin faded in the wake of AIM-HIGH[22] and HPS2-THRIVE.[23] Neither of these trials showed a cardiovascular benefit for niacin use, and the signal for harm in HPS2-THRIVE probably deterred many clinicians from prescribing the drug. However, there was no signal for increased mortality in AIM-HIGH,[24] and reanalysis of the trial data suggests that the increased risk seen in HPS2-THRIVE may have come from the laropiprant antiflushing agent used in the formulation tested rather than the niacin itself.[25] Also, AIM-HIGH and HPS2-THRIVE included a general population of patients, not specifically those with elevated Lp(a) levels. Whether niacin would show a benefit in a population of patients with high Lp(a) levels remains to be seen.

Hormone Therapy?

Another possible treatment for Lp(a) reduction is estrogen replacement therapy. Estrogen reduces Lp(a) levels by up to 37% and would be a potent treatment, at least in postmenopausal women.[26] But much like niacin, hormonal therapy is no longer routinely used. The negative results of the Women's Health Initiative trial resulted in a veritable sea change when it comes to hormonal therapy use, and the potential for an increased risk for breast cancer, stroke, or pulmonary embolism would probably dissuade many clinicians and patients.[27] Still, it is possible that a trial testing estrogen therapy specifically in women with high Lp(a), if it showed a risk reduction, would renew interest in this medication.

Looking forward, the new class of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may prove helpful in lowering Lp(a) levels. Already approved for lowering LDL-C in patients with cardiovascular disease and familial hypercholesterolemia, a recent meta-analysis[28] of the PCSK9 inhibitor trials has shown they lower Lp(a) levels by about 26%, and post hoc analyses of the FOURIER trial also suggest that the Lp(a) lowering confers a benefit.[29]

Finally, a new class of medications, antisense oligonucleotides that bind the messenger RNA coding for Lp(a), are under development. Preliminary studies have shown that they can lower Lp(a) levels. Research that will probably be published in the next year or so will determine whether they also reduce cardiovascular risk.

To Care or Not?

So is it worth caring or worrying about Lp(a)? The answer is almost certainly yes. There is compelling evidence to suggest that Lp(a) is causative for both cardiovascular disease and aortic stenosis.

What to do with the information is another matter. Consensus statements recommend screening patients with premature cardiovascular disease and no other risk factors, which seems like a reasonable strategy.[30] With new therapies around the corner, Thanassoulis believes we should increasingly screen our patients for high Lp(a). He points out that it's a relatively inexpensive test that can be done basically once, because Lp(a) levels are largely genetically determined and do not change much over time without therapy.

Treating risk factors in these high-risk patients more aggressively also seems logical. But data on treatment specifically to lower Lp(a) levels are lacking. To date, no medication is approved for this purpose. Direct evidence of benefit would probably be needed to allay the safety concerns about niacin or estrogen therapy and to justify the costs of PCSK9 inhibitors or the investigational antisense medications. The good news is that the next few years promise to provide some of that much-needed data. For, like Sherlock Holmes, we cannot make bricks without clay.

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Thanassoulis has reported receiving personal fees as part of advisory boards and speakers bureaus for Sanofi/Regeneron, Amgen, Boehringer Ingelheim, and Servier, and research grants from Servier and Ionis.


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