Role of Lp(a) Still to Be Determined, but NHLBI Sees a Path Forward

A new review provides direction on everything from standardizing assay values to large-scale testing of new therapies that lower Lp(a) levels.

Role of Lp(a) Still to Be Determined, but NHLBI Sees a Path Forward

The National Heart, Lung, and Blood Institute (NHLBI) has issued new a report outlining the next steps needed to identify and reduce the risk of cardiovascular disease and calcific aortic valve disease associated with elevated lipoprotein(a), also known as Lp(a).

The NHLBI review provides direction on everything from standardizing the name and measurement of Lp(a) to setting specific research priorities, including studies that would provide insight into the various mechanisms in which drug therapies influence Lp(a) levels.

Sotirios Tsimikas, MD (University of California San Diego, La Jolla), who led the working group drafting the recommendations, said there has been a lot of research into the role of Lp(a) in cardiovascular and calcific aortic valve disease in the last several years but no formal direction.

“What’s happening is we have these divergent sets of data and up to this point the field has been going on ad hoc, depending on who’s working on it,” he told TCTMD. “The NHLBI wanted to make a statement to help move the field forward for the next 5 to 10 years.” The new report, he added, is derived from experts in the field and includes a variety of perspectives with the intention of establishing some “recommendations to fill in the gaps of what is not known yet and where the field should go.”

Published online January 8, 2017, in the Journal of the American College of Cardiology, the experts outline six research priorities:

  • Define the mechanisms of Lp(a) synthesis, assembly, clearance, and other influences on circulating levels
  • Understand the mechanisms underpinning Lp(a) and associated oxidized phospholipids in mediating the risk of cardiovascular disease and aortic stenosis
  • Develop a globally standardized measurement of Lp(a) for commercial laboratories (report values in nmol/L) and to define population risk in different racial/ethnic groups
  • Understand the mechanisms of how different drug regimens affect Lp(a) levels
  • Focus on populations at risk for CVD with high Lp(a) levels requiring special research emphasis
  • Test the Lp(a) hypothesis

The Lp(a) Hypothesis

Lp(a) is composed of an apolipoprotein B-containing LDL-like particle attached to the plasminogen-like glycoprotein apo(a). Lp(a) levels circulating within plasma are primarily determined by the LPA gene locus that encodes apo(a), as well as by the APOE gene locus and PCSK9 loss-of-function mutations. 

Epidemiology studies have shown that increased plasma concentrations of Lp(a) are associated with an increased risk of CVD and aortic stenosis, said Tsimikas. Additionally, mendelian gene randomization and genome-wide association studies point to a similarly increased risk, he said.

So far, the PCSK9 and CETP inhibitors have been shown to modestly decrease Lp(a), as has niacin, but more potent and specific therapies, such as antisense oligonucleotides currently in development, can reduce Lp(a) more than 90%. One of the major steps will be to test whether lowering Lp(a) with one of these specific therapeutic agents reduces the risk of cardiovascular events when given on top of guideline-recommended preventive therapy.

Regarding this Lp(a) hypothesis, “the reason it hasn’t been tested so far is that there hasn’t been a therapy to lower Lp(a) effectively,” said Tsimikas. Several phase II studies testing antisense oligonucleotides, which work by preventing the translation of apo(a) mRNA, have been conducted and future studies are planned and/or underway.

Mark Feinberg, MD (Brigham and Women’s Hospital, Boston, MA), who was not involved in the NHLBI review, told TCTMD that while there are compelling epidemiologic and genetic data showing an association between Lp(a) and CVD and aortic valve disease, there is weaker evidence to show that lowering Lp(a) improves the pathophysiology associated with coronary artery disease and calcific aortic valve disease.  

Like Tsimikas, Feinberg said there is a need for large-scale, randomized clinical trials testing the Lp(a) hypothesis, particularly since “we’ve been burned before with surrogate endpoints.” Only such a study can definitively determine whether lowering Lp(a) with antisense oligonucleotides or other therapies translates into a reduction in clinical outcomes.

That said, Feinberg believes Lp(a) provides useful information, particularly as physicians assess residual risk outside of lipid-lowering with statin therapy. “We’re already looking at many patients we consider optimally treated but who are still high risk because they’re having events,” he explained.

Guidelines and the Role of Lp(a)

In 2016, the European Society of Cardiology/European Atherosclerosis Society recommended physicians measure Lp(a) in patients with premature CVD, familial hypercholesterolemia, a family history of premature CVD or elevated Lp(a), recurrent CVD despite optimal lipid-lowering therapy, or those with a 5% or higher 10-year risk of fatal CVD. The Canadian Cardiovascular Society and National Lipid Association make similar recommendations, although the American College of Cardiology/American Heart Association cholesterol guidelines focus primarily on LDL cholesterol.

In the right patient, Tsimikas said, measuring Lp(a) levels can provide useful information as it can identify an etiology outside of LDL cholesterol levels for CVD events. “I think it’s important for patients to know—even if you can’t do anything about it—because then you can at least define something genetic within them, not just something they’re doing behaviorally,” he said. “I think it’s important for some patients to get a sense of where the risk is coming from.”

Tsimikas added that their group has published studies showing Lp(a) can help with risk stratification in intermediate-risk patients. In those studies, approximately 20% to 40% of such patients can be reclassified as high or low risk depending on Lp(a) levels. Some patients with high Lp(a) levels might also wish to enroll in phase II studies testing the various Lp(a)-lowering agents, he added. 

Regarding calcific aortic valve disease, Tsimikas noted that the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) study showed that patients with mild-to-moderate aortic stenosis who progressed the fastest were those with elevated Lp(a) levels. Individuals with elevated Lp(a) levels might be watched more closely, he said, noting that there is yet no study showing that reducing Lp(a) levels slows the rate of aortic valve disease progression.

He pointed out, too, that not every patient with mild-to-moderate aortic stenosis has elevated Lp(a). In only about 40% of patients does Lp(a) appear to be a trigger for disease progression.

Feinberg said that while statins and ezetimibe (Zetia, Merck/Schering-Plough) failed to slow or halt the progression of calcific aortic valve disease in several studies (SALTIRE, ASTRONOMER, and SEAS), these therapies lowered LDL cholesterol and not Lp(a). “Perhaps we just had the wrong target,” he suggested. And while there might be a role for Lp(a) inhibition in CVD and calcific aortic valve disease, “it is important to identify patients prospectively before they have the full manifestation of disease to have the biggest impact,” Feinberg stressed.

Sources
Disclosures
  • Tsimikas reports no relevant conflicts of interest.

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