Who Should Have Lp(a) Levels Tested? Experts Take Sides

Over the past decade, interest has exploded in the low-density lipoprotein (LDL) variant lipoprotein (a), or Lp(a), as researchers have learned more about its cholesterol-carrying properties, its distribution across populations, and, of greatest concern, its link to atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD) in particular.

Lp(a) levels are driven by genetics and knowing one’s Lp(a) level can shed light on individual CV risk. Although multiple tests measuring Lp(a) levels are available, the first RNA-based therapies to target a component of Lp(a), apolipoprotein(a), are still in phase 3 clinical trials (pelacarsen and olpasiran).

Which raises the question debated Saturday at the 2024 Congress of the American Society for Preventive Cardiology (ASPC): is Lp(a) actionable in primary prevention today?

Vera Bittner, MD, MSPH | Image: University of Alabama at Birmingham

Arguing “yes” in what was a mostly light-hearted debate was Vera A. Bittner, MD, MSPH, professor of medicine and section head of General Cardiology, Prevention, and Imaging at the University of Alabama at Birmingham. Taking a modified “no” position—that not everyone should be tested for Lp(a)—was Roger Blumenthal, MD, professor of cardiology and the director of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Clinical Connection.

Roger Blumenthal, MD | Image: Johns Hopkins

Lp(a) does its damage by connecting with cholesterol and causing fatty material builds up in the artery walls. It is not the same as LDL cholesterol, but rather an LDL-like particle that contains apo(a) linked to a single apoB molecule. Bittner cited work in the Journal of the American College of Cardiology that found while Lp(a) particles were less abundant than LDL particles, when present Lp(a) is far more dangerous: about 6 times more atherogenic than LDL.

Some have argued that Lp(a) does not make as great a contribution to CVD on a population level, but it does on an individual level. Bittner focused on the impact that including one’s Lp(a) level into calculating lifetime CV risk could have on that individual patient who might be unmoved by a comparatively low risk percentile based only on LDL measures.

“As we say, a picture’s worth a thousand words,” she said, displaying an example in a graph. “Showing somebody that the risk is not 25% but 68% will hopefully get more buy in from the individual in lifestyle modifications.”

Bittner has explored this directly: she was an author on a study that tested patients for Lp(a) and followed them over a 14-year period. Results showed that high Lp(a) levels were associated with increased risk of CHD in patients with inflammatory markers.¹

She emphasized that because Lp(a) levels are genetically driven, testing only needs to be done once—preferably earlier in life. A study of infants’ cord blood in Copenhagen suggests that this could even be used as a proxy for who may be at risk of developing elevated Lp(a) in adulthood.²

Although Lp(a) was discovered in 1963, its value as predictor of major adverse cardiovascular events (MACE) came into sharper focus over the past decade, when patients enrolled in various cardiovascular outcomes trials, especially those required by FDA for PCKS9 inhibitors. A year after she was a co-author for the 2018 ODYSSEY OUTCOMES trial, which showed reduced risk of recurrent events among patients with a prior acute coronary syndrome who took alirocumab (Praluent, Sanofi),³ Bittner was first author on a paper that showed how baseline Lp(a) values of the participants drove these results.⁴

In 2019, she noted, guidelines from both the American College of Cardiology/American Heart Association and the European Society of Cardiology began to call for Lp(a) testing.

For Bittner, the need to test is clear. She told the audience he looked up testing costs on Google and learned they ranged from $49 to $60 (in fact, free on-site Lp(a) testing has been a popular giveaway at recent cardiology meetings).

“If you don’t measure it, if you don’t know how to treat it,” she said. “I would argue that if you don’t know about your patients’ Lp(a), you also cannot define your primary prevention strategy.”

Blumenthal, for his part, conceded there’s plenty of Lp(a) testing at his institution. But whether population-level testing makes sense right now is a separate question. He framed this as a question of being “precise” vs “pragmatic,” noting that the US health system already falls short in measuring traditional factors, such as blood pressure, and LDL cholesterol. Studies show Black individuals are known to have higher Lp(a) levels, and right now, Blumenthal said, there is no strategy to address this.

He agreed with Bittner’s assessment that there are “different intensities of lifestyle modification,” once high-risk patients are identified. However, Blumenthal added, “Do we really need something else to tell us that a person is at high risk?”

Instead, he said, “My thought is we need to prioritize who should be tested.” Citing work that was another theme of ASPC regarding coronary calcium scores, he said if the score is zero, even if Lp(a) is elevated, “It doesn’t make much difference over the next 15 years.”

By contrast, Blumenthal said, Lp(a) testing should be prioritized for those with subclinical atherosclerosis or aortic valve calcification, or for patients who cannot tolerate maximum statin doses to determine the next step in treatment.

Adding to testing costs does not make sense in most cases, he said, when, “I can just take a tape measure and know who’s at high risk.”

In her rebuttal, Bittner noted the argument that “We don’t do a good job with traditional risk factors, so we shouldn’t measure anything else is probably not a good one.”

The failure to get most patients to change their diet and exercise habits should not stop health systems from learning more about them, she said, especially information about early CV risk. But Blumenthal asked whether clinicians would really be any less aggressive with a high-risk patient.

“I think it’s a waste of money to measure it in everybody,” he said.

References

1. Colantonio LD, Goonewardena SN, Wang Z, et al. Incident CHD and ischemic stroke associated with lipoprotein(a) by levels of Factor VIII and inflammation. J Clin Lipidol. 2023;17(4):529-537. doi: 10.1016/j.jacl.2023.06.001.
2. Strandkjaer N, Hansen MK, Nielsen ST, et al. J Clin Endocrinol Metab. 2022;107(2):324-335. Lipoprotein(a) levels at birth and in early childhood: the COMPARE study. doi: 10.1210/clinem/dgab734
3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2079-2107. doi: 10.1056/NEJMoa1801174
4. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020;75(2):133-144. doi: 10.1016/j.jacc.2019.10.057.