Lp(a): Aiming at a Moving Target, Waiting for Ammunition

Medscape

2 days ago

The evidence implicating high levels of lipoprotein(a), or Lp(a), as a risk predictor for heart attack, stroke, and other cardiovascular conditions has outpaced the science of what to do about the marker. But recent studies may be challenging the prevailing thinking about Lp(a) by showing it may also be predictive of atherosclerotic cardiovascular disease (ASCVD) away from the heart, such as carotid artery stenosis and peripheral artery disease, and that follow-up testing may benefit people with borderline levels of the blood fat.
Before clinicians do anything about elevated Lp(a), however, they must first test for it. And experts in interventional cardiology have acknowledged that testing for Lp(a) as part of the cardiometabolic lipid panel lags far behind where it should be.
Nishant P. Shah, MD, a specialist in cardiometabolic intervention at Duke University in Durham, North Carolina, led a retrospective study last year of five large US health systems. He and his colleagues found that only 0.4% of patients with ASCVD had been tested for Lp(a).
Nishant P. Shah, MD
'Lp(a) testing is extremely low across the country, even in patients who have had established cardiovascular disease or established cardiovascular events,' Shah told Medscape Medical News .'There are disparities in who is getting tested for Lp(a). Our study showed that patients of the Black race, older patients, those with high BMIs, and women are less likely to be tested than others.' In other words, testing lags even further behind in at-risk groups.
The lack of testing Shah's group reported among people with ASCVD has been confirmed by other studies. A 2023 study from Germany found similarly low rates, and a US database study the same year reported rates of 0.7% in patients on lipid-lowering therapies for secondary prevention of ASCVD.
As a result, the American Heart Association launched a nationwide program, called the Community Health Centers Discovery Project, to bring Lp(a) testing to 20 community health centers across the country.
Kaavya Paruchuri, MD
'Research shows that individuals from racially and ethnically diverse backgrounds are both more likely to have elevated Lp(a) levels and to experience disproportionate rates of heart disease,' said Kaavya Paruchuri, MD, a preventive cardiologist at Massachusetts General Hospital in Boston and an American Heart Association volunteer. 'By expanding access to Lp(a) testing in these settings, we can help identify patients at increased risk and support more informed conversations about prevention and risk-reduction strategies.'
Barriers to Testing
The barriers to more widespread testing are 'multifactorial,' Shah said. The relevance of Lp(a) has only emerged in the past decade or so, leaving generations of cardiologists and primary care providers lacking education about the marker. No Lp(a)-lowering drug has been approved, and while no fewer than six investigational agents are in clinical trials, none is on the brink of approval.
The 2018 clinical guidelines from the American Heart Association/American College of Cardiology recommended selective screening; that is, people who have severe high cholesterol, ASCVD, or a family member who's had early ASCVD. In Europe, clinical guidelines recommend Lp(a) screening for all adults to identify those with high levels of the substance.
'Unfortunately, awareness of Lp(a) as a cardiovascular risk factor remains low amongst both patients and clinicians,' Paruchuri said. 'Furthermore, clinicians may be hesitant to order Lp(a) as there is no clearly defined treatment available to lower Lp(a), and they are unsure how to optimally handle abnormally elevated Lp(a) results.'
Shah also noted that some health insurance plans do not cover the test. 'Providers may not know if the test is covered by insurance or not,' he said.
The 2018 US guidelines noted that Lp(a) is a modified form of low-density lipoprotein (LDL) that appears to possess atherogenic potential. The consensus among researchers who have investigated Lp(a) is that it is a genetic biomarker. As such, levels may not vary from one test to the next unless Lp(a) is targeted with a drug. Lp(a) levels ≥ 50 mg/dL are considered to be elevated.
Despite the lack of a treatment, experts said one case for the cost-effectiveness of Lp(a) testing is that it would be a once-and-done assay in most patients with risk factors for ASCVD.
Emerging Revelations About Lp(a)
'I don't have the Lp(a) test repeated for patients, as I have not seen any strong evidence supporting that it being reduced or increased changes cardiovascular disease or other health issues,' Robert C. Block, MD, MPH, preventive cardiologist at the University of Rochester Medical Center, in Rochester, New York, told Medscape Medical News . 'Not repeating it also is more cost-effective. My point when seeing patients is that this makes sense until we have clinical trial data supporting that lowering it via an agent changes risk.'
Robert C. Block, MD, MPH
But a just-published study of almost 12,000 adult patients at three Mayo Clinic locations may upend that thinking. The Mayo researchers said that after one Lp(a) test, normal or high levels typically do not change: 96.4% of people with normal Lp(a) and 89.9% with high levels in the study had the same levels of the molecule when they were retested.
However, the study did find that almost half of the people with borderline Lp(a) — a range of 30 to 50 mg/dL — changed their category (normal, borderline, or high) after retesting, and a quarter of them had a change greater than 10 mg/dL. Women, patients who had ASCVD, those with LDL cholesterol (LDL-C) levels of ≥ 100 mg/dL, or those on statin therapy had higher odds of a change in Lp(a) of > 10 mg/dL.
'These findings highlight that patients with borderline Lp(a) levels may require more than one Lp(a) measurement for a comprehensive ASCVD risk assessment,' the authors of the study wrote.
Also adding a dimension to the understanding of Lp(a) is a large database analysis in the UK that has linked high Lp(a) to peripheral artery disease and carotid artery stenosis, among other extracoronary ASCVDs. Patients in the study — which used > 70 mg/dL (or 150 nmol/L) as a threshold for predicting ASCVD complications — with peripheral artery disease and elevated Lp(a) were at 57% greater risk for having a major adverse limb event than patients with normal concentrations of the molecule. Those with carotid stenosis and high Lp(a) had a 40% greater risk for stroke than patients with normal levels.
According to the researchers, lowering Lp(a) concentrations by 35 mg/dL (75 nmol/L) would reduce the risk for incident peripheral artery disease by 18% and for incident carotid stenosis by 17%. 'Participants with established extracoronary atherosclerotic vascular disease and elevated Lp(a) concentrations are at high risk for progression to major atherosclerotic complications,' they reported.
Again, however, how to reduce Lp(a) is unclear.
Consistent intake of niacin is one strategy for reducing Lp(a), the UK researchers stated, but only 77 (0.02%) of the 460,544 participants in the analysis were taking the nutrient.
Niacin has had its own star-crossed history as a risk-reduction strategy in ASCVD. Both the 2011 AIM-HIGH trial and the 2014 HPS2-THRIVE study found that people who took niacin supplements did not reduce their risk for ASCVD, although participants in AIM-HIGH on niacin had a 25% reduction in Lp(a) levels. These studies moved the consensus away from niacin therapy.
Another recent revelation about Lp(a) is its apparent independence from LDL-C. Lowering LDL-C with statins does not affect cardiac risks associated with elevated Lp(a), said Sotirios Tsimikas, MD, who was the corresponding author for a 2024 meta-analysis on the question.
Sotirios Tsimikas, MD
'Lp(a) is an independent risk factor at all levels of achieved LDL when you treat somebody with an LDL-lowering agent,' said Tsimikas, a cardiologist at the Sulpizio Cardiovascular Center and director of vascular medicine at the University of California San Diego (UCSD) Health. 'The implication is you have to treat it as your own independent risk factor and not assume that when you treat the LDL-C, even at very low levels, that you reduce Lp(a)-mediated risk.'
In a study, patients with Lp(a) > 50 mg/dL but in the lowest quartile of LDL-C after treatment — in the 3.1-77 mg/dL range — had a 38% greater ASCVD risk than those with Lp(a) levels below the 50 mg/dL threshold. Tsimikas said this study built on research his group published in 2018. 'What this paper showed with more granularity was that the LDL level that was achieved in the statin trials did not reduce the Lp(a) risk,' he said.
The State of Clinical Trials
Block and his group have reported on clinical trials of six investigative therapies targeting Lp(a). Three subcutaneous therapies are in phase 3 trials: Pelacarsen, an antisense oligonucleotide that has demonstrated an 80% reduction in Lp(a); and two small interfering RNAs (siRNAs), olpasiran and lepodisiran, both of which have demonstrated up to a 98% reduction in Lp(a).
Likewise, three agents are in phase 2 trials: Zeriasiran, a subcutaneous siRNA agent that has shown up to a 98% reduction in Lp(a); and two oral agents, muvalaplin, an Lp(a) inhibitor that has demonstrated up to an 85% reduction in levels of the molecule, and obicetrapib, a cholesterol ester transport protein inhibitor that has shown up to a 57% reduction in the substance and is used in conjunction with evolocumab.
Deeper in the pipeline is at least one potential one-time gene therapy, CTX320, which is in preclinical stages.
The pelacarsen trial is scheduled for completion early next year. The olpasiran trial is scheduled for completion at the end of 2026. 'We're right on the cusp of knowing if we lower Lp(a), do we get a benefit that's clinically meaningful?' Tsimikas said.
Modify What You Can — Wait for the Calvary
Despite the lack of commercially available therapies, providers can employ several interventions to manage ASCVD risks in patients with elevated levels of Lp(a).
'The theme here is to modify what you can modify until we have more directed therapy with good clinical trial outcomes,' Shah said. 'Drop LDL as low as you can. Consider starting aspirin therapy, especially if patients have multiple risk factors — and absolutely they should be on aspirin therapy if they've had a prior cardiovascular event. Then I look to modify other things. Are they hypertensive? Can I get them better? Are they obese? Can I reduce their weight? Do they have diabetes? What can we do to control this more?' First-degree relatives of people with high Lp(a) levels should get their Lp(a) levels tested, he added.
Motivated patients could be encouraged to enroll in a clinical trial. 'As more people understand that there are changes you can make today, they may be more likely to test for Lp(a),' Shah said.
Until clinical trial results are reported, clinicians are in a 'gray zone,' Tsimikas said.
To get through that 'gray zone,' more education of providers and patients is needed, healthcare systems need to support more widespread Lp(a) testing, and insurance companies need to cover testing, he said.
'What I'm seeing is that a lot of physicians have become aware of Lp(a), and I'm seeing a lot of testing that normally I wouldn't,' Tsimikas said. 'I think the tide is already turning on this.'
Block has no relevant relationships to disclose. Paruchuri reported having financial relationships with Allelica, Amgen, Apple, AstraZeneca, Boston Scientific, Genentech/Roche, Ionis, Novartis, and NewAmsterdam Pharma. Shah reported having received research grants from Amgen and Janssen and is a consultant/advisor for Esperion, Amgen, and Novartis.
Tsimikas is a co-inventor and receives royalties from patents owned by UCSD. He is also a cofounder and holds equity in Oxitope and Kleanthi Diagnostics and has a dual appointment at UCSD and Ionis Pharmaceuticals.