Speaker: ‘De-risk’ patients with high Lp(a) to prevent atherosclerotic events
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Key takeaways:
- Although Lp(a)-lowering therapies are not yet available, measurement may still benefit patients.
- Identifying those with high Lp(a) could provide targets for improved risk factor control.
PHILADELPHIA — Despite there being few options to directly lower lipoprotein(a) as of yet, measurement is none the less important to identify those who would benefit from improved risk factor control, a speaker reported.
At the Heart in Diabetes CME Conference, Kausik K. Ray, FMedSci, president of the European Atherosclerosis Society (EAS), director of the Imperial Centre for Cardiovascular Disease Prevention and the Imperial Clinical Trials Unit and head of ICTU-Global at Imperial College London, discussed the significance of a single lifetime measurement of Lp(a), the benefit of risk factor control, and the current status of Lp(a)-lowering therapies in development.
‘De-risk as much as possible’
“Even though you might not be able to do anything about [Lp(a)] ... you try to de-risk as much as possible. This is what we basically now recommend,” Ray said during a presentation. “It should be measured at least once in your lifetime, because the levels are relatively constant. You might want to think about screening early if you’ve got a family history of premature atherosclerotic cardiovascular disease or the person themselves has a premature cardiovascular event and in family members where Lp(a) levels are high, you’ve probably got a high chance of picking up other individuals in the family early through family cascade testing.”
Ray said Lp(a) is one important facet of determining ASCVD risk, but traditional risk factors such as age, sex, BP, smoking, diabetes, BMI and family history have a significant modifying effect. Citing an EAS consensus statement published in the European Heart Journal in 2022, he showed how, alongside traditional risk factors, untreated elevated Lp(a) can increase lifetime ASCVD risk up to more than 43-fold in those with high baseline risk.
The EAS document provides a risk calculator based on both traditional risk factors and untreated Lp(a) levels at baseline, demonstrating a gradient of risk as both untreated risk factors and untreated Lp(a) level rise.
“What our EAS consensus statement produced was essentially a set of tables and a calculator which essentially gave you this information,” Ray said. “But in this middle or ‘gray zone,’ it might actually help you identify people that you want to do a little bit more with.”
LDL lowering to ‘offset’ Lp(a)
One risk factor featured in Ray’s presentation is the benefit of LDL lowering in the setting of high Lp(a) and the importance of timely initiation of LDL-lowering therapies.
“The amount of LDL lowering you need to achieve to offset Lp(a) levels depends upon both the level and how late you start,” he said. “If you start very late and you’re trying to offset a very high number, you’re going to need more LDL lowering. If in the same individual you start earlier, you’re going to need less. And if you have less Lp(a) to offset, the amount of lowering you need in LDL cholesterol is also less.”
Previously, the only therapy that existed to lower Lp(a) was lipoprotein apheresis, cited in a 2016 study in Arteriosclerosis, Thrombosis and Vascular Biology, in which patients assigned to apheresis experienced an annual average of 0.41 fewer major adverse CV events over 5 years compared with the 2 years before apheresis (P < .0001).
Today, however, “We have monoclonal antibodies and we have inclisiran (Leqvio, Novartis),” to lower Lp(a), Ray said. “Inclisiran is still undergoing outcome trials.”
The presentation also referenced the ODYSSEY Outcomes trial of alirocumab (Praluent, Sanofi/Regeneron), a PCSK9 inhibitor, for LDL lowering compared with placebo for patients with ACS already on statin therapy.
As Healio previously reported, LDL lowering with alirocumab reduced risk for MACE, defined as CHD death, nonfatal MI, ischemic stroke or unstable angina requiring hospitalization, and all-cause mortality in this patient population.
In a post hoc analysis of ODYSSEY Outcomes published in the European Heart Journal, researchers reported that baseline Lp(a) level was prognostic of total CV events, and lowering Lp(a) with alirocumab was independently associated with improved outcomes after ACS.
Moreover, patients with higher baseline Lp(a) level experienced markedly greater risk reduction with alirocumab compared with those with lower baseline Lp(a), according to the study.
“Because these therapies increase LDL receptor expression, when you drive down LDL to really low levels, there might be less competition with the LDL receptor. So you might clear some of the Lp(a),” Ray said. “But what we really need are treatments that will stop the production of Lp(a).”
Such therapies to target Lp(a) production currently in development include:
pelacarsen (Novartis/Ionis), an antisense oligonucleotide therapy with phase 3 results expected in 2025;
olpasiran (Amgen), a small-interfering RNA therapy that entered phase 3 study in 2023; and
SLN360 (Silence Therapeutics), another small-interfering RNA therapy currently in phase 2 study.
“Lp(a) is likely to be a causal risk factor,” Ray said. “Measuring it helps you because you might want to do something now, like control traditional risk factors, but you are also identifying people that may well benefit. There is some data that low levels might associate with a small excess risk of diabetes. We don’t know if that’s just chance or real, but the larger trials will perhaps look at that in more detail.”
References:
- Kronenberg F, et al. Eur Heart J. 2022;doi:10.1093/eurheartj/ehac361.
- Roeseler E, et al. Arterioscler Thromb Vasc Biol. 2016;doi:10.1161/ATVBAHA.116.307983.
- Szarek M, et al. Eur Heart J. 2020;doi:10.1093/eurheartj/ehaa649.
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Ray KK. Session 3: Dyslipidemia today and tomorrow. Presented at: Heart in Diabetes CME Conference; June 7-9, 2024; Philadelphia.
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