Lack of Lp(a) screening a ‘missed opportunity’; promising therapies on the horizon
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Key takeaways:
- Lp(a) screening should be done once for all adults and high-risk children.
- Lp(a) level can help guide CVD risk assessment and management strategies.
- Multiple Lp(a)-lowering therapies expected soon.
Improved screening for elevated lipoprotein(a) levels among all adults may improve CVD risk assessment and outcomes, especially with multiple Lp(a)-lowering therapies currently in the research pipeline, a speaker reported.
At the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease, Nathan D. Wong, PhD, MPH, professor of medicine, epidemiology and biostatistics and population health and disease prevention and director of the UCI Heart Disease Prevention Program at the University of California, Irvine, discussed Lp(a) and its role in CV risk; who should receive testing for Lp(a); and the current and emerging therapies for treatment.
CV risk associated with Lp(a)
“There are some large genetic studies, such as this CARDIoGRAMplusC4D CAD consortium that suggest that [Lp(a)] may be the most or at least one of the most important genetic determinants of coronary disease,” Wong said during the presentation. “There are also recently published data from the UK Biobank involving a Mendelian randomization study that shows, on a per particle basis, that [Lp(a)] may be sixfold more atherogenic than LDL cholesterol. We know from a wealth of epidemiologic, genome-wide association and Mendelian randomization studies that higher levels are associated with a wide range of cardiovascular conditions.”
Adverse outcomes associated with elevated Lp(a) include MI, aortic valve stenosis, ischemic stroke, atrial fibrillation, peripheral artery disease, CV mortality and all-cause mortality, according to the presentation.
“People with the highest levels were at a two- to threefold increased risk for peripheral arterial disease, abdominal aortic aneurysm as well as major adverse limb events,” Wong said. “In our paper earlier this year, published in Journal of the American College of Cardiology, we pooled five major U.S. cohort studies comprising over 27,000 individuals as one of the longest follow-ups — 21 years. We showed overall that comparing people above the 90th percentile, average about 53 mg/dL, vs. below the 50th percentile, there was about a 46% higher risk. These risks were higher for myocardial infarction and revascularization.
“Interestingly, we found that in people with preexisting diabetes, Lp(a) was associated with perhaps ... about a 92% increased risk compared to a 41% increased risk in people without diabetes.”
Importance of Lp(a) screening for risk assessment
Wong stated that adding Lp(a) to CVD risk assessment may enable reclassification of people to either lower- or higher-risk groups and may improve classification accuracy. Citing a study published in JACC, Wong stated that adding Lp(a) to CVD risk assessment subsequently led to approximately 40% of patients being reclassified, and consequently dyslipidemia management guidelines were updated to recommend Lp(a) testing, especially for those at intermediate CV risk.
“Very few, many times less than 1%, of a given patient population has been tested [for Lp(a)],” Wong said. “Various guidelines around the world have recommended certain groups that should be tested. They are pretty much completely aligned [on testing] in those with personal or family history of premature atherosclerotic CVD. There’s some variation in whether people with moderate or high ASCVD risk or refractory LDL elevations. Recently the U.S. National Lipid Association (NLA) updated its recommendations that are now aligned with Europe and Canada that recommend screening at least once in a lifetime.”
In 2024, the NLA issued a focused update to its 2019 scientific statement in the Journal of Clinical Lipidology, which now emphasizes taking an Lp(a) measurement at least once in a lifetime for all adults and selected children determined to be high risk with:
- clinically suspected or genetically confirmed familial hypercholesterolemia;
- first-degree relatives with a history of premature ASCVD;
- ischemic stroke of unknown cause; or
- first-degree relatives with elevated Lp(a).
In the document, high-risk Lp(a) was defined as 50 mg/dL or more or 125 nmol/L, and low-risk Lp(a) was defined as less than 30 mg/dL or less than 75 nmol/L.
“If you see a high-risk level ... you can consider more intensive overall risk assessment to reduce the patient’s overall risk,” Wong said. “Cascade screening of family members, lifestyle modifications and certainly therapies that we can use to reduce risk.”
Available Lp(a) therapeutics
Currently, the only FDA-approved therapy for targeting Lp(a) is apheresis, and is approved for use in patients with FH and ASCVD with Lp(a) of 60 mg/dL or more and LDL of 100 mg/dL or more on maximally tolerated lipid-lowering therapy, according to the presentation.
A single 3- to 4-hour Lp(a) apheresis treatment is associated with an approximately 50% to 85% reduction in Lp(a) and oxidized phospholipids; however, there are not many centers that do apheresis, and the procedure is labor-intensive, Wong said.
Among patients with elevated Lp(a), observational analyses of large studies such as MESA in the Journal of the American Heart Association, FOURIER in Circulation and ODYSSEY OUTCOMES in JACC, showed significant reductions in CHD risk with aspirin use (HR = 0.54; 95% CI, 0.32-0.94), as well as with use of the PCSK9 inhibitors evolocumab (Repatha, Amgen; Lp(a) reduction of 27%; ASCVD treatment effect greater in patients above the median Lp(a) vs. below it) and alirocumab (Praluent, Sanofi/Regeneron; 25% of ASCVD risk reduction attributed to Lp(a) reduction in patients in the highest quartile of Lp[a]), Wong said.
“In terms of RNA-targeted therapies, we have the antisense nucleotides and the small interfering RNA therapies, both of which prevent the production of [apolipoprotein A] and therefore Lp(a),” Wong said. “Pelacarsen (Novartis/Ionis) is the furthest along of these, showing an 80% reduction in Lp(a) on average from monthly administration. We’re anxiously awaiting the results of the HORIZON outcomes trial [of Pelacarsen] due to read out next year. It’s probably going to be one of the most important clinical trials of the whole decade that is going to set the mood for the other therapies to follow.”
Other Lp(a)-lowering therapies in the pipeline include olpasiran (Amgen), which was associated with sustained reductions in Lp(a) concentrations among patients with ASCVD in the phase 2 OCEAN(a)-DOSE study; zerlasiran (Silence Therapeutics), a novel injectable small interfering RNA molecule that lowered Lp(a) by more than 80% compared with placebo at 36 weeks, according to data from the ALPACAR trial; and oral muvalaplin (Eli Lilly), which reduced Lp(a) up to 85.8% over 12 weeks compared with placebo, according to data from the KRAKEN trial.
“The failure to screen and identify those with Lp(a)-associated risks represents a missed opportunity to address this risk not only with our existing repertoire of treatments, but hopefully in the future with promising therapies in development targeting Lp(a),” Wong said during the presentation.
References:
- Bhatia HS, et al. J Am Heart Assoc. 2024;doi:10.1161/JAHA.123.033562.
- Bittner VA, et al. J Am Coll Cardiol. 2020;doi:10.1016/j.jacc.2019.10.057.
- Koschinsky ML, et al. J Clin Lipidol. 2024;doi:10.1016/j.jacl.2024.03.001.
- O’Donoghue ML, et al. Circulation. 2018;doi:10.1161/CIRCULATIONAHA.118.037184.
- Willeit P, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.03.061.
- Wong ND, et al. J Am Coll Cardiol. 2024;doi:10.1016/j.jacc.2024.02.031.
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