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A Drug Cut Lp(a) by 80 Percent Without Reducing Cardiovascular Events

Writer: Joyce Knieff, ND, LAc
Joyce Knieff, ND, LAc
Oct 12
6 min read

If you have ever had a cardiology appointment where someone mentioned lipoprotein(a), you were probably told two things. The first is that it is inherited, it does not respond much to diet or exercise, and there is no approved treatment that targets it. The second is that a treatment was coming. For several years, that second part has been true, and the drug furthest along was pelacarsen.


A white bowl of sliced strawberries and blueberries
Photo: Adél Grőber / Unsplash

In early September, its sponsor announced that the Phase 3 outcomes trial did not meet its primary endpoint, which is the main outcome a trial is designed to measure [1].


What the researchers found


The trial, called Lp(a)HORIZON, enrolled people with elevated lipoprotein(a) and established cardiovascular disease [1]. Its primary endpoint was a combination of cardiovascular death, non-fatal heart attack, non-fatal stroke, and urgent coronary revascularization requiring hospitalization, measured against placebo. Revascularization is a procedure, such as a stent or bypass surgery, that restores blood flow to the heart. That endpoint was not met.


There are two cautions about this result. The announcement was a topline result, meaning the headline finding released before the full data, so the full dataset, the subgroup analyses, and the peer-reviewed publication are all still to come, and the details often change how a result should be interpreted. The second caution is that "did not meet the primary endpoint" is not the same as "the drug does nothing." Pelacarsen reliably lowers lipoprotein(a). In a separate Phase 3 trial published earlier this year in 51 German patients who were dependent on lipoprotein apheresis, a blood-filtering procedure performed weekly, pelacarsen reduced Lp(a) by 72 percent against placebo at one year and largely removed the need for the procedure [2]. The molecule does what it was designed to do. What has not been demonstrated is that doing it prevents heart attacks.


Why lowering Lp(a) may not be enough


Lipoprotein(a) is an LDL-like particle with an extra protein attached, and its level is set mostly by the genes you were born with [3]. Roughly one in five people worldwide carries a level high enough to be considered elevated [4]. Unlike LDL cholesterol, it stays fairly stable across your life and barely changes with diet, exercise, or statins [3]. The association with heart attack, stroke, and calcific aortic valve disease (calcium buildup that stiffens the heart's aortic valve) is consistent across observational and genetic studies, which is why lowering it seemed like such a promising idea.


There is a specific reason this result was foreseeable, and it has been discussed in the literature for a while. Genetic and modeling work suggests the absolute drop needed for a meaningful reduction in events is on the order of 50 mg/dL [5]. A percentage looks impressive in a press release, and an 80 percent reduction only produces a drop of 50 mg/dL or more if you started high enough. In a trial population with moderately elevated levels, a large percentage change can still be a small absolute change.


This has happened in cardiology before. Extended-release niacin lowers Lp(a) by about 23 percent, pooled across 14 randomized placebo-controlled trials with more than 9,000 participants [6]. Then HPS2-THRIVE randomized 25,673 adults with vascular disease to extended-release niacin with laropiprant or placebo on top of statin therapy [7]. Over a median of 3.9 years, major vascular events occurred in 13.2 percent of the niacin group and 13.7 percent of the placebo group, a difference that was not statistically significant. Serious adverse events, including problems with diabetes control, infection, and bleeding, were more common in the treatment group. Changing a number on a lab report and changing what happens to a person are two separate claims, and the second one requires its own trial.


When one risk factor can't be changed


The obvious naturopathic response would be to say that this is what happens when medicine focuses on a single molecule, and that lifestyle is the answer instead. That would not be accurate. Lipoprotein(a) is one of the few cardiovascular risk factors that does not respond much to the things I can help someone change [3].


What the result actually supports is something I find myself saying constantly in practice. When one risk factor is fixed, the whole picture is what you work with. Someone with a high Lp(a) still has an LDL number, a blood pressure, a fasting insulin, a sleep pattern, an activity level, and an inflammatory load, and every one of those is modifiable. A person carrying an inherited risk they cannot change has more reason to address the ones they can, not less. That is how I approach these cases: the unchangeable number makes everything else more important to manage, rather than making the rest pointless.


The other thing this reinforces is a habit of skepticism about surrogate markers generally. A surrogate marker is a lab number used as a stand-in for an outcome like a heart attack. In my field, plenty is sold on the strength of a biomarker that changed. The question to keep asking is whether anyone has shown that changing it changes how people actually do.


Where an inherited number leaves the rest of your risk


  1. Find out whether you have ever been tested. A standard lipid panel does not include lipoprotein(a); it has to be ordered separately. Because the level is genetically determined and stable, once in a lifetime is generally enough for most people [3].

  2. If it is elevated, redirect the effort. Ask your provider how aggressively your LDL, blood pressure, and blood sugar should be managed given that number, since those targets sometimes shift when Lp(a) is high.

  3. Be cautious with supplements advertised for Lp(a). Niacin lowers it by roughly 23 percent [6] and L-carnitine added to a statin lowered it by about 19 percent in a 12-week randomized trial [8]. Nobody has demonstrated for either one that the reduction prevents cardiovascular events, and the large niacin outcomes trial found harms [7].

  4. Tell your family. Because it is inherited, an elevated result in you is a reason for first-degree relatives to ask about testing.

  5. Do not let a normal result end the conversation. Lp(a) is one contributor among many, and a normal Lp(a) is no evidence about the rest of your cardiovascular risk.


The trials of the other agents in this class are still running [4,5]. This one result does not settle whether lowering lipoprotein(a) helps. Whether it helps was an open question, which is exactly why the trial was run.


References


Primary research located and verified via PubMed.


  1. Napitupulu J. "Pelacarsen Fails to Meet Primary Endpoint in Phase 3 Lp(a) Trial." The Clinical Trial Vanguard, September 5, 2026. https://www.clinicaltrialvanguard.com/news/pelacarsen-fails-to-meet-primary-endpoint-in-phase-3-lpa-trial/ (digest source article; sponsor topline announcement, not a peer-reviewed publication)

  2. Parhofer KG, Julius U, Herzog AL, et al. Pelacarsen and lipoprotein(a) apheresis in secondary prevention: the Lp(a)FRONTIERS APHERESIS trial. Eur Heart J. 2026;47(25):3284-3294. PMID 41721795. https://doi.org/10.1093/eurheartj/ehag073 (Novartis-sponsored; several authors are Novartis employees, disclosed in the paper)

  3. Duarte Lau F, Giugliano RP. Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review. JAMA Cardiol. 2022;7(7):760-769. PMID 35583875. https://doi.org/10.1001/jamacardio.2022.0987

  4. Miramontes González JP. Lipoprotein(a): Cardiovascular Risk and Emerging Targeted Therapies. Am J Cardiovasc Drugs. 2026 (published online August 31, 2026). PMID 42675370. https://doi.org/10.1007/s40256-026-00825-5

  5. Alhomoud IS. Emerging therapies targeting lipoprotein(a): the next frontier in cardiovascular risk reduction. Front Med (Lausanne). 2025;12:1727918. PMID 41488100. https://doi.org/10.3389/fmed.2025.1727918

  6. Sahebkar A, Reiner Ž, Simental-Mendía LE, Ferretti G, Cicero AFG. Effect of extended-release niacin on plasma lipoprotein(a) levels: A systematic review and meta-analysis of randomized placebo-controlled trials. Metabolism. 2016;65(11):1664-1678. PMID 27733255. https://doi.org/10.1016/j.metabol.2016.08.007 (held in the Yggdrasil Abstract Library)

  7. HPS2-THRIVE Collaborative Group; Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203-212. PMID 25014686. https://doi.org/10.1056/NEJMoa1300955

  8. Florentin M, Elisaf MS, Rizos CV, et al. L-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study. Lipids. 2017;52(1):1-9. PMID 27914033. https://doi.org/10.1007/s11745-016-4216-z (held in the Yggdrasil Abstract Library)


A note before you go


This article is educational and is not medical advice. Nothing here is a recommendation to start, stop, or change any medication or supplement, and a trial result reported in the news is not a reason to alter a cardiovascular plan that someone built with you. If lipoprotein(a) is part of your history, or you are wondering whether it should be tested, that belongs in a conversation with the provider who knows your numbers and your family history. Please bring the whole picture to them rather than this one number.



If this resonates with what you're experiencing and you'd like to explore a naturopathic approach, book a consultation with our clinic.




 
 
 

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