Reducing inflammation and reducing lipoprotein(a) levels (Lp(a)) have been identified as ways to reduce the risk of developing heart disease.
However, two large clinical trials have shown that these new drugs, while targeting a specific pathway, have failed to reduce the risk of major cardiovascular events.
Due to the results seen with Pelacarsen (Novartis and Ionis) and Ziltivekimab (Novo Nordisk), there has been some debate in the cardiology community about whether reducing a biomarker will help prevent heart attacks and strokes.
This drug was designed to reduce Lp(a) levels. This is a type of cholesterol mostly determined by genetics. It is estimated that 1 in 5 people worldwide have increased levels.
Increased levels increase the risk of heart attacks, stroke, and other cardiovascular problems. There are not many widely approved treatment options to specifically reduce Lp(a) levels.
A phase 3 trial (Lp(a)HORIZON) was carried out to determine if Pelacarsen would be beneficial for cardiovascular conditions. Over 8,300 patients with high Lp(a) levels and established cardiovascular disease were enrolled who had high Lp(a) and established cardiovascular disease from 42 different countries.
Although it successfully reduced Lp(a), by around 78%, it failed to reduce cardiac events.
12.3% of patients experienced the primary outcome after a median follow-up time of 4.7 years, compared to 12.1% of patients on placebo. This was not statistically significant.
It was a difficult result, as researchers were expecting to see a meaningful change due to Lp(a) being reduced.
However, it does not prove Lp(a) is not important, just that, in this group of patients, reducing Lp(a) did not reduce major cardiovascular events.
The second setback was with the ZEUS trial. It investigated a novel drug called Ziltivekimab that targeted the Interleukin-6 (IL-6) protein.
Chronic inflammation is becoming a recognised cause of cardiovascular disease. IL-6 is involved in this has therefore become an area of interest.
6,376 patients with atherosclerotic cardiovascular disease, chronic kidney disease and high inflammation. The aim was to determine if blocking IL-6 would reduce the risk of heart attacks, strokes and cardiovascular death.
The drug was successful at reducing inflammation markers. These included high-sensitivity C reactive protein (hs-CRP) and free IL-6. These were significantly lowered, however, the results were neutral.
17.6% of patients taking Ziltivekimab experienced the primary cardiovascular outcome after a median follow-up of 33 months, compared to 17.7% of those on placebo. This was not statistically significant.
Despite the inflammation markers being reduced, patients did not experience less major cardiovascular events.
There is no clear answer to why these trials failed. However, results make researchers reconsider the association between biomarkers and disease.
Maybe the patients were not treated early enough. Both groups of patients had significant cardiovascular disease, so it may have been difficult to reverse the damage to the vascular system, and other processes, by just targeting one pathway.
This is one possible explanation, rather than an established reason for the trial outcomes. The American Heart Association noted that ZEUS participants had exceptionally high cardiovascular risk and advanced disease, which may have limited the potential benefit of targeting inflammation at this stage. Researchers have also highlighted the need to investigate whether targeting inflammatory pathways earlier could produce different results.
Many patients also had established treatments for cardiovascular disease. They may have already been taking medication to lower their cholesterol, so it may have been difficult to show much benefit from the new drug.
These are just theories, but they show how complex cardiovascular disease can be. Just because a biomarker shows strong association with the disease does not mean it is the best thing to target.
Despite being disappointing, this does not mean we should stop researching in this area.
Other companies are researching drugs to lower Lp(a) including Amgen and Eli Lilly. Their experimental drugs use a technology called small interfering RNA (siRNA), which works by switching off the instructions that tell the liver to produce Lp(a). This helps reduce the amount of Lp(a) released into the bloodstream. Amgen's olpasiran is being studied in the phase 3 OCEAN(a)-Outcomes trial, while Eli Lilly's lepodisiran is being evaluated in the phase 3 ACCLAIM-Lp(a) trial. Both trials aim to determine whether lowering Lp(a) levels can also reduce the risk of heart attacks, strokes and other major cardiovascular events
The results from ZEUS may make researchers think about which patients would benefit most from targeting inflammation, when treatment should begin, and whether targeting IL-6 enough.
Both of these trials remind us that some drugs can show amazing results in the lab but do not improve patient outcomes.
References:
1. Cho, Leslie, Stephen J. Nicholls, Seth Frndak, et al. “Pelacarsen and Cardiovascular Outcomes in Patients with High Lipoprotein(a).” The New England Journal of Medicine, November 7, 2026. https://doi.org/10.1056/NEJMoa2610159.
2. Ridker, Paul M., A. Michael Lincoff, Nikolaus Marx, et al. “Interleukin-6 Inhibition with Ziltivekimab for Atherosclerotic Disease.” The New England Journal of Medicine, November 7, 2026. https://doi.org/10.1056/NEJMoa2612126.
3. American Heart Association. “Lp(a)HORIZON Trial: Lp(a) Fell by 78%, but Cardiovascular Outcomes Unexpectedly Neutral.” November 7, 2026. https://newsroom.heart.org/news/lp-a-horizon-trial-lp-a-fell-by-78-but-cardiovascular-outcomes-unexpectedly-neutral.
4. Novartis. “Novartis Announces Lp(a)HORIZON Phase III Topline Results for Pelacarsen in Patients with Elevated Lp(a) and Established Cardiovascular Disease (CVD).” September 4, 2026. https://www.novartis.com/news/media-releases/novartis-announces-lpahorizon-phase-iii-topline-results-pelacarsen-patients-elevated-lpa-and-established-cardiovascular-disease-cvd.
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