Experimental Heart Disease Drugs Fail Despite Hitting Their Targets: What the Novartis and Novo Nordisk Trials Reveal

Published November 7, 2026 · Medical news analysis

Two experimental heart disease drugs reached their biological targets this year, and neither one prevented heart attacks or strokes. At the American Heart Association’s Scientific Sessions 2026 in Chicago, researchers presented full results from Novartis’s pelacarsen and Novo Nordisk’s ziltivekimab. Both were published the same day in the New England Journal of Medicine. Pelacarsen lowered lipoprotein(a) by about 78%. Ziltivekimab sharply reduced markers of inflammation. Yet in large Phase 3 trials, patients on either drug had about as many serious cardiovascular events as patients on placebo.

The results are a reminder that improving a number on a blood test isn’t the same as protecting the heart. They also raise hard questions for two of the most closely watched areas of cardiovascular disease research.

What Happened in the Novartis Pelacarsen Trial

Pelacarsen is an antisense oligonucleotide, a type of drug that blocks the liver from making a key building block of lipoprotein(a). It was tested in Lp(a)HORIZON, one of the largest Lp(a) clinical trials ever run.

The trial at a glance

• Participants: 8,323 adults with established cardiovascular disease, at 797 sites in 42 countries. Most had already had a heart attack. (American Heart Association)
• Entry requirement: Lp(a) of at least 70 mg/dL. The median at enrollment was 109 mg/dL.
• Treatment: Pelacarsen 80 mg or placebo, given as a monthly injection under the skin, on top of standard care. About three-quarters of participants were on high-intensity statins.
• Primary goal: fewer cardiovascular deaths, nonfatal heart attacks, nonfatal strokes and urgent procedures to reopen the heart’s arteries (known as revascularizations).

The key numbers

Pelacarsen cut Lp(a) by roughly 78% at one year. However, major cardiovascular events occurred in 12.3% of patients on pelacarsen and 12.1% on placebo over a median of 4.7 years, a hazard ratio of 1.02. That is a statistical tie, according to the results reported at AHA 2026. The outcome was the same in patients with the highest Lp(a) levels (90 mg/dL or more) and across the other endpoints analyzed.

On safety, serious adverse events were slightly less common with pelacarsen. Flu-like symptoms, injection-site reactions and allergic reactions were more frequent, including 19 cases of anaphylaxis versus none on placebo. About 21% of pelacarsen patients stopped treatment because of side effects, compared with more than 7% on placebo.

Steven Nissen, MD, of Cleveland Clinic, the trial’s senior author, said plainly that the drug didn’t work, and that there was no hint of benefit even in subgroups. Novartis has since ended other pelacarsen studies, citing the HORIZON outcome in trial registry updates.

Lipoprotein(a) and Heart Disease: Why the Target Mattered

Lipoprotein(a), usually written Lp(a), is a cholesterol-carrying particle similar to LDL (“bad”) cholesterol. It has an extra protein, apolipoprotein(a), attached. Your Lp(a) level is set mostly by your genes and stays fairly stable throughout life. Diet and exercise barely change it, and statins don’t lower it.

Roughly 1 in 5 people have elevated Lp(a). Large genetic and population studies have linked high levels to heart attacks, strokes and narrowing of the aortic valve. Researchers think Lp(a) may contribute to plaque buildup, inflammation and blood clotting. That strong genetic evidence is why many cardiologists expected that lowering Lp(a) would prevent heart attacks. It’s also why HORIZON’s result surprised the field.

The Novo Nordisk Heart Disease Drug: Ziltivekimab and the ZEUS Trial

Ziltivekimab is a monoclonal antibody that blocks interleukin-6 (IL-6), a signaling protein that drives inflammation. Inflammation inside artery walls is thought to help plaques grow and rupture, which can trigger heart attacks and strokes. A widely used blood marker of this inflammation is high-sensitivity C-reactive protein (hsCRP).

The trial at a glance

• Participants: 6,376 adults with atherosclerotic cardiovascular disease, significant chronic kidney disease and an hsCRP of at least 2 mg/L, at 757 sites in 38 countries. (American Heart Association)
• Treatment: Ziltivekimab 15 mg or placebo, given as a monthly injection, for a median of about 2.4 years.
• Primary goal: fewer heart attacks, strokes and cardiovascular deaths.

The key numbers

Ziltivekimab lowered hsCRP by 64% and IL-6 by 76%. But the primary endpoint occurred in 561 people on the drug and 565 on placebo, with a hazard ratio of 0.99. Deaths from any cause didn’t differ between the groups. Serious infections were somewhat more common with the drug (20% versus 18%), a known risk of blocking IL-6. Novo Nordisk first announced the miss in July. STAT later reported that the company stopped two other ziltivekimab trials, HERMES and ATHENA, after a monitoring committee judged that they were unlikely to succeed.

Why Did Two Promising Experimental Cardiovascular Treatments Fail?

Both trials ran into the same basic problem. A drug can change a biomarker without changing what actually happens to patients. Researchers have offered several possible explanations. They are hypotheses, not proven conclusions.

Possible explanations for pelacarsen

• The reduction may not have been big enough in absolute terms. Genetic analyses published before the trial suggested that a very large absolute drop in Lp(a) might be needed to produce a measurable benefit. Some patients may not have reached that threshold even with a 78% cut.
• Other risks were already well controlled. Most participants were already on intensive cholesterol and blood pressure treatment, which may have left less room to show added benefit.
• Who was enrolled. The AHA noted that 78% of participants identified as white and fewer than 4% were of African ancestry, a group with about twice the average Lp(a) levels. The trial also ran during the COVID-19 pandemic, which may have affected event counts in ways that can’t be measured.
• Drug-specific factors. Some cardiologists, including HORIZON’s Canadian lead investigator, George Thanassoulis, MD, of McGill University, told Medscape that features of this particular drug or trial may be to blame, rather than the Lp(a) theory itself.

Possible explanations for ziltivekimab

• “Too little, too late.” Paul Ridker, MD, of Mass General Brigham, the trial’s lead author, suggested that participants with advanced kidney and heart disease may have been too sick to benefit. More than 6% died during the trial, about double the rate in comparable studies of people without severe kidney disease.
• The wrong point in the pathway. Earlier trials of drugs acting at other points in the same inflammation cascade did show benefit. Those include the CANTOS trial of canakinumab, an IL-1β blocker, and studies of low-dose colchicine. Researchers are now looking at targets further “upstream,” such as the NLRP3 inflammasome.
• The marker isn’t the cause. In ZEUS, people with higher baseline hsCRP or IL-6 still had more events, so inflammation remained a strong predictor of risk. Lowering those markers with this drug simply didn’t change outcomes.

What Experts Say About the Lp(a) Hypothesis

Nissen cautioned that the HORIZON results don’t mean Lp(a) is irrelevant. He said testing Lp(a) remains worthwhile, because high levels usually cause no symptoms. He also said patients enrolled in other Lp(a) trials shouldn’t drop out. Ridker likewise said inflammation remains an important target, and he urged doctors to keep measuring it.

Other observers have been more skeptical. Some analysts and researchers say HORIZON raises a real question: is Lp(a) a cause of heart disease that drugs can fix, or mainly a marker of risk? Questions like that are usually settled by more than one trial.

What This Means for Patients and Healthcare Professionals

• No approved Lp(a)-lowering drug exists yet, and pelacarsen now appears unlikely to reach the market.
• Elevated Lp(a) is still a recognized risk-enhancing factor in major guidelines. Knowing your level can help you and your doctor decide how aggressively to manage risks you can change, such as LDL cholesterol, blood pressure, blood sugar and smoking.
• Proven heart attack prevention hasn’t changed. That includes statins and other LDL-lowering drugs when appropriate, blood pressure control, diabetes management, not smoking, and regular physical activity such as walking.
• Patients in ongoing trials should talk to their study team before making any change.

This article doesn’t offer individual medical advice. Talk to your doctor about your own Lp(a) result, your inflammation markers and your overall cardiovascular risk. Your routine checkup is a good time to ask.

What’s Next for Cardiovascular Disease Research

Other Lp(a)-lowering drugs

Nissen noted that three other cardiovascular outcomes trials of Lp(a)-lowering drugs are underway. Most use small interfering RNA (siRNA), a newer way of silencing the gene that makes Lp(a). In earlier studies these drugs lowered Lp(a) by more than 90%, and they are given less often than pelacarsen:

Drug (company)	Type	Phase 3 trial	Status
Olpasiran (Amgen)	siRNA, every 12 weeks	OCEAN(a)-Outcomes, about 7,300 patients	Results expected around 2027
Lepodisiran (Eli Lilly)	siRNA, infrequent dosing	ACCLAIM-Lp(a), includes some people without a prior event	Expected around 2029
Muvalaplin (Eli Lilly)	Daily pill	MOVE-Lp(a)	Ongoing

Because these drugs lower Lp(a) more deeply, and some trials enroll patients with higher levels, their results will be a crucial test of whether HORIZON reflects a problem with the drug or with the target.

The future of anti-inflammatory therapy

Researchers are now discussing testing IL-6 blockers in people with less advanced disease, and exploring drugs that act earlier in the inflammation pathway. Low-dose colchicine remains the main anti-inflammatory therapy with outcome-trial evidence in selected heart patients.

Conclusion: Why Evidence-Based Innovation Matters

The pelacarsen and ziltivekimab trials show why large cardiovascular outcomes trials remain essential. Both drugs did what they were designed to do in the lab and in the blood, and both fell short where it matters most: preventing heart attacks, strokes and deaths. That’s disappointing, but it isn’t wasted effort. These results will shape how future trials choose patients, set targets and measure success.

One negative trial doesn’t overturn years of genetic evidence linking Lp(a) to heart disease. It doesn’t erase the case for inflammation as a risk driver either. It does raise the bar. The next wave of experimental heart disease drugs will need to show, in large trials, that they help people live longer and healthier lives, not just that they improve lab numbers.

Find more evidence-based health guides on Learning Joan.

This article is for general information only and is not a substitute for professional medical advice. Both trials were funded by their manufacturers (Novartis and Novo Nordisk).