Two closely watched heart drug trials delivered the same surprise on Saturday: each experimental medicine sharply lowered the risk marker it was designed to target, yet neither reduced heart attacks, strokes or deaths. The results of the Lp(a) HORIZON and ZEUS trials were presented Nov. 7 at the American Heart Association’s Scientific Sessions 2026 in Chicago and published the same day in The New England Journal of Medicine.
For patients, the findings do not change what is available today, since neither drug is approved. But they reset expectations for two new approaches to preventing heart disease.
What did the Lp(a) HORIZON trial find?
The trial tested pelacarsen, a monthly injection from Novartis designed to block the liver’s production of lipoprotein(a), or Lp(a), a cholesterol-carrying particle linked to clogged arteries. According to the American Heart Association news release, the study enrolled 8,323 adults with established cardiovascular disease and high Lp(a) levels of 70 mg/dL or more at 797 sites in 42 countries, running from 2019 to 2026.
Pelacarsen lowered Lp(a) by an average of 78%. But there was no difference between the drug and placebo in the time to a major cardiovascular event, defined as a nonfatal heart attack, stroke, urgent procedure to reopen a clogged heart artery or cardiovascular death. Results were also unchanged in people with levels of 90 mg/dL or more and in extended analyses, including death from any cause, published in NEJM Evidence.
“I cannot avoid the disappointing conclusion – it didn’t work,” said senior author Dr. Steven E. Nissen of the Cleveland Clinic, who called the neutral result “unexpected and surprising to the medical community.”
Were there safety concerns with pelacarsen?
Serious adverse events were similar, reported in 37.3% of the pelacarsen group and 41.1% of the placebo group. However, flu-like symptoms, injection site reactions and acute allergic reactions were more common with the drug. Anaphylaxis, a severe allergic reaction, occurred in 19 patients taking pelacarsen and none on placebo, with no deaths from these reactions, the AHA reported. About 21% of patients on pelacarsen stopped their study medication because of side effects, compared with more than 7% on placebo.
What did the ZEUS trial find?
ZEUS tested ziltivekimab, a Novo Nordisk antibody that blocks interleukin-6, a protein that drives inflammation. The trial enrolled 6,376 adults with plaque-related heart and vascular disease, significant chronic kidney disease and elevated inflammation, measured by a high-sensitivity C-reactive protein (hs-CRP) test of at least 2 mg/L, at 757 sites in 38 countries.
Compared with placebo, the monthly 15-milligram injection cut hs-CRP by 64% and interleukin-6 by 76%. Yet the main outcome, heart attack, stroke or cardiovascular death, occurred in 561 patients on ziltivekimab and 565 on placebo, according to the AHA release. Deaths were also nearly identical, at 538 and 542. Serious infections were somewhat more common with the drug, 20% versus 18%.
Lead author Dr. Paul M. Ridker of Mass General Brigham said participants had such advanced disease that the treatment may have been “too little, too late.” More than 6% died during the trial, about double the rate in other recent studies of patients with atherosclerosis but without severe kidney disease, the researchers noted.
Why do these results matter?
Both trials tested a widely studied idea: that high Lp(a) and chronic inflammation each raise heart risk beyond standard risk factors. About 1 in 5 people worldwide, roughly 1.4 billion, are thought to have elevated Lp(a), according to the AHA. Lp(a) is largely inherited, it barely responds to diet, exercise or statins, and there is currently no FDA-approved medication to lower it, the association said.
The researchers stressed that the targets still matter. Nissen noted that three other cardiovascular outcome trials are testing different Lp(a)-lowering compounds. Ridker pointed to earlier trials in which the anti-inflammatory drugs canakinumab and low-dose colchicine did lower the risk of heart attack and stroke, and said future studies will test interleukin-6 blockers in patients with less severe disease.
What should patients take away right now?
The study authors cautioned against reading the results as a sign that these risk factors do not matter. The 2026 multi-society guideline on the management of dyslipidemia recommends that Lp(a) be measured at least once in adulthood, and Nissen called testing “still absolutely worthwhile” because high levels usually cause no symptoms. He also urged anyone enrolled in another Lp(a) trial not to drop out because of these findings.
Proven steps remain the foundation: controlling blood pressure, cholesterol and blood sugar, not smoking, staying active and eating a healthy diet, the habits the AHA groups as Life’s Essential 8. Both trials were funded by their drugmakers, Novartis for Lp(a) HORIZON and Novo Nordisk for ZEUS.
Key Takeaways
- Pelacarsen lowered Lp(a) by 78% in 8,323 heart patients but did not reduce heart attacks, strokes or cardiovascular deaths.
- Ziltivekimab cut inflammation markers by 64% to 76% in 6,376 patients with heart and kidney disease, with no reduction in major cardiovascular events.
- Neither drug is FDA-approved, and there is still no approved medicine to lower Lp(a).
- Experts still advise measuring Lp(a) at least once and managing blood pressure, cholesterol and blood sugar.
Frequently Asked Questions
What is Lp(a)?
Lipoprotein(a) is a cholesterol-carrying particle in the blood that can contribute to plaque buildup in arteries. Levels are largely inherited and are not lowered much by diet, exercise or statins.
Did pelacarsen work in the Lp(a) HORIZON trial?
It lowered Lp(a) by 78% on average but did not reduce heart attacks, strokes or cardiovascular deaths compared with placebo.
What is ziltivekimab?
Ziltivekimab is an experimental antibody that blocks interleukin-6, a protein involved in inflammation. In the ZEUS trial it lowered inflammation markers but did not reduce major cardiovascular events.
Should I still get my Lp(a) tested?
The AHA and the study’s senior author say yes. Current guidelines recommend measuring Lp(a) at least once in adulthood, because high levels usually cause no symptoms. Ask your doctor whether the test is right for you.
Are these drugs available?
No. Neither drug is FDA-approved, and no approved medicine currently lowers Lp(a).
Sources: American Heart Association news releases on Lp(a) HORIZON and ZEUS (Nov. 7, 2026); The New England Journal of Medicine (Lp(a) HORIZON, ZEUS); NEJM Evidence (extended analyses); ClinicalTrials.gov (NCT04023552, NCT05021835).
Featured image: Cardiologists perform a catheterization procedure in the cardiac catheterization laboratory at Naval Medical Center San Diego. (Navy Medicine photo, public domain, via Wikimedia Commons)
