Ziltivekimab failed to reduce the combined risk of heart attack, stroke, or cardiovascular death among 6,376 adults with advanced atherosclerotic cardiovascular disease and chronic kidney disease, according to clinical trial findings presented on November 7, 2026.
The global phase 3 clinical trial, known as the Ziltivekimab Cardiovascular Outcomes Study (ZEUS), tested ziltivekimab against a placebo.
The treatment successfully lowered blood levels of high-sensitivity C-reactive protein by 64%.
Interleukin-6 levels dropped by 76%.
These biochemical reductions did not translate into a statistically significant decrease in major cardiovascular events.
Dr. Paul Ridker and Dr. C. Michael Gibson discuss the ZEUS trial and its implications for the inflammatory hypothesis: Ziltivekimab 15 mg SC once-monthly achieved robust reductions in inflammatory biomarkers but showed neutral effects on the composite of CV death/MI/stroke in… pic.twitter.com/GSvXRe31jz
Researchers at Mass General Brigham detailed these results at the American Heart Association’s Scientific Sessions 2026.
The findings were simultaneously published in The New England Journal of Medicine.
Trial Design and Participant Characteristics in ZEUS
The double-blind, placebo-controlled, event-driven trial enrolled participants at 757 research sites across 38 countries between September 2021 and December 2024.
Eligible adults had established atherosclerotic cardiovascular disease, clinically substantial kidney disease, and elevated cardiovascular inflammation defined as a high-sensitivity C-reactive protein test result of at least 2 milligrams per liter.
Participants were randomized 1:1 to receive either a monthly 15-milligram subcutaneous injection of ziltivekimab or a placebo.
🔥 ZEUS: Lower inflammation inhibiting IL-6 with Ziltivekimab, no reduction in CV events 👥 6,376 (27% women) with ASCVD + CKD 💉 Ziltivekimab vs placebo ❤️ MACE: 17.6% vs 17.7% HR 0.99 (95% CI 0.88–1.11) ⚠️ Moderate ⤴️ risk of serious infections as expected ✅Highest… pic.twitter.com/v8QHoNabrK
The full analysis population comprised 6,376 patients, with a mean age of 69.4 years, of whom 27.5% were women, 4.2% self-identified as Black or African American, and 24.3% were of Asian ethnicity.
The cohort carried a heavy burden of comorbid conditions: 92% had high blood pressure, nearly 66% had Type 2 diabetes, 42.2% had heart failure, and the mean baseline estimated glomerular filtration rate was 44.5 mL/min/1.73 m².
Ziltivekimab Fails to Reduce Cardiovascular Events in Trial
Over a median follow-up of 33 months, the primary endpoint of a three-point composite of heart attack, stroke, or cardiovascular death occurred in 17.6% of patients in the ziltivekimab group and 17.7% of the placebo group, yielding a hazard ratio of 0.99 that lacked statistical significance.
Today #AHA26 and @NEJM the 2 big trials of secondary prevention of heart disease with an IL-6 antibody and Lp(a) antisense oligonucleotide. No beneficial effect, overall and across all subgroupshttps://t.co/lbsVSUEArahttps://t.co/D021HH9iij pic.twitter.com/lQWqSVWpeb
None of the confirmatory secondary endpoints favored the medication, including four-point major adverse cardiovascular events, death from any cause, and a composite kidney endpoint.
Regarding safety, serious adverse event rates were comparable between the two study arms.
Serious infections occurred more frequently among participants receiving ziltivekimab at 20.4% compared to 17.9% in the placebo group.
Serious venous thromboembolism rates reached 1.6% versus 0.6%.
Investigators noted that established risk factors only partly explained the venous thromboembolism imbalance, leaving uncertainty about whether it reflected the pathway inhibition, the enrolled population, or chance.
ZEUS trial: Ziltivekimab 15 mg SC once-monthly yielded comparable 3-point MACE incidence rate vs. placebo (6.7 vs. 6.8 per 100 person-years) over a median on-treatment period of 33 months in high-risk patients with ASCVD and CKD, showing no significant clinical benefit.… pic.twitter.com/YWGqMMyAL9
Evaluating Downstream Versus Upstream Inflammation Targets
Researchers pointed out that the trial cohort was exceptionally vulnerable, experiencing a mortality rate during the study that was double that seen in contemporary trials of atherosclerosis patients without severe kidney disease.
In Mass General Brigham announcements, trial leaders suggested that the enrolled population may have had advanced, non-modifiable disease where anti-inflammatory therapy arrived too late in the disease course.
In retrospect, participants in ZEUS had quite severe disease, which may have been non-modifiable, so targeting inflammation in this group was likely, unfortunately, ‘too little, too late.’ These findings, while neutral, raise important questions about which approaches to reducing inflammation might be most effective and for which patients,
Paul Ridker, MD, Mass General Brigham researcher
The findings contrast with earlier positive results from the CANTOS trial, which targeted a mid-stream interleukin known as IL-1b using canakinumab.
ZEUS results presented at #ScientificSessions26. Lowering interleukin-6 levels with ziltivekimab did not lower the risk of cardiovascular events in patients with ASCVD, CKD, and cardiovascular inflammation compared to placebo. pic.twitter.com/ONhbgZkdi0
Investigators noted that moving upstream in the inflammatory cascade—such as targeting the NLRP3 inflammasome with agents currently in development—or testing downstream interleukin-6 inhibition in patients with less severe, earlier-stage disease represent logical next steps for cardiovascular research.
Preventive Approaches in Stable Atherosclerosis
While investigations into specific biological inhibitors continue, public health guidance emphasizes that lifestyle factors such as diet, exercise, and smoking cessation remain effective tools for reducing inflammation and cardiac risk.
Established medications including statins and GLP-1 receptor agonists possess anti-inflammatory properties.
ZEUS: Anti-inflammatory therapy targeting IL-1β with ziltivekimab did not lower risks of cardiovascular events compared with placebo in high-risk patients with #ASCVD, chronic kidney disease and systemic inflammation. Read more: https://t.co/fn03OisMT2#ScientificSessions26 pic.twitter.com/hLyO6aKhsR
Physicians also have access to approved anti-inflammatory treatments like low-dose colchicine, which is supported by the LoDoCo2 and COLCOT trials for lowering heart attack and stroke rates in stable atherosclerosis.
Professional medical societies continue to advocate for broad screening using inexpensive blood tests to identify high-sensitivity C-reactive protein levels so that clinicians can detect and manage substantial inflammatory risk early.
Patient Questions About Ziltivekimab Trials
| Trial Name | Target Population | Current Status |
|---|---|---|
| ZEUS | ASCVD, CKD, and inflammation | Completed (neutral primary endpoint) |
| HERMES | Heart failure with preserved or midrange ejection fraction | Discontinued early following data monitoring review |
| ATHENA | Heart failure and inflammation | Discontinued early following data monitoring review |
| ARTEMIS | Post-heart attack acute treatment | Ongoing with readout expected in the first half of 2027 |
Following the ZEUS results, sponsor Novo Nordisk discontinued two other phase 3 trials evaluating ziltivekimab—HERMES and ATHENA—after a data monitoring committee concluded they were unlikely to succeed.
Development continues for the ARTEMIS trial, which is evaluating the monoclonal antibody as an acute treatment in patients following a heart attack.
What remains unknown is whether patients with less severe disease or different clinical profiles will benefit from interleukin-6 inhibition, and how future trials will determine optimal patient selection.