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ZEUSPreventionNew England Journal of Medicine

Interleukin-6 Inhibition with Ziltivekimab for Atherosclerotic Disease

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What happened

Ziltivekimab fails to reduce 3-point major cardiovascular events vs. placebo in patients with ASCVD and CKD.

HR 0.99
95% CI 0.88-1.11
P=0.84
n=6,376

Key points

Context & question: Guha notes ziltivekimab lowered hsCRP while major CV events were 17.6% vs 17.7%. His question is whether starting IL-6 blockade earlier changes its cardiovascular effect. To determine whether neutralizing interleukin-6 with the monoclonal antibody ziltivekimab reduces major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease, chronic kidney disease, and elevated inflammation.
Methods & population: Multinational, double-blind, randomized, placebo-controlled trial including 6376 adults with atherosclerotic cardiovascular disease, chronic kidney disease, and high-sensitivity C-reactive protein (CRP) ≥2 mg/L; Patients were randomly assigned 1:1 to subcutaneous ziltivekimab (15 mg once monthly, N=3184) or placebo (N=3192); The primary endpoint was a composite of 3-point major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) over a median follow-up of 33 months.
Finding & limits: A primary endpoint event occurred in 561 patients receiving ziltivekimab and 565 patients receiving placebo. Experts ask whether starting IL-6 blockade earlier, or in a different population, would change the cardiovascular effect, and whether upstream targets such as the NLRP3 inflammasome are the better path. Subgroups did not identify a confirmed beneficiary, and the baseline IL-6 analysis was post hoc.

Discussion

磯

磯田菊生Nov 12

Tocilizumab, which we used in our basic research (Front Cardiovasc Med. 2017:4:84), significantly suppressed chronic inflammation in conditions such as rheumatoid arthritis and Takayasu’s arteritis, and it also significantly suppressed the chronic inflammation associated with atherosclerosis. We would like to know whether ziltivekimab is similarly effective against these chronic inflammatory diseases. We are considering the possibility that certain IL-6-inhibiting drugs may be able to reduce 3-point major cardiovascular events.

Expert perspectives 25

Daniel Edmonston

Practice takeDuke University

ZEUS is clearly neutral, but it does not show CKD is too advanced to treat.

Federica Fogacci

Endpoint critiqueGeneral / Preventive / Lipids · University of Bologna

No subgroup found a confirmed beneficiary, and high inflammatory risk may not be IL-6-dependent.

Guidelines questionCross-Cutting Cardiology · Augusta University

Would starting IL-6 blockade earlier change its cardiovascular effect?

Show 22 more perspectives

Results readoutHeart Failure / Cardiomyopathy · Hospital Clínico Universitario de Valencia

ZEUS showed no efficacy on any endpoint plus a safety signal across infections, VTE, bleeding and platelets.

ContextCross-Cutting Cardiology

The wrong conclusion from ZEUS is that targeting inflammation doesn't work.

Chayakrit Krittanawong

ContextInterventional Cardiology

Krittanawong calls ZEUS a reality check for anti-inflammatory drugs in heart disease.

Shayan Mohammadmoradi

Results readoutUniversity of Kentucky

Mohammadmoradi stresses that hitting the target did not lower events, while serious infections were 20.4% vs 17.9%.

Results readoutTwitter (United States)

Dupuis notes tertiles of inflammation did correlate with more CV events, yet primary and secondary endpoints were neutral.

C. Michael Gibson

Results readoutInterventional / Structural Cardiology · Beth Israel Deaconess Medical Center

Gibson reports 3-point MACE of 6.7 vs 6.8 per 100 person-years over a median 33 months, with no significant clinical benefit.

Results readoutInterventional / Structural Cardiology · Montreal Heart Institute

Avram highlights no CV benefit despite inflammation lowering, with serious infections 20.4% vs 17.9%.

Results readoutCardiac Imaging

Parwani calls ZEUS negative: it lowers inflammation but brings no reduction in CV events.

ContextPabna University of Science and Technology

Roy argues timing is the lesson, since the drug cut a key inflammation marker but events did not fall.

Expert perspective

Paul M. Ridker8d ago

General · Brigham and Women's Hospital

While the lack of clinical benefit in ZEUS is disappointing, we already know from prior research that targeting inflammation can significantly reduce cardiovascular risk, so it's important not to overinterpret these findings. Our job is to find the right anti-inflammatory treatment for the right patient group.

ZEUS co-author

Expert perspective

Paul M. Ridker8d ago

General · Brigham and Women's Hospital

Given our neutral findings, one logical next step is to move upstream, instead of downstream, to find the right target. For example, there are multiple new agents in development that can inhibit the upstream NLRP3 inflammasome. At the same time, it remains quite possible that downstream IL-6 inhibition is in fact effective, but that ZEUS targeted the wrong patient population.

ZEUS co-author

Expert perspective

Damian Rasch6d ago

@NEJM Ziltivekimab did exactly what it was built to do, IL-6 down 76% and hsCRP down 64%, and MACE didn’t move (HR 0.99). The same day pelacarsen cut Lp(a) 78% and HORIZON landed at 1.02. Both trials enrolled people around 60 to 70 with established disease, and in ZEUS everyone had CKD

ZEUS

Expert perspective

Patrick Joyce7d ago

@KrittanawongMD CANTOS worked downstream of IL-6, ZEUS blocked IL-6 directly and didn’t. That argues against wrong target. @ResearchHub could you design a trial testing ziltivekimab in high-hsCRP patients without advanced CKD, to separate wrong-target from too-late-in-disease?

ZEUS

Expert perspective

Paul H7d ago

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. #Ziltivekimab

t.coZEUS

Expert perspective

Viet Le DMSc PA-C FACC FAHA HF-Cert7d ago

🧵 ZEUS reports today. We have compelling biology connecting inflammation and atherosclerosis. But the question for an outcomes trial is harder: does modifying that pathway actually improve cardiovascular outcomes? #ScientificSessions26 @AHAScience 1/8

t.coZEUS

Expert perspective

Venk Murthy MD PhD8d ago

The incredible neutrality of Lp(a) lowering in HORIZON and IL6 lowering in ZEUS suggest to me we need a: 1. Wholesale rethinking of genetic evidence 2. Even broader rethinking of KOL pantheon

t.coZEUS

Expert perspective

Martin Holst Lange8d ago

Forschungszentrum Jülich

ZEUS was designed to test whether inhibition of the IL-6 pathway could translate reductions in cardiovascular inflammation into fewer major cardiovascular events. Although ziltivekimab produced the expected biological effect, this did not result in MACE benefits in this population.

ZEUS

Expert perspective

Pablo Corral8d ago

The neutral ZEUS result should not be interpreted as disproving the prognostic association between hsCRP and cardiovascular events. However, an HR of 0.99 despite clear IL-6 target engagement and substantial hsCRP reduction should prompt…

ZEUS

Expert perspective

John M. Mandrola8d ago

Electrophysiology · Baptist Health System

Even worse than a null primary endpoint with tight confidence intervals was that serious infections were higher in the ziltivekimab arm.

ZEUS

Expert perspective

Mauricio Soto V8d ago

Live from @American_Heart #ScientificSessions26 ZEUS: IL-6 inhibition with ziltivekimab in 6,376 patients with ASCVD, CKD, and inflammation. IL-6 ↓76%, hs-CRP ↓64% MACE: 561 vs 565 A much sicker population than in CANTOS, COLCOT, or LoDoCo2. Too advanced to modify? @NEJM

t.coZEUS

Expert perspective

Martha Gulati8d ago

🔥 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

t.coZEUS

Expert perspective

Hiram Mendoza9d ago

🫀 #AHA26 preview: none of the 6 core Late-Breaking Science sessions is dedicated to heart failure this year. Still, 4 trials HF clinicians should not miss 👇 • Yoga-CaRe HF: yoga-based cardiac rehab in HFrEF (Sat 7, 15:15 CT) • ZEUS: ziltivekimab (IL-6 inhibition) in CVD +

t.coZEUS

Outstanding questions

Open questions from this trial that would benefit from expert input.

Ask about this paper

Answers are grounded in this paper and cite their sources.

Full evidence

Why the trial, tables, limitations, PICO, abstract, media & sources

Why the trial?

Although the inflammatory cytokine interleukin-6 is hypothesized to be a therapeutic target in patients with atherosclerotic cardiovascular disease and chronic kidney disease, it was unknown whether neutralizing it reduces clinical risk. The ZEUS trial was conducted to determine if lowering interleukin-6 levels with the monoclonal antibody ziltivekimab reduces the risk of adverse cardiovascular events in these patients.

Does subcutaneous ziltivekimab (15 mg once monthly) reduce the risk of 3-point major adverse cardiovascular events compared with placebo in adults with atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation?

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Structured PICO

Does subcutaneous ziltivekimab (15 mg once monthly) reduce the risk of 3-point major adverse cardiovascular events compared with placebo in adults with atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation?

Population

6,376 adults (mean age 69.4 years, 27.5% women) with established atherosclerotic cardiovascular disease, chronic kidney disease, and high-sensitivity CRP ≥2 mg/L, followed for a median of 33 months.

Intervention

Ziltivekimab 15 mg subcutaneous once monthly for a median follow-up of 33 months

Comparator

Placebo administered once monthly

Outcome

3-point major adverse cardiovascular event (MACE), a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, over a median follow-up of 33 monthscomposite endpoint

Main Result

Hazard Ratio0.99 (95% CI 0.88–1.11)

Absolute Event Rate17.6% vs 17.7%

p-valuep=0.84

Despite substantially lowering free interleukin-6 and high-sensitivity CRP levels, monthly subcutaneous ziltivekimab did not reduce major adverse cardiovascular events in high-risk patients with atherosclerotic cardiovascular disease, chronic kidney disease, and systemic inflammation.

Where experts stand

Chronic kidney disease evidence still forming

Experts read ZEUS as a clear null result: the drug lowered inflammation but did not prevent heart attacks, strokes, or cardiovascular deaths, and it brought more serious infections, so it does not change practice.

Reactions agree that ziltivekimab hit its biological target without reducing cardiovascular events, and several flag a safety cost from infections. The split is over why it failed: some point to patients who were too sick or treated too late, while others reject the idea that kidney disease was too advanced and call for rethinking which inflammatory targets matter. The live question is whether a different target or an earlier, healthier population could still show benefit.

Agreement

Multiple clinicians state the same core reading: ziltivekimab clearly lowered inflammatory markers but did not reduce major cardiovascular events. Several also note that serious infections were higher on the drug.

6 clinicians say this directly

Main debate

Wrong patients or too late in disease, versus a true neutral result in this population.

Wrong population or too late2

These posts suggest IL-6 blockade might still work in a different or earlier population.

vs

Not too advanced to treat1

Edmonston argues ZEUS shows no event benefit on contemporary therapy and does not show CKD is too advanced to treat.

+2Not placed7 reporting, watching, or context only

3 takes classified by contention axis so far — the map appears as more land.

Still unclear

Experts ask whether starting IL-6 blockade earlier, or in a different population, would change the cardiovascular effect, and whether upstream targets such as the NLRP3 inflammasome are the better path. Subgroups did not identify a confirmed beneficiary, and the baseline IL-6 analysis was post hoc.

Implication

Ziltivekimab did not reduce MACE in ASCVD with CKD; challenges IL-6 inhibition for event reduction and leaves alternative anti-inflammatory targets open.

Abstract

Background The inflammatory cytokine interleukin-6 is hypothesized to be a therapeutic target for patients with atherosclerotic cardiovascular disease and chronic kidney disease. Whether neutralizing interleukin-6 levels with ziltivekimab, a monoclonal antibody, reduces the risk of adverse cardiovascular events remains unknown. Methods We conducted a multinational, double-blind, randomized, placebo-controlled trial involving adults with established atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation (defined by a high-sensitivity C-reactive protein [CRP] level of ≥2 mg per liter). Patients were randomly assigned in a 1:1 ratio to receive subcutaneous ziltivekimab (15 mg once monthly) or placebo. The primary efficacy end point was a 3-point major adverse cardiovascular event (MACE). This composite end point included death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results A total of 6376 patients were included in the full analysis population: 3184 were assigned to receive ziltivekimab and 3192 to receive placebo. The mean age of the patients was 69.4 years, and 27.5% were women. At 24 months, the between-group difference in the median percent change in the levels of inflammatory biomarkers among patients receiving ziltivekimab as compared with those receiving placebo was −76 percentage points for free interleukin-6 and −64 percentage points for high-sensitivity CRP. During a median follow-up of 33 months, a primary end-point event occurred in 561 patients (17.6%) in the ziltivekimab group and in 565 patients (17.7%) in the placebo group (hazard ratio, 0.99; 95% confidence interval, 0.88 to 1.11; P=0.84). Serious adverse events occurred in 54.6% of the patients in the ziltivekimab group and in 54.8% of those in the placebo group; serious infections occurred in 20.4% and 17.9%, respectively. Conclusions Among patients with atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation, a strategy of lowering interleukin-6 levels with ziltivekimab did not result in a lower risk of cardiovascular events than placebo.

Coverage & sources

Journal, society, and media accounts. Useful signal, not independent expert judgment.

Cite This Study

Ridker et al. (2026) conducted an RCT in Atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation (n=6,376). Ziltivekimab vs. Placebo was evaluated on 3-point major adverse cardiovascular event (MACE) composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (HR 0.99, 95% CI 0.88-1.11, p=0.84). Ziltivekimab did not reduce 3-point major cardiovascular events compared with placebo in patients with ASCVD, CKD, and inflammation.

synapsesocial.com/papers/6ad94e21101c3306835df8be https://doi.org/10.1056/nejmoa2612126