TL;DR
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The ZEUS trial found that monthly ziltivekimab did not reduce major cardiovascular events compared with placebo in patients with ASCVD, CKD and elevated inflammation. The drug substantially lowered IL-6 and hs-CRP, but serious infections and venous thromboembolism were more frequent in the treatment group. The results do not establish that inflammation is irrelevant to cardiovascular disease; researchers say the patient group, timing or treatment strategy may matter.
Ziltivekimab did not reduce major cardiovascular events compared with placebo in the ZEUS trial of people with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and elevated inflammation, despite substantially lowering inflammatory markers. The results, presented at the American Heart Association’s annual meeting in Chicago and published in the New England Journal of Medicine, challenge expectations that blocking interleukin-6 would prevent events in this high-risk group.
Over a median 33 months, the trial’s primary endpoint — death from cardiovascular causes, nonfatal heart attack or nonfatal stroke — occurred in 561 of 3,184 participants (17.6%) assigned to ziltivekimab and 565 of 3,192 (17.7%) assigned to placebo. The hazard ratio was 0.99 (95% confidence interval 0.88 to 1.11; P=0.84), indicating no demonstrated reduction in the primary outcome.
The global, double-blind trial enrolled 6,376 people with established ASCVD, CKD and high-sensitivity C-reactive protein (hs-CRP) above 2 milligrams per liter. Participants received a 15-milligram injection of ziltivekimab or placebo once a month. The treatment produced a 76% placebo-adjusted reduction in free IL-6 and a 64% placebo-adjusted change in hs-CRP from baseline, according to results presented by trial investigator Paul M. Ridker of Harvard Medical School and Mass General Brigham.
The report said there was also no similar treatment effect on the secondary outcomes listed, including a broader cardiovascular composite, a kidney composite, a heart-failure composite and all-cause mortality. Serious adverse events were similar: 54.6% with ziltivekimab and 54.8% with placebo. Serious infections occurred in 20.4% versus 17.9%, and venous thromboembolism in 1.6% versus 0.6%; both differences were reported as statistically significant. The supplied report does not provide further detail about those events.
Lower Inflammation, No Event Reduction
ZEUS separates a measurable biological effect from a clinical benefit: ziltivekimab lowered IL-6 and hs-CRP, but the trial did not show fewer major cardiovascular events for the patients studied. The findings are relevant to clinicians and researchers evaluating whether targeting inflammation can add protection for people who already have vascular disease and significant kidney impairment.
They do not prove that inflammation plays no role in atherosclerosis. Ridker reported that higher levels of CRP and IL-6 were associated with higher risk of the primary endpoint and all-cause death. That association, however, does not establish that lowering those markers with this drug, in this population and over this period, prevents events. The imbalance in serious infections and venous thromboembolism also matters when weighing the treatment’s observed effects.
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How ZEUS Fits Earlier Trials
Ziltivekimab is a monoclonal antibody that targets the IL-6 ligand. Earlier phase II research showed it could lower CRP, helping inform the monthly dose selected for ZEUS. The trial’s topline findings were released in July 2026; the full results were presented and published in November.
Ridker contrasted the neutral ZEUS result with earlier studies of anti-inflammatory treatment, including CANTOS, LoDoCo2 and COLCOT, which he said showed event reductions in other populations or with other drugs. He also pointed to differences between ZEUS and CANTOS: ZEUS participants had significant CKD and more diabetes and heart failure, and the all-cause mortality rate during the trial was twice as high. He raised the possibility that advanced disease could be less responsive to treatment, while stressing that this is an interpretation rather than a proven explanation.
Ridker said genetic evidence implicating IL-6 in cardiovascular risk does not guarantee that intervening later in life will reverse that risk. As he put it, “genetic causality is not therapeutic reversibility.” AHA discussant Priscilla Hsue of the University of California, San Francisco, also questioned whether treatment came too late, targeted the wrong part of the pathway or used the wrong strategy.
““The relevant question moving forward is what drug, in which patient group?””
— Paul M. Ridker, ZEUS investigator, Harvard Medical School and Mass General Brigham
Why Biomarker Changes Did Not Translate
The trial does not identify why substantial reductions in IL-6 and hs-CRP were not accompanied by fewer cardiovascular events. The explanations raised by Ridker and Hsue — including advanced disease, treatment timing or the choice of target — remain hypotheses, not findings proven by ZEUS.
The report also does not provide detailed explanations for the higher rates of serious infection and venous thromboembolism, or enough information to determine how those risks might apply to other patient groups. ZEUS tested a defined population with established ASCVD, significant CKD and elevated hs-CRP; its result should not automatically be generalized to every group with cardiovascular disease or inflammation.
Other Ziltivekimab Trials Continue
Further evidence may come from trials testing ziltivekimab in different settings. Ridker said the ARTEMIS trial in acute coronary ischemia has been allowed to continue. He also reported that HERMES, which studied people with heart failure with mildly reduced or preserved ejection fraction, was halted for futility.
Researchers will need to assess the full ZEUS findings, including the safety results, alongside evidence from other trials before drawing conclusions about which inflammatory targets or patient groups might benefit. For now, ZEUS provides no evidence that monthly ziltivekimab reduces cardiovascular events in the population it studied.
Key Questions
What did the ZEUS trial find?
Ziltivekimab did not reduce the primary cardiovascular endpoint compared with placebo. Events occurred in 17.6% of the treatment group and 17.7% of the placebo group over a median 33 months.
Did ziltivekimab lower inflammation?
Yes. The trial reported a 76% placebo-adjusted reduction in free IL-6 and a 64% placebo-adjusted change in hs-CRP from baseline, but those biomarker changes did not correspond to a demonstrated reduction in the primary endpoint.
Who took part in ZEUS?
The trial enrolled 6,376 people with established ASCVD, CKD and hs-CRP above 2 milligrams per liter. Participants were assigned to monthly ziltivekimab or placebo.
Were there safety differences between the groups?
Overall serious adverse events were similar. Serious infections and venous thromboembolism were more frequent with ziltivekimab in the reported results: 20.4% versus 17.9% for serious infections and 1.6% versus 0.6% for venous thromboembolism.
Does the result show inflammation does not matter in heart disease?
No. The result means ziltivekimab did not reduce events in this specific trial population. Investigators noted that higher inflammatory markers were associated with risk, while saying more research is needed to understand which treatments and patient groups could benefit.
Source: medpagetoday.com
