TL;DR
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The ZEUS trial found that monthly ziltivekimab did not reduce cardiovascular events compared with placebo among 6,376 people with established ASCVD, CKD and elevated inflammation. The drug substantially lowered IL-6 and CRP, but the primary outcome occurred in 17.6% of the treatment group and 17.7% of the placebo group over a median 33 months.
The ZEUS trial found that ziltivekimab did not reduce major cardiovascular events compared with placebo in people with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and elevated inflammation. The antibody sharply lowered inflammatory markers, but over a median 33 months the primary outcome occurred in 17.6% of participants assigned to the drug and 17.7% assigned to placebo.
ZEUS enrolled 6,376 patients with established ASCVD, CKD and high cardiovascular inflammation, defined as a high-sensitivity C-reactive protein (hs-CRP) level above 2 mg/L. Participants were randomly assigned to monthly injections of ziltivekimab, a monoclonal antibody that targets the interleukin-6 (IL-6) ligand, or placebo. The primary composite outcome included death from cardiovascular causes, nonfatal heart attack or nonfatal stroke.
That outcome occurred in 561 of 3,184 patients (17.6%) in the ziltivekimab group and 565 of 3,192 (17.7%) in the placebo group. The hazard ratio was 0.99, with a 95% confidence interval of 0.88 to 1.11 and P=0.84, showing no statistically significant reduction. Investigators also reported no treatment benefit on the assessed secondary outcomes, which included broader cardiovascular, kidney and heart-failure composites and all-cause mortality.
The biological effect was clear: compared with placebo, treatment produced a 76% reduction in free IL-6 and a 64% reduction in hs-CRP from baseline. Serious adverse events occurred at similar rates, 54.6% with ziltivekimab and 54.8% with placebo. Serious infections were reported in 20.4% versus 17.9%, and venous thromboembolism in 1.6% versus 0.6%; the report described both differences as statistically significant.
Biomarker Gains Did Not Prevent Events
The findings separate a measurable change in inflammation from a demonstrated improvement in patient outcomes. Ziltivekimab reduced IL-6 and CRP substantially, yet the trial did not show fewer heart attacks, strokes or cardiovascular deaths in this high-risk group. Lowering a biomarker, by itself, cannot be taken as proof that a treatment prevents clinical events.
The result matters for decisions about developing and testing anti-inflammatory medicines for cardiovascular disease. It does not establish that inflammation is irrelevant: ZEUS investigators reported that higher IL-6 and CRP levels were associated with greater risk of the primary outcome and death. Rather, the trial leaves open whether a different drug, treatment timing or patient group could benefit. The reported differences in serious infections and venous thromboembolism also warrant attention when weighing the trial’s safety findings, though the supplied report does not provide further detail on those events.
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Why ZEUS Tested IL-6 Blockade
ZEUS tested whether directly blocking IL-6 could reduce events in patients who already had vascular disease, significant CKD and evidence of inflammation. The monthly 15 mg dose was selected after a phase II study showed substantial CRP reduction, according to investigator Paul M. Ridker, who presented the results at the American Heart Association’s annual meeting in Chicago. The findings were published at the same time in the New England Journal of Medicine. Topline results had been released in July 2026.
The outcome contrasts with earlier studies cited by Ridker, including CANTOS, which tested canakinumab, and COLCOT and LoDoCo2, which tested colchicine and reported cardiovascular event reductions in their respective settings. Those trials involved different medicines and populations, so their results do not show that ziltivekimab should have had the same effect. Ridker noted that ZEUS participants had more CKD, diabetes and heart failure than the CANTOS population, and that all-cause mortality was twice as high. He raised the possibility that advanced disease may be less responsive to modifying inflammation.
“Genetic causality is not therapeutic reversibility. Both the Mendelian randomization and the clinical trials are correct.”
— Paul M. Ridker, MD, ZEUS investigator, Harvard Medical School and Mass General Brigham Hospital
Which Patients Might Still Benefit
ZEUS does not establish why reducing IL-6 and CRP failed to lower cardiovascular events. Possible explanations raised by Ridker and discussant Priscilla Hsue include treatment being started too late in advanced disease, targeting the IL-6 ligand rather than its receptor, or acting too far downstream in the inflammatory pathway. These are questions, not conclusions demonstrated by the trial.
The supplied results do not provide a detailed breakdown of the serious infection and venous thromboembolism findings, nor do they establish whether any subgroup experienced a benefit. Hsue’s questions about drug target and timing also remain unresolved. The evidence therefore supports a neutral result for the population and regimen tested; it does not answer whether IL-6 inhibition could help a different group or under a different treatment strategy.
ARTEMIS Trial Continues
Further results from studies in other patient groups may help clarify whether ziltivekimab has a role outside the ZEUS population. Ridker said the HERMES study, which examined people with heart failure with mildly reduced or preserved ejection fraction, had also been halted for futility. The ARTEMIS study in patients with acute coronary ischemia was allowed to continue, according to his remarks; its outcome remains pending.
Ridker also pointed to research on other points in the inflammatory pathway, including direct targeting of NLRP3, and to existing approaches that affect cardiovascular outcomes in some settings. The next evidence will need to show whether a different target or patient population can translate inflammation reduction into fewer clinical events. Until those results are available, ZEUS does not support a cardiovascular event-reduction claim for ziltivekimab in patients like those enrolled.
Key Questions
What did the ZEUS trial find?
Among 6,376 patients with ASCVD, CKD and elevated inflammation, ziltivekimab did not reduce the primary composite of cardiovascular death, nonfatal heart attack or nonfatal stroke compared with placebo over a median 33 months.
Did ziltivekimab lower inflammation markers?
Yes. The trial reported placebo-adjusted reductions of 76% in free IL-6 and 64% in hs-CRP from baseline, despite no reduction in the primary cardiovascular outcome.
Does the result mean inflammation does not matter in cardiovascular disease?
No. The trial did not show that ziltivekimab prevented events in the population studied. Investigators also reported that higher IL-6 and CRP levels were associated with higher risk. The findings do not settle whether other anti-inflammatory approaches or patient groups may benefit.
What safety differences were reported?
Serious adverse events were similar: 54.6% with ziltivekimab and 54.8% with placebo. Serious infections were reported in 20.4% versus 17.9%, and venous thromboembolism in 1.6% versus 0.6%; the report said these differences were statistically significant.
What research is continuing?
Ridker said ARTEMIS, a study in acute coronary ischemia, was continuing. He also said HERMES, which studied a heart-failure population, had been halted for futility. Results from ARTEMIS had not been reported in the source material.
Source: medpagetoday.com
