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In the ZEUS trial, ziltivekimab did not reduce the primary cardiovascular endpoint compared with placebo among 6,376 people with ASCVD, CKD and elevated inflammation. The drug substantially lowered IL-6 and CRP, but event rates were nearly identical; serious infections and venous thromboembolism were more frequent in the treatment group.
The anti-inflammatory drug ziltivekimab did not reduce major cardiovascular events in the ZEUS trial, which enrolled people with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and elevated inflammation. Over a median 33 months, the primary endpoint occurred in 17.6% of patients receiving the drug and 17.7% receiving placebo, despite large reductions in inflammatory markers.
ZEUS was a global, double-blind, randomized, placebo-controlled trial involving 6,376 patients. Participants received either ziltivekimab, a monoclonal antibody that targets the interleukin-6 (IL-6) ligand, or placebo. The monthly dose was 15 mg by subcutaneous injection; patients had established ASCVD and CKD, as well as high-sensitivity C-reactive protein (hs-CRP) levels above 2 mg per liter.
The primary outcome combined death from cardiovascular causes, nonfatal heart attack or nonfatal stroke. It occurred in 561 of 3,184 patients in the ziltivekimab group and 565 of 3,192 in the placebo group. The hazard ratio was 0.99 (95% confidence interval 0.88-1.11; P=0.84), indicating no demonstrated reduction in the primary outcome. The report also found no similar treatment benefit on secondary endpoints covering a broader cardiovascular composite, kidney outcomes, heart-failure outcomes or death from any cause.
The drug did change laboratory measures: compared with placebo, it produced a 76% reduction in free IL-6 and a 64% reduction in hs-CRP from baseline. Serious adverse events were reported in 54.6% of patients receiving ziltivekimab and 54.8% receiving placebo. Serious infections occurred in 20.4% versus 17.9%, and venous thromboembolism in 1.6% versus 0.6%; the report described both differences as statistically significant. These safety findings are comparisons between the trial groups and do not, on their own, explain the lack of cardiovascular benefit.
Biomarker Changes and Cardiovascular Events
In ZEUS, ziltivekimab lowered IL-6 and hs-CRP but did not produce a detectable reduction in the trial’s primary clinical outcome. The findings show that changes in these laboratory measures did not correspond to fewer cardiovascular events in the population studied.
The result does not establish that inflammation is irrelevant to cardiovascular disease. ZEUS investigators reported that higher baseline levels of CRP and IL-6 were associated with greater risk of the primary outcome and all-cause death. That association is distinct from evidence that a particular drug, used in a particular patient group, can prevent those events. The trial found no cardiovascular-event prevention benefit for ziltivekimab in the population studied.
Serious infections and venous thromboembolism were more frequent with treatment in the reported data. The trial report supplied these group rates but did not establish the mechanism behind the differences. Treatment decisions require assessment of the available evidence, including benefits, harms and individual patient needs.
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Where ZEUS Fits in Inflammation Research
Topline ZEUS results were released in July 2026. The full findings were presented by Paul M. Ridker of Harvard Medical School and Mass General Brigham at the American Heart Association’s annual meeting in Chicago on November 7 and published at the same time in the New England Journal of Medicine, according to MedPage Today.
Ridker contrasted ZEUS with earlier studies, including CANTOS, which tested canakinumab, and LoDoCo2 and COLCOT, which tested colchicine. He said those trials showed that anti-inflammatory treatment can reduce event rates in some patients with stable coronary disease. He also pointed to differences in the populations: ZEUS participants had significant CKD and more diabetes and heart failure than the CANTOS population, and their all-cause mortality rate during the trial was twice as high. He suggested that more advanced disease could be less responsive to treatment, while presenting that as a possible explanation rather than a proven cause of the result.
ZEUS tested a drug acting directly on the IL-6 ligand. The source report notes that genetic studies have linked IL-6 to cardiovascular risk, but Ridker cautioned that genetic evidence does not prove that treatment later in life can reverse that risk. The trial therefore addresses a specific intervention and patient group; it does not test every way of targeting inflammation.
“Genetic causality is not therapeutic reversibility.”
— Paul M. Ridker, ZEUS investigator, as quoted by MedPage Today
Why Biomarker Changes Did Not Translate
The trial establishes that ziltivekimab did not reduce the measured cardiovascular outcomes in the studied population during the reported follow-up. It does not settle why the treatment failed to change event rates. Ridker raised advanced disease and the timing of treatment as possible factors; Hsue asked whether treatment came too late, whether targeting the ligand was the wrong approach, or whether a different point in the inflammatory pathway should be targeted. Those are hypotheses, not findings proven by ZEUS.
It is also unclear from the supplied report how the findings will apply to people with less advanced disease or to other groups. The reported safety differences warrant attention, but the available material does not provide further analysis to explain them. Nor does the trial show that every anti-inflammatory drug or strategy will have the same result.
Other Trials and Treatment Questions
Further evidence may come from other studies of ziltivekimab in different populations. The report says HERMES, which studied people with heart failure and mildly reduced or preserved ejection fraction, was halted for futility, while ARTEMIS, involving acute coronary ischemia, was allowed to continue. Results from ARTEMIS could clarify whether findings differ in that setting; the source material gives no timeline for its results.
For now, the ZEUS data do not support using ziltivekimab to prevent cardiovascular events in patients matching the trial population. Ridker pointed to established risk-reduction approaches, including lifestyle measures and medicines such as statins, colchicine, canakinumab and GLP-1 drugs, while the report does not provide a new treatment recommendation. Clinicians will need to weigh the complete evidence for each option, and researchers will continue testing which inflammatory targets, if any, can improve clinical outcomes for specific groups.
Key Questions
What did the ZEUS trial find?
It found no reduction in the primary cardiovascular endpoint with ziltivekimab compared with placebo. Events occurred in 17.6% versus 17.7% of participants over a median 33 months.
Did ziltivekimab lower inflammation markers?
Yes. The trial reported placebo-adjusted reductions from baseline of 76% in free IL-6 and 64% in hs-CRP, even though cardiovascular events were not reduced.
Who took part in ZEUS?
The trial included 6,376 people with established ASCVD, CKD and hs-CRP above 2 mg per liter. They were randomly assigned to monthly ziltivekimab or placebo.
Were there safety differences between the groups?
Serious adverse-event rates were similar. Serious infections were reported in 20.4% with ziltivekimab and 17.9% with placebo; venous thromboembolism occurred in 1.6% and 0.6%, respectively. The report described both differences as statistically significant.
Does the result mean inflammation is not involved in heart disease?
No. ZEUS tested one drug in a specific patient population. Investigators reported that higher CRP and IL-6 levels were associated with higher risk, while the trial did not show that ziltivekimab reduced events in these patients.
Source: medpagetoday.com
