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The ZEUS trial found that ziltivekimab did not reduce its primary cardiovascular outcome compared with placebo among 6,376 people with ASCVD, CKD and elevated inflammation. The drug substantially lowered IL-6 and CRP, but serious infections and venous thromboembolism were more frequent in the treatment group.
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 sharply lowering inflammatory markers. The findings, presented November 7 at the American Heart Association’s annual meeting and published in the New England Journal of Medicine, challenge the prospect of using this IL-6-targeting drug to prevent events in this high-risk population.
ZEUS enrolled 6,376 patients in a global, double-blind, randomized, placebo-controlled trial. Participants had established ASCVD, CKD and cardiovascular inflammation, defined as a high-sensitivity C-reactive protein (hs-CRP) level above 2 milligrams per liter. They received either 15 milligrams of ziltivekimab under the skin once a month or placebo.
Over a median follow-up of 33 months, the primary outcome—death from cardiovascular causes, nonfatal heart attack or nonfatal stroke—occurred in 561 patients (17.6%) assigned ziltivekimab and 565 (17.7%) assigned placebo. The hazard ratio was 0.99 (95% confidence interval 0.88 to 1.11; P=0.84), indicating no detected reduction in the outcome. Similar lack of benefit was reported across secondary outcomes, including a broader cardiovascular composite, kidney outcomes, heart-failure outcomes and all-cause mortality.
The treatment did affect biomarkers: researchers reported a 76% placebo-adjusted reduction in free IL-6 and a 64% placebo-adjusted 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%, respectively; both differences were reported as statistically significant. The supplied report does not provide further detail on those events.
Biomarker Gains Did Not Reduce Events
The results distinguish lowering inflammation markers from improving clinical outcomes. Ziltivekimab had a strong effect on IL-6 and CRP, but the trial found no corresponding reduction in its primary cardiovascular endpoint. For clinicians and patients, that means the biomarker changes alone do not establish that this treatment prevents heart attacks, strokes or cardiovascular deaths in people matching the ZEUS population.
The safety findings also matter when weighing a treatment with no demonstrated cardiovascular benefit in this trial. Serious infections and venous thromboembolism were more frequent with ziltivekimab, although the reported figures do not by themselves establish the cause of each event. The findings do not show that inflammation is irrelevant to cardiovascular disease; they show that this particular intervention, in this group and over this follow-up period, did not lower the measured event rate.
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Why ZEUS Tested IL-6 Blockade
Ziltivekimab is a monoclonal antibody that targets the IL-6 ligand. Its monthly dose was selected after a phase II study showed substantial CRP reduction, according to trial investigator Paul M. Ridker. The ZEUS population had established cardiovascular disease and significant kidney disease, with elevated hs-CRP required for enrollment.
Ridker said higher baseline levels of CRP and IL-6 were associated with greater risk of the primary outcome and all-cause death. He also noted that ZEUS differed from the CANTOS trial population, including more CKD, diabetes and heart failure, and a reported all-cause mortality rate twice as high as in CANTOS. Prior studies cited in the report—including CANTOS, LoDoCo2 and COLCOT—had found cardiovascular benefits with other anti-inflammatory approaches. Those results involve different drugs and trial populations, so they do not establish that ziltivekimab should have the same effect.
Ridker said the ZEUS result leaves open whether the disease was too advanced for intervention, whether the target or treatment strategy was unsuitable, or whether a later-life intervention can reverse risk suggested by genetic studies. He cautioned that genetic evidence of a causal pathway does not guarantee that a drug can reverse its effects.
“The relevant question moving forward is what drug, in which patient group?”
— Paul M. Ridker, MD, ZEUS investigator, Harvard Medical School and Mass General Brigham
What ZEUS Cannot Explain
The trial establishes that ziltivekimab did not reduce the specified outcomes in the population and follow-up studied; it does not identify why. The explanations raised by Ridker and Hsue—including advanced disease, timing, target selection or pathway strategy—remain possibilities, not findings proven by the trial.
The report does not give detailed event counts for the secondary outcomes or additional information about the infection and clotting events. It also does not establish whether a different dose, earlier treatment or another patient group would have a different result. ZEUS’s findings should not be assumed to apply to every anti-inflammatory treatment or to people outside its eligibility criteria.
Other Trials Will Test Different Groups
The report says the ARTEMIS trial of ziltivekimab in people with acute coronary ischemia was allowed to continue. Ridker also said the HERMES study in people with heart failure with mildly reduced or preserved ejection fraction had been halted for futility. The source does not provide further details on ARTEMIS’s timeline or planned reporting date.
Researchers and clinicians will be watching for results from ARTEMIS and for further analyses that may clarify the ZEUS safety findings and whether any patient subgroup could benefit. Until then, the available evidence described here does not support claiming that ziltivekimab reduces cardiovascular events in patients like those enrolled in ZEUS.
Key Questions
Did ziltivekimab reduce cardiovascular events in ZEUS?
No reduction was detected in the primary composite outcome of cardiovascular death, nonfatal heart attack or nonfatal stroke. Events occurred in 17.6% of the ziltivekimab group and 17.7% of the placebo group over a median of 33 months.
Did the treatment lower inflammation markers?
Yes. Researchers reported a 76% placebo-adjusted reduction in free IL-6 and a 64% placebo-adjusted reduction in hs-CRP from baseline, despite no reduction in the primary clinical outcome.
Who took part in the ZEUS trial?
The trial included 6,376 people with established ASCVD, CKD and elevated inflammation, defined as hs-CRP above 2 milligrams per liter. Participants were assigned ziltivekimab or placebo.
Were safety events different between groups?
Serious adverse events were similar overall: 54.6% with ziltivekimab and 54.8% with placebo. Serious infections and venous thromboembolism were more frequent in the ziltivekimab group in the reported results.
Does ZEUS show that inflammation does not matter in heart disease?
No. The trial tested one drug in a specific high-risk population. Discussant Priscilla Hsue said the findings should not be taken to mean inflammation is unimportant; they leave open which treatments and patient groups may benefit.
Source: medpagetoday.com
