TL;DR
Turn quiet afternoons into listening time
- Thousands of audiobooks, podcasts and originals
- Listen on your phone, tablet or Echo — also offline
- Cancel anytime
The ZEUS trial found that ziltivekimab did not reduce cardiovascular events compared with placebo among 6,376 people with atherosclerotic cardiovascular disease, chronic kidney disease and elevated inflammation. The drug substantially lowered IL-6 and CRP, but event rates were nearly identical over a median 33 months; serious infections and venous thromboembolism were more frequent with treatment.
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, researchers reported November 7. The result matters because the drug sharply lowered inflammatory markers, yet the trial’s primary outcome occurred at nearly the same rate in both groups.
Over a median 33 months, the primary composite event—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), showing no statistically significant reduction. The findings were presented at the American Heart Association annual meeting in Chicago and published at the same time in the New England Journal of Medicine.
The global, double-blind trial enrolled 6,376 participants with established ASCVD, CKD and cardiovascular inflammation, defined as high-sensitivity C-reactive protein (hs-CRP) above 2 mg/L. Participants received a 15-mg subcutaneous injection of ziltivekimab once a month or placebo. The treatment produced a 76% placebo-adjusted reduction in free interleukin-6 (IL-6) and a 64% placebo-adjusted reduction in hs-CRP, but the investigators reported no similar treatment effect across secondary outcomes, including a broader cardiovascular endpoint, kidney outcomes, heart-failure outcomes and all-cause death.
Serious adverse events occurred at similar rates: 54.6% with ziltivekimab and 54.8% with placebo. Some specific events were more frequent in the treatment group. Serious infections occurred in 20.4% versus 17.9%, and venous thromboembolism in 1.6% versus 0.6%; the report described these differences as statistically significant. The supplied report does not provide further detail on other safety findings or establish why these event rates differed.
Biomarker Gains Did Not Lower Events
The findings separate biological activity from clinical benefit: ziltivekimab reduced IL-6 and CRP, but those changes did not translate into fewer cardiovascular events in the population studied. For clinicians and patients, the trial does not support assuming that lowering these markers with this treatment will prevent heart attacks, strokes or cardiovascular deaths in people with this combination of established disease and CKD.
The result also does not show that inflammation is irrelevant to cardiovascular disease. Trial discussant Priscilla Hsue said the neutral outcome should not be read as evidence that inflammation does not matter, and Ridker’s team reported that higher baseline levels of CRP and IL-6 were associated with higher risks of the primary outcome and all-cause death. Those observations describe risk associations; they do not prove that treating the markers with ziltivekimab changes outcomes.
The safety differences add to the practical importance of the result. With no demonstrated reduction in the primary outcome and higher reported rates of serious infection and venous thromboembolism, the trial provides no basis for assuming that the biomarker reductions alone justify treatment in this patient group. The findings are specific to the trial population and regimen and do not determine the effects of other anti-inflammatory drugs or treatment strategies.
Products Worth Considering
Withings BPM Vision Blood Pressure Monitor with Wi-Fi and Bluetooth
Withings BPM Connect Blood Pressure Monitor with Wi-Fi and Bluetooth
Withings BeamO Contactless Smart Thermometer, ECG Monitor, and Stethoscope
As an affiliate, we earn on qualifying purchases.
Why ZEUS Tested IL-6 Blockade
Ziltivekimab is a monoclonal antibody that targets the IL-6 ligand, a component of the inflammatory pathway. A phase II study had shown substantial CRP reductions, and researchers selected a monthly 15-mg dose for ZEUS. The trial tested whether that biological effect could reduce clinical events in people with established ASCVD, CKD and elevated hs-CRP.
The result follows earlier research in which some anti-inflammatory approaches reduced cardiovascular events in particular settings. Ridker cited the CANTOS trial of canakinumab and the LoDoCo2 and COLCOT trials of colchicine. Those studies involved different drugs and trial populations, so their results do not establish that IL-6 blockade should work in ZEUS’s population.
Ridker said ZEUS participants had substantial CKD, more diabetes and heart failure than participants in CANTOS, and an all-cause mortality rate twice as high. He suggested that advanced disease might be less amenable to modification, while stressing that this is an explanation to investigate, not a conclusion proven by the trial. He also said genetic evidence linking IL-6 to disease does not guarantee that starting a drug later in life will reverse that risk.
“Genetic causality is not therapeutic reversibility.”
— Paul M. Ridker, MD, of Harvard Medical School and Mass General Brigham
What the Trial Cannot Explain
ZEUS establishes that the tested ziltivekimab regimen did not significantly reduce the primary endpoint in this enrolled population during the reported follow-up. It does not establish why the result was neutral. The suggestions that treatment began too late in disease, that IL-6 ligand was the wrong target, or that another point in the inflammatory pathway should be targeted remain hypotheses raised by researchers, not findings demonstrated by ZEUS.
The trial also cannot settle whether people with less advanced disease, a different risk profile or another form of cardiovascular illness might respond differently. The source report says increasing CRP and IL-6 levels predicted greater risk, but it does not provide enough detail here to assess treatment effects within specific biomarker subgroups. The observed infection and venous-thromboembolism differences are reported, but their causes and implications for other settings are not established in the material available.
Other Ziltivekimab Trials Continue
Further evidence may come from studies testing ziltivekimab in different clinical settings. Ridker said the HERMES trial, which studied people with heart failure with mildly reduced or preserved ejection fraction, had also been halted for futility. The ARTEMIS trial in acute coronary ischemia was allowed to continue, he said; the supplied report does not give its expected completion date or a results timeline.
Researchers will also need to examine why substantial biomarker reductions failed to change clinical outcomes in ZEUS and whether any different patient group or treatment approach can show benefit. Until such evidence is available, the trial’s conclusion remains specific: ziltivekimab did not reduce cardiovascular events in the studied group. Ridker also 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 offer individual treatment advice or compare those options directly in ZEUS.
Key Questions
What did the ZEUS trial find?
Ziltivekimab did not reduce the primary cardiovascular outcome compared with placebo. The event occurred in 17.6% of the treatment group and 17.7% of the placebo group over a median 33 months.
Did ziltivekimab lower inflammation markers?
Yes. The trial reported a 76% placebo-adjusted reduction in free IL-6 and a 64% placebo-adjusted reduction in hs-CRP. Those biomarker changes did not correspond to a reduction in the primary clinical outcome.
Who was included in ZEUS?
The trial enrolled 6,376 people with established ASCVD, CKD and elevated cardiovascular inflammation, defined as hs-CRP above 2 mg/L. Participants were assigned monthly ziltivekimab injections or placebo.
Were there safety differences between the groups?
Overall 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 ZEUS show that inflammation does not affect cardiovascular disease?
No. The result shows that this ziltivekimab regimen did not reduce events in the ZEUS population. Researchers said the findings do not rule out a role for inflammation or benefits from other approaches, but those possibilities require evidence from other studies.
Source: medpagetoday.com
