The phase III ZEUS trial has found that ziltivekimab, a novel interleukin-6 inhibitor, did not significantly reduce the combined risk of heart attack, stroke or cardiovascular death in adults with atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease, despite substantially lowering markers of inflammation in the blood. The results were presented at the American Heart Association's Scientific Sessions 2026 and simultaneously published in The New England Journal of Medicine.
ZEUS, a multi-center, international, placebo-controlled trial, enrolled more than 6,300 very high-risk adults with confirmed atherosclerotic cardiovascular disease, clinically significant chronic kidney disease and elevated high-sensitivity C-reactive protein (hs-CRP). Many participants also had Type 2 diabetes, hypertension and heart failure. The trial was designed to test whether blocking interleukin-6, a key inflammatory signaling protein, could reduce cardiovascular events in this population with considerable unmet clinical needs.
While ziltivekimab lowered hs-CRP by 64% and interleukin-6 by 76% compared to placebo, the primary endpoint of heart attack, stroke or cardiovascular death occurred in 561 participants on ziltivekimab and 565 on placebo—a difference that was not statistically significant. Overall deaths were also similar: 538 in the ziltivekimab group versus 542 in the placebo group. Serious infections were more common with ziltivekimab (20% vs. 18%), an expected side effect of anti-inflammatory therapy.
"While the lack of clinical benefit in ZEUS is disappointing, we already know from prior research that targeting inflammation can significantly reduce cardiovascular risk, so it's important not to overinterpret these findings," said lead study author Paul M. Ridker, M.D., M.P.H., FAHA, director of the Center for Cardiovascular Disease Prevention at Mass General Brigham. He noted that participants had advanced disease that may have been "too little, too late" for the medication to meaningfully reduce risk, as more than 6% died during the trial—double the rate of other contemporary atherosclerosis studies without severe kidney disease.
The findings underscore the continued importance of inflammation as a treatment target while raising questions about patient selection and timing. Ridker emphasized that previous trials with other anti-inflammatory agents, such as canakinumab and low-dose colchicine, did show cardiovascular benefit in earlier-stage disease. Ongoing and planned trials will explore downstream interleukin-6 inhibition in less severe disease and upstream targeting of the NLRP3 inflammasome.
For patients and clinicians, the results reinforce the need to measure inflammation and manage overall cardiovascular risk. The American Heart Association's 2026 guideline for cardiovascular-kidney-metabolic (CKM) syndrome highlights the interconnectedness of heart disease, kidney disease, diabetes and obesity, and the organization's Life's Essential 8 outlines lifestyle steps to improve cardiovascular health. The trial was funded by Novo Nordisk. For more details, the abstract is available in the Scientific Sessions 2026 Online Program Planner.
