Despite failing to meet its primary endpoint, the ZEUS trial of ziltivekimab carries an important message for cardiovascular medicine: inflammation remains a valid therapeutic target, but the timing and patient population may be critical to success. The phase III study, presented at the American Heart Association’s Scientific Sessions 2026 and simultaneously published in The New England Journal of Medicine, tested whether blocking interleukin-6 with ziltivekimab could reduce heart attack, stroke, or cardiovascular death in adults with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and elevated inflammation markers.
The trial enrolled more than 6,300 participants across 38 countries, all at exceptionally high risk: 92% had high blood pressure, nearly 66% had Type 2 diabetes, and 42% had heart failure. Over a median follow-up of about 2.4 years, ziltivekimab reduced high-sensitivity C-reactive protein by 64% and interleukin-6 by 76% compared with placebo. Yet the primary composite endpoint occurred in 561 participants on ziltivekimab and 565 on placebo, a difference that was not statistically significant. Overall deaths were similarly balanced.
Lead author Paul M. Ridker, M.D., M.P.H., FAHA, of Harvard Medical School and Mass General Brigham, said the results should not be overinterpreted. “While the lack of clinical benefit in ZEUS is disappointing, we already know from prior research that targeting inflammation can significantly reduce cardiovascular risk,” he said. He pointed to previous trials showing that interleukin-1 inhibition with canakinumab or low-dose colchicine can lower heart attack and stroke risk. “Our job is to find the right anti-inflammatory treatment for the right patient group,” Ridker added.
Researchers noted that ZEUS participants had advanced disease that may have been too far along to benefit. More than 6% died during the trial, double the rate in other contemporary atherosclerosis studies without severe kidney disease. Serious infections were slightly more common with ziltivekimab (20% vs. 18%), a known effect of anti-inflammatory therapy. “In retrospect, participants in ZEUS had quite severe disease, which may have been non-modifiable, so targeting inflammation in this group was likely, unfortunately, ‘too little, too late,’” Ridker said.
The findings do not negate the extensive evidence linking inflammation to cardiovascular risk. Participants with higher baseline levels of hs-CRP or IL-6 remained at greater risk throughout the trial, reinforcing the role of inflammation in this population. The hypothesis for ZEUS was built on genetic, population, and experimental evidence, and the trial’s neutral result raises questions about which patients and which inflammatory pathways to target. Ridker suggested future research should explore downstream IL-6 inhibition in earlier-stage disease and upstream targeting of the NLRP3 inflammasome.
For clinicians, the takeaway is that measuring inflammation remains essential. “We can’t treat what we don’t know about,” Ridker said, urging patients and providers to focus on proven risk-reduction strategies, including healthy lifestyle habits and managing blood pressure, cholesterol, and blood sugar. The American Heart Association’s Life’s Essential 8 outlines those steps, while its 2026 guideline for cardiovascular-kidney-metabolic (CKM) syndrome emphasizes the interconnectedness of heart disease, kidney disease, diabetes and obesity. The ZEUS results, while neutral, sharpen the focus on a promising but complex therapeutic avenue.
