Researcher shares key insights after ZEUS trial delivers neutral result
Results from the ZEUS trial presented at the American Heart Association Scientific Sessions 2026 showed that ziltivekimab, new anti-inflammatory drug, lowered interleukin-6 (IL-6) and C-reactive protein (CRP) levels, but failed to significantly reduce the risk of heart attack, stroke or cardiovascular death compared to a placebo. The results were simultaneously published in The New England Journal of Medicine.[1]
There were high hopes that this trial would show positive results and lead to a new anti-inflammatory drug for coronary disease. Instead, many attendees in the standing-room only crowd at the meeting were left to ponder what went wrong. The American Heart Association even added additional time to the session to facilitate more discussions.
Trial principal investigator Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Mass General Brigham and a professor of medicine at Harvard Medical School, discussed the trial with Cardiovascular Business. He explained that the global study enrolled 6,376 patients across 38 countries to evaluate ziltivekimab, a monoclonal antibody that targets IL-6, a downstream inflammatory molecule. The trial targeted patients with established atherosclerotic cardiovascular disease, systemic inflammation and significant chronic kidney disease (CKD). These are individuals who face a particularly high risk of heart disease and who are unable to take the only FDA-cleared drug for coronary inflammation, colchicine.
"We're in a revolution for atherosclerosis treatment right now because we recognize that inflammation is a fundamental driver of what makes this disease so bad for our patients in addition to hyperlipidemia," Ridker said.
He noted that there was evidence from three completed clinical trials, CANTOS, COLCOT and LoDoCo2, that if inflammation is targeted with IL-6 inhibitors or colchicine, there can be a 15-30% reduction in major adverse cardiovascular events. The big question was which population to target, and it was decided that patients who cannot take colchicine made a lot of sense.
However, ZEUS enrolled a substantially sicker population than earlier studies. Participants were older and had more disease compounded by advanced kidney disease, with many also experiencing longstanding diabetes and heart failure. Ridker suggested the disease may have progressed beyond a point where suppressing inflammation could meaningfully change outcomes.
"Maybe that wasn't the best idea in retrospect, but these patients have incredibly high unmet needs. So we said, let's take inflammation biology there and see if it works. Well, 6,376 patients in 38 countries later, we have a completely neutral result," Ridker explained.
The primary endpoint occurred in 561 patients receiving ziltivekimab compared with 565 patients in the placebo group. The safety results were generally reassuring, with no adverse effect on total mortality, although researchers observed a small increase in infections. Ridker said the findings do not invalidate the broader concept of targeting inflammation to reduce cardiovascular risk, but suggest the choice of drug and patient population are critical.
Ridker led the 2017 CANTOS trial, which showed inhibiting interleukin-1 beta (IL-1β), an inflammatory molecule upstream of IL-6, reduced major adverse cardiovascular events by approximately 15-17%. Those results are what led many to be hopeful for this new IL-6 targeted agent. But in CANTOS, the overall mortality rate was about three deaths per 100 person-years. In ZEUS, mortality was roughly twice as high, reflecting the additional disease burden.
"The horse was out of the barn," Ridker said, explaining that the findings may reflect the difficulty of modifying cardiovascular risk in patients with such advanced disease. However, he believes IL-6 inhibition remains a viable therapeutic target, particularly in patients with earlier-stage, more modifiable atherosclerosis. Other ongoing and planned studies are evaluating IL-6 inhibition in less advanced disease.
Another promising direction is moving upstream in the inflammatory pathway to target the NLRP3 inflammasome, which regulates IL-1 and IL-18. Ridker said that multiple NLRP3 inhibitors are now in development, including potential oral small-molecule therapies.
"There are nine different NLRP3 inhibitors, maybe more than that at this point," he said. "So there's tremendous excitement on going upstream to hit the same thing we know worked."
Imaging may help better identify inflammatory disease
Ridker also discussed emerging imaging approaches that might help better select and monitor patients with coronary inflammation in future clinical trials.
One area of interest is the fat attenuation index (FAI), also called pericoronary fat imaging, which uses coronary CT angiography (CCTA) to assess changes in the fat surrounding coronary arteries caused by inflammation. The technology offered by Caristo gained U.S. Food and Drug Administration (FDA) approval this past summer. It is more specific for the coronaries than hs-CPR testing, which offers a systemic evaluation of inflammation throughout the body. FAI is also quantified very accurately by artificial intelligence, allowing serial assessments by CCTA over time to watch for increases or decreases in cocrnary inflammation.
Ridker said recent research has shown that both CRP and FAI are associated with approximately a four-fold increase in cardiovascular risk, but combining the two measures is associated with an approximately 20-fold increase in risk assessment accuracy. He suggested CRP could remain an initial screening tool, while FAI might serve as an intermediate measure for selecting patients in Phase 2 studies to determine whether an anti-inflammatory drug changes characteristics of there pericoronary fat.
Ultimately, Ridker said the ZEUS findings reinforce the need to identify the right anti-inflammatory treatment for the right patient, rather than abandoning inflammation as a therapeutic target. He also emphasized the importance of preventive care, including diet, exercise and smoking cessation, along with established therapies such as statins and GLP-1 receptor agonists, which also have anti-inflammatory properties.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: [email protected]