Heart researchers unpack neutral findings from ZEUS, an anti-inflammatory clinical trial
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Like cholesterol, inflammation causally contributes to the risk of cardiovascular disease, but findings from the clinical trial ZEUS indicate that the road to targeting inflammation may be less straightforward than once thought. ZEUS, a global phase 3 clinical trial led by Mass General Brigham researcher Paul Ridker, M.D., tested a drug that targets interleukin-6 (IL-6), a downstream inflammatory molecule. IL-6 inhibitors are commonly used to treat autoimmune disorders. However, while the new drug known as ziltivekimab lowered IL-6 levels, it did not reduce cardiovascular event rates compared to placebo.
In a late-breaking clinical trial presentation at the American Heart Association Scientific Session and in a simultaneous publication in New England Journal of Medicine, Ridker and colleagues detail the findings and lay out several potential explanations, including differences between the population enrolled in ZEUS and those enrolled in previous trials and the difference between IL-6 and other inflammation targets.
"The findings from ZEUS illustrate why clinical trials are so important: We don't yet have all of the answers and science is often about trial and error," said Ridker. "We already know from prior studies that targeting inflammation can reduce rates of heart attack and stroke. The critical question is which drug works best in which patients."
Testing a different inflammatory target
Previous work in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), also led by Ridker, showed that targeting a midstream interleukin known as IL-1b significantly lowered rates of recurrent heart attacks and strokes. In ZEUS, researchers tested ziltivekimab, a monoclonal antibody that targets a similar pathway but downstream at the level of IL-6.
"Given our neutral findings, one logical next step is to move upstream, instead of downstream, to find the right target," said Ridker. "For example, there are multiple new agents in development that can inhibit the upstream NLRP3 inflammasome. At the same time, it remains quite possible that downstream IL-6 inhibition is in fact effective, but that ZEUS targeted the wrong patient population."
Advanced disease may limit benefit
Like CANTOS, ZEUS enrolled people with atherosclerotic cardiovascular disease and systemic inflammation. But unlike CANTOS, ZEUS participants were a decade older, had significant kidney disease and often had longstanding diabetes and heart failure.
"In people with nonmodifiable disease, the horse may already have been out of the barn," Ridker said, noting that other ongoing and planned trials of IL-6 inhibition are focused instead on modifiable earlier-stage disease.
In the Ziltivekimab Cardiovascular Outcomes Study (ZEUS), researchers did not see a statistically significant difference in the rate of a combination of heart attack, stroke or cardiovascular death (the primary endpoint occurred in 561 participants in the treatment group compared to 565 in the placebo group). Safety was reassuring, with no adverse effect on total mortality, though a small increase in rates of infection was observed.
Proven options remain underused
The authors conclude that further trials are needed to understand how and in whom anti-inflammatory therapy can be given to reduce cardiovascular event rates. But they also note that for patients with stable atherosclerotic disease, the LoDoCo2 and COLCOT trials have already shown that the generic drug colchicine—which is also an anti-inflammatory medication—significantly reduces risk of cardiovascular events. Low-dose colchicine is approved by the U.S. FDA for use as an anti-inflammatory drug to lower rates of heart attack and stroke.
"What ZEUS shows us is that this particular drug in this particular setting didn't work," said Ridker. "But it's important to remember that we have other proven anti-inflammatory drugs such as low-dose colchicine that are being underutilized today in our patients with stable atherosclerosis. The results of ZEUS, taken together with the results of our other studies, help point us where we should go next."
Ridker points out that part of that direction should be quality preventive care; diet, exercise and smoking cessation all reduce inflammation and all lower cardiac risks, while other common drugs including statins and GLP-1 receptor agonists like semaglutide and tirzepatide also have important anti-inflammatory properties.
"Doctors will not treat what they do not measure," Ridker said, noting that a recent American College of Cardiology scientific statement called for broad screening for high-sensitivity C-reactive protein (hsCRP), an inexpensive blood test indicating substantial inflammatory risk.
Publication details
Interleukin-6 Inhibition with Ziltivekimab for Atherosclerotic Disease, New England Journal of Medicine (2026). DOI: 10.1056/NEJMoa2612126
Journal information: New England Journal of Medicine
Key medical concepts
Interleukin-6AtherosclerosisInflammation
Clinical categories
CardiologyCommon illnesses & PreventionClinical pharmacologyHealthy living Provided by Mass General Brigham Who's behind this story?
Gaby Clark
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