The full ZEUS results, presented on Saturday at the American Heart Association Scientific Sessions in Chicago and published simultaneously in the New England Journal of Medicine, confirm that Novo Nordisk’s ziltivekimab does not prevent cardiovascular events in patients with atherosclerotic cardiovascular disease, chronic kidney disease and systemic inflammation. The trial randomised 6,376 patients at 757 sites in 38 countries to a 15 mg subcutaneous injection of the interleukin-6 ligand antibody once a month or to placebo, enrolling between September 2021 and December 2024.
Over a median follow up of 33 months, the three point composite of cardiovascular death, nonfatal heart attack and nonfatal stroke occurred in 17.6 percent of the ziltivekimab group (561 of 3,184 patients) and 17.7 percent of the placebo group (565 of 3,192), a hazard ratio of 0.99 with a 95 percent confidence interval of 0.88 to 1.11 and a p value of 0.84. The four point composite and death from any cause were also identical between groups, at 18.4 against 18.5 percent and 16.9 against 17.0 percent. No confirmatory secondary endpoint favoured the drug. Lead investigator Paul Ridker of Brigham and Women’s Hospital described the comparison as about as neutral as one can get.
The drug did what it was designed to do biologically. At 24 months the between group difference in median percent change was minus 76 percentage points for free interleukin-6 and minus 64 percentage points for high sensitivity C reactive protein, and lipoprotein(a) levels fell by 29 percent, while traditional lipids were unchanged. The confidence interval around the primary result excludes a relative risk reduction larger than about 12 percent, which argues against an effect of the size seen with interleukin-1 beta inhibition in the earlier CANTOS trial, at least in this population.
The safety balance ran against the drug. Overall serious adverse event rates were similar, 54.6 percent on ziltivekimab against 54.8 percent on placebo, but serious infections were more frequent on the drug (20.4 against 17.9 percent), as were deaths from infection (3.2 against 2.5 percent), cellulitis (2.9 against 1.0 percent), serious venous thromboembolism (1.6 against 0.6 percent) and platelet counts below 100 billion per litre (7.4 against 3.2 percent).
Novo Nordisk had already announced the topline failure on July 31, 2026, and in September it halted the HERMES trial of ziltivekimab in heart failure. The ARTEMIS trial, testing the drug in patients who have had a heart attack, is still running. ZEUS was the first trial of interleukin-6 inhibition for atherosclerotic disease, and its investigators stress that it tests this drug in this population rather than the whole inflammation hypothesis, but for Novo the cardiovascular programme built on the antibody now rests on a single remaining outcomes trial.