Ziltivekimab Falls Short for Cutting Cardiovascular Events in ASCVD, CKD

Despite lowering inflammatory markers, treatment with the monoclonal antibody ziltivekimab did not reduce cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and CV inflammation.

Results of the ZEUS trial showed no reduction in the primary composite endpoint including death from CV causes, nonfatal myocardial infarction (MI), or nonfatal stroke with treatment. Over a median follow-up of 33 months, a primary endpoint event occurred in 561 patients (17.6%) in the investigational ziltivekimab group, and 565 patients (17.7%) in the placebo group (hazard ratio 0.99, 95% CI 0.88-1.11, P=0.84).

This was despite treatment producing substantial reductions in the inflammatory biomarkers free interleukin-6 (IL-6), a 76% placebo-adjusted change from baseline, and high-sensitivity C-reactive protein (CRP), a 64% placebo-adjusted change, reported Paul M. Ridker, MD, of Harvard Medical School and Mass General Brigham Hospital in Boston, at the American Heart Association (AHA) annual meeting in Chicago. The results were published simultaneously in the New England Journal of Medicine. Topline ZEUS results were released July 2026.

Ridker and colleagues confirmed though that high levels of inflammation were linked to events, with increasing tertiles of CRP and IL-6 predicting high risk of the primary endpoint and of all-cause death.

The results contrast with those of previous trials including CANTOS with canakinumab (Ilaris), plus LoDoCo2 and COLCOT, both using colchicine, that have proven anti-inflammatory therapy can reduce event rates in patients with stable coronary disease, Ridker said.

"The relevant question moving forward is what drug, in which patient group?" he noted. ZEUS included "a selected population with established ASCVD and significant CKD, raising the possibility that highly advanced disease may be less amenable to anti-inflammatory modification. The horse may already have been out of the barn."

Compared with the CANTOS study population, ZEUS patients had significant CKD, more diabetes and heart failure (HF), and the all-cause mortality rate over the trial was twice as high, suggesting "late-stage, non-modifiable disease," he said.

The other issue is whether results from Mendelian randomization studies can translate into clinical improvement. "We had very good genetic data that on an evolutionary basis, IL-6 levels were in the causal pathway," he said, but "genetic causality is not therapeutic reversibility. Both the Mendelian randomization and the clinical trials are correct." The question is whether a relatively short-term intervention later in life can make an impact on clinical outcomes.

Other trials are looking at ziltivekimab in different patient populations, including those who have HF with midrange or preserved ejection fraction (HERMES), and those with acute coronary ischemia (ARTEMIS). HERMES has also been halted due to futility, Ridker noted, but ARTEMIS has been allowed to continue, "so we're optimistic on that."

In the meantime, clinicians can still reduce inflammation through diet, exercise, and smoking cessation, he said, and available drugs including statins, colchicine, canakinumab, and GLP-1 drugs have all been shown to affect outcomes in patients with this residual inflammatory risk.

"We all know that the NLRP3 to IL-1 to IL-6 pathway is exceptionally complex," he concluded, "but several promising opportunities remain for downstream IL-6 inhibition, probably in a lower risk population with modifiable disease, and then some very exciting opportunities to move upstream, to target NLRP3 directly itself, where we have orally available agents for this process."

AHA discussant Priscilla Hsue, MD, of the University of California San Francisco, said she looked at a variety of factors that might explain these findings. "Was the drug given too late?" she concluded. "Was it the wrong drug targeting the ligand and not the receptor? Was it the wrong strategy going downstream as opposed to upstream?"

But she added that despite the neutral results, "Dr. Ridker and the ZEUS investigators should be congratulated. The results of this trial are critically important to our understanding of the biology of inflammation in atherosclerosis. I want to stress the take home from this session should not be that inflammation doesn't matter. Rather, the need for science, mechanistic studies, and trials is more important in 2026 than ever."

Ziltivekimab is a monoclonal antibody that directly targets the IL-6 ligand. The dose selected for the trial was 15 mg given subcutaneously once a month, shown in phase II study to substantially reduce CRP, Ridker noted.

The trial was a global, double-blind, randomized, placebo-controlled trial that included 6,376 patients with established ASCVD, CKD and CV inflammation, defined as a hs-CRP level of >2 mg per liter. Patients were randomly assigned to receive ziltivekimab (n=3,184) or placebo (n=3,192).

A similar lack of treatment effect was seen on secondary endpoints, including a 4-point major adverse CV event (MACE) endpoint of death from CV causes, nonfatal MI, or nonfatal stroke, plus hospitalization for unstable angina requiring urgent hospitalization, or a composite kidney endpoint, a composite HF endpoint, or all-cause mortality.

Serious adverse events were equal between groups, occurring in 54.6% of patients in the ziltivekimab group and in 54.8% on placebo. Serious infections occurred in 20.4% and 17.9%, respectively, which was a significant difference (P<0.05). Venous thromboembolism was also significantly higher with treatment (1.6% vs 0.6%), and there was an increase in hemorrhage that did not reach statistical significance.