The New England Journal of Medicine · Nov 7, 2026
Interleukin-6 Inhibition with Ziltivekimab for Atherosclerotic Disease
By Ridker PM, Lincoff AM, Marx N et al.
Background The inflammatory cytokine interleukin-6 is hypothesized to be a therapeutic target for patients with atherosclerotic cardiovascular disease and chronic kidney disease. Whether neutralizing interleukin-6 levels with ziltivekimab, a monoclonal antibody, reduces the risk of adverse cardiovascular events remains unknown. Methods We conducted a multinational, double-blind, randomized, placebo-controlled trial involving adults with established atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation (defined by a high-sensitivity C-reactive protein [CRP] level of ≥2 mg per liter). Patients were randomly assigned in a 1:1 ratio to receive subcutaneous ziltivekimab (15 mg once monthly) or placebo. The primary efficacy end point was a 3-point major adverse cardiovascular event (MACE). This composite end point included death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results A total of 6376 patients were included in the full analysis population: 3184 were assigned to receive ziltivekimab and 3192 to receive placebo. The mean age of the patients was 69.4 years, and 27.5% were women. At 24 months, the between-group difference in the median percent change in the levels of inflammatory biomarkers among patients receiving ziltivekimab as compared with those receiving placebo was −76 percentage points for free interleukin-6 and −64 percentage points for high-sensitivity CRP. During a median follow-up of 33 months, a primary end-point event occurred in 561 patients (17.6%) in the ziltivekimab group and in 565 patients (17.7%) in the placebo group (hazard ratio, 0.99; 95% confidence interval, 0.88 to 1.11; P=0.84). Serious adverse events occurred in 54.6% of the patients in the ziltivekimab group and in 54.8% of those in the placebo group; serious infections occurred in 20.4% and 17.9%, respectively. Conclusions Among patients with atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation, a strategy of lowering interleukin-6 levels with ziltivekimab did not result in a lower risk of cardiovascular events than placebo. (Funded by Novo Nordisk; ZEUS ClinicalTrials.gov number, NCT05021835.)