Novo Nordisk’s phase 3 Zeus trial of ziltivekimab, an IL-6 inhibitor intended to reduce cardiovascular inflammation risk, missed its primary endpoint in a population with atherosclerotic cardiovascular disease, chronic kidney disease, and inflammation. The mechanism inhibited the IL-6 pathway and lowered high-sensitivity C-reactive protein, but did not translate into a statistically meaningful reduction in major adverse cardiovascular events. Novo reported a hazard ratio of 0.99 (95% CI 0.88–1.11) versus placebo, with more than 6,300 patients enrolled. The failure triggered renewed scrutiny of the broader cardiovascular inflammation hypothesis and adds pressure on Novo’s pipeline planning as it seeks portfolio diversification. Novo indicated it still has paths to salvage the concept through ongoing Artemis and Hermes studies, signaling that decision-making may hinge on whether other inflammatory readouts can prove predictive for clinical endpoints.