Novo Nordisk has reported that ziltivekimab, an investigational antibody targeting interleukin-6, failed to reduce the risk of major cardiovascular events in the Phase 3 ZEUS trial, despite producing the expected reductions in markers of inflammation.
The trial enrolled more than 6,300 people with atherosclerotic cardiovascular disease, chronic kidney disease, and elevated inflammation. Participants received either once-monthly ziltivekimab or placebo in addition to standard care. The primary outcome was major adverse cardiovascular events, or MACE, defined as cardiovascular death, nonfatal heart attack, or nonfatal stroke.
Ziltivekimab successfully inhibited the interleukin-6 pathway and lowered high-sensitivity C-reactive protein, but these biological changes did not translate into a statistically significant improvement in cardiovascular outcomes.
The trial reported a hazard ratio of 0.99 for major adverse cardiovascular events. A hazard ratio compares the rate at which an event occurs over time in a treatment group with the rate in a control group. A value of 1.0 indicates no difference between the groups, a value below 1.0 suggests a lower event rate with treatment, and a value above 1.0 suggests a higher event rate.
The reported 95% confidence interval ranged from 0.88 to 1.11. Because this interval includes 1.0, the result was not statistically significant. The study therefore did not provide sufficient evidence that ziltivekimab reduced the risk of cardiovascular death, nonfatal heart attack, or nonfatal stroke compared with placebo.
Overall rates of adverse events and serious adverse events were similar between the groups. However, serious infections occurred more frequently among participants receiving ziltivekimab, a known concern with treatments that suppress IL-6 activity. There was no difference in all-cause mortality.
The result is important beyond Novo Nordisk’s drug-development program. It shows that successfully inhibiting an inflammatory pathway and lowering associated biomarkers does not necessarily translate into fewer cardiovascular events. However, the topline findings do not establish that inflammation has no role in cardiovascular disease or that other anti-inflammatory approaches cannot provide benefit.
The findings are relevant to type 2 diabetes care because many people with diabetes also live with cardiovascular disease, chronic kidney disease, or both. Full ZEUS results are expected to be presented at a scientific meeting later in 2026. Two additional ziltivekimab trials, HERMES in heart failure and ARTEMIS following acute heart attack, are continuing, with results expected during the first half of 2027.
Sources
Novo Nordisk: "Novo Nordisk provides update on the ZEUS phase 3 trial in people with ASCVD, CKD and inflammation"
Fierce Biotech: "Novo Nordisk left praying to Artemis and Hermes to salvage CKD program after phase 3 fail"
BioPharma Dive: "Novo setback casts doubt on a new way to treat heart disease"