ZEUS Trial: IL-6 Inhibition Fails to Cut Cardiovascular Events Save

Know-it-now

• ZEUS was a phase 3 trial testing IL-6 inhibition with ziltivekimab in over 6,000 high risk cardiovascular patients and failed to show improved outcomes
• Atherosclerosis may have an inflammatory component, but anti-inflammatory therapies have not shown benefit (ZEUS, CANTO, CIRT, COLCOT, LoDoCo2).  IL-6 and IL-1 aren’t prime drivers.
• Biomarker targeting (IL-6 & CRP) isn’t enough.

The phase 3 ZEUS trial (published in JAMA Dec. 2025)  tested the IL-6 ligand inhibitor ziltivekimab (ZVK) in over 6,000 patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and elevated hsCRP—a population enriched for an inflammatory driver of risk. Although ZVK significantly lowered IL-6 and CRP levels, it did not improved outcomes (HR 0.99 (95% CI, 0.88–1.11) for MI, stroke, or CV death.

All-cause mortality was unchanged and serious infections were more common with ziltivekimab.  

Rheumatologists are familiar with inflammation driven disease and higher CV risks that maybe abrogated by DMARDs or biologics.  We curiously watch as our antirheumatic therapies have been tested in cardiology with mixed results; this includes IL-1 inhibitor (CANTOS study), IL-6 inhibitor (ZEUS), methotrexate (CIRT) and colchicine (COLCOT, LoDoCo2) studies..

ZEUS doesn't disprove vascular inflammation biology, but it undercuts the assumption that lowering an inflammatory biomarker pharmacologically reliably lowers CV risk. 

Sources: Ridker PM et al. JAMA Cardiol 2026;11(1):89-97 (ZEUS design/baseline);

Mandrola JM. Rethinking Inflammation and ASCVD: Four Lessons From the ZEUS Trial.

Medscape, August 12, 2026; Ridker PM et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events (CIRT). N Engl J Med 2019;380(8):752-762.