ZEUS Trial: Ziltivekimab Fails to Reduce MACE in ASCVD Patients

Ziltivekimab does not reduce the risk of MACE in patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and inflammation beyond what occurs with placebo, according to top-line results from the phase III ZEUS trial released by drugmaker Novo Nordisk. 

The fully human monoclonal antibody targets the interleukin-6 (IL-6) pathway to reduce inflammation, with the hope that it would thereby improve outcomes. However, this did not come to pass.

“ZEUS was designed to test whether inhibition of the IL-6 pathway could translate reductions in cardiovascular inflammation into fewer major cardiovascular events. Although ziltivekimab produced the expected biological effect, this did not result in MACE benefits in this population,” Novo Nordisk’s chief scientific officer, Martin Holst Lange, said in a press release.

The double-blind, placebo-controlled trial enrolled more than 6,300 individuals with ASCVD, CKD, and high-sensitivity C-reactive protein (hs-CRP) levels ≥ 2 mg/L. Participants were randomized to once-monthly ziltivekimab 15 mg or placebo. Although the drug reduced IL-6 and hs-CRP levels, as expected, there was no accompanying reduction in the combined risk of CV death, nonfatal MI, or nonfatal stroke with ziltivekimab versus placebo (HR 0.99; 95% CI 0.88-1.11).

Adverse events and serious adverse events, as well as all-cause mortality, did not differ between the study arms. However, as would be expected when targeting IL-6, the ziltivekimab-treated patients had a higher rate of serious infections than did the placebo group.

Novo Nordisk said the HERMES and the ARTEMIS trials, which are testing ziltivekimab in patients with heart failure and those who have had an MI, respectively, will continue as planned. Full results from ZEUS will be presented later this year at a scientific conference.

The negative outcome is already spurring debate, with cardiologists taking to social media to discuss whether this marks an end to the inflammatory hypothesis of cardiovascular disease or should at least inspire a rethink.

Last October, an American College of Cardiology scientific statement, while acknowledging some uncertainties, asserted that clinicians should take inflammation into account when addressing cardiovascular risk.

The 2019 US primary prevention guidelines consider “persistently elevated inflammatory markers” to be a risk-enhancing factor. Based on positive findings from the LoDoCo2 trial, the US Food and Drug Administration approved colchicine in 2023 as the first anti-inflammatory drug to prevent CV events in patients who have established ASCVD or are at risk of developing it. Colchicine’s use is also endorsed by both European and South American CV prevention guidelines and approved by Health Canada.

Yet the field is not without controversy—most recently, results from the CLEAR SYNERGY (OASIS 9) trial, released in late 2024, disappointingly showed that colchicine fails to reduce MACE when used in patients treated with PCI after acute MI.