Cardiovascular inflammation is a key driver of atherosclerotic disease, particularly among high-risk patients with chronic kidney disease (CKD). The Ziltivekimab Cardiovascular Outcomes Trial (ZEUS) has been designed to determine if targeting the interleukin-6 (IL-6) signalling pathway with ziltivekimab can improve outcomes in this population.¹

ZEUS (NCT05021835) is a multinational, double-blind, placebo-controlled, event-driven, randomised clinical trial. The study has enrolled 6,376 participants with established atherosclerotic cardiovascular disease (ASCVD), moderate to severe CKD, and systemic inflammation, defined as a high-sensitivity C-reactive protein (hsCRP) level of 2 mg/L or greater.¹

Participants were randomised on a 1:1 basis to receive either ziltivekimab 15 mg, administered subcutaneously once a month, or a matching placebo. The primary outcome is the time to first occurrence of 3-point major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

Key secondary outcomes include an expanded MACE composite, hospitalisations for heart failure, and all-cause mortality. A secondary kidney composite outcome will also be assessed, which includes a sustained decline in estimated glomerular filtration rate (eGFR) of over 40%, end-stage kidney disease, or death from kidney or cardiovascular causes.¹

The baseline characteristics of the trial cohort have been published. The mean age of participants was 69.5 years, and 27.5% were female. Comorbidities were common, with 92.0% having hypertension, 65.7% having diabetes, and 41.3% having heart failure. At randomisation, the mean eGFR was 44.5 mL/min/1.73 m², the median hsCRP was 4.5 mg/L, and the median IL-6 level was 4.9 pg/mL. A significant proportion of patients were receiving modern guideline-directed medical therapy, including sodium-glucose cotransporter-2 (SGLT2) inhibitors (36.8%) and glucagon-like peptide-1 (GLP-1) receptor agonists (11.3%).¹

The ZEUS trial will provide a formal test of the inflammation hypothesis in a high-risk population with both ASCVD and CKD. According to the study authors, a successful trial "would provide a fully novel approach for prevention of myocardial infarction, stroke, cardiovascular death, and kidney function decline among high-risk patients with CKD".¹ The results are anticipated to clarify the role of targeted IL-6 inhibition as a potential therapeutic strategy to reduce residual inflammatory risk.

This study was funded by Novo Nordisk.

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References

1. Ridker PM, Baeres FMM, Hveplund A, et al. Rationale, Design, and Baseline Clinical Characteristics of the Ziltivekimab Cardiovascular Outcomes Trial: Interleukin-6 Inhibition and Atherosclerotic Event Rate Reduction. JAMA Cardiol. Published online December 10, 2025. https://doi.org/10.1001/jamacardio.2025.4491