JAMA CardiolHeart & CardiovascularRCTDecember 10, 2025

Rationale, Design, and Baseline Clinical Characteristics of the Ziltivekimab Cardiovascular Outcomes Trial: Interleukin-6 Inhibition and Atherosclerotic Event Rate Reduction.

Ridker PM, Baeres FMM, Hveplund A, Engelmann MMD, Hovingh GK, Lincoff AM, Marx N, Navar AM, Sattar N, Tuttle K, Perkovic V

View on PubMed DOI: 10.1001/jamacardio.2025.4491

Key Finding

The ZEUS trial enrolled 6,376 high-risk patients with heart disease, kidney disease, and inflammation to test whether blocking interleukin-6 with ziltivekimab can prevent heart attacks, strokes, and kidney decline - results still pending.

What This Study Found

Think of chronic inflammation like a slow-burning fire inside your blood vessels that gradually damages your heart and kidneys. This fire is fueled by a protein called interleukin-6 (IL-6), which acts like gasoline on the flames. The ZEUS trial is testing whether a new drug called ziltivekimab can act like a fire extinguisher, blocking IL-6 to cool down this dangerous inflammation. The researchers recruited 6,376 patients who already have this inflammatory fire burning hot - they all have existing heart disease, kidney disease (average kidney function at 44.5 mL/min, which is moderate impairment), and elevated inflammation markers (median C-reactive protein of 4.5 mg/L, which is quite high since normal is under 3). Half got monthly injections of ziltivekimab, half got placebo shots. These aren't your typical healthy volunteers - this is a high-risk group where 92% have high blood pressure, 66% have diabetes, and 41% have heart failure. The trial will track whether the inflammation-blocking drug prevents major cardiovascular events like heart attacks and strokes, and whether it slows the decline of kidney function. Notably, 37% were already on SGLT2 inhibitors and 11% on GLP-1 drugs, showing this adds to existing treatments rather than replacing them.

Statistics Decoded

6,376 participants makes this a large, well-powered study. Mean age of 69.5 years with 27.5% female shows this targets older, predominantly male populations at highest risk. The baseline eGFR of 44.5 mL/min indicates moderate kidney disease (normal is >90). Median hsCRP of 4.5 mg/L is significantly elevated (normal <3 mg/L), confirming these patients have serious inflammation. The 1:1 randomization means 3,188 got drug, 3,188 got placebo - this equal split maximizes statistical power to detect differences. The high rates of diabetes (65.7%) and heart failure (41.3%) show these are very sick patients where benefits would be most meaningful.

Why This Matters

If successful, this would be the first drug to prevent heart attacks and kidney decline by targeting inflammation rather than cholesterol or blood pressure, potentially helping millions of CKD patients who remain at high cardiovascular risk despite current treatments. This could establish inflammation blocking as a new pillar of cardiovascular prevention alongside statins and blood pressure medications.

Original Abstract

Cardiovascular inflammation is a major determinant of atherosclerotic disease, and inhibition of the central signaling cytokine, interleukin 6 (IL-6), is a promising target for intervention. Patients with chronic kidney disease (CKD) commonly have plasma elevations of inflammatory biomarkers, such as high-sensitivity C-reactive protein (hsCRP) and IL-6, and are at high risk for life-threatening atherosclerotic events as well as loss of kidney function and might therefore benefit from IL-6 inhibition. The Ziltivekimab Cardiovascular Outcomes Trial (ZEUS; NCT05021835) will determine the safety and efficacy of IL-6 inhibition with ziltivekimab among patients with atherosclerotic cardiovascular disease (ASCVD), CKD, and systemic inflammation. ZEUS is a multinational, double-blind, placebo-controlled, event-driven, randomized clinical trial inclusive of 6376 participants with ASCVD, CKD, and an hsCRP level greater than or equal to 2 mg/L who were randomized in a 1:1 fashion to receive either ziltivekimab, 15 mg, administered subcutaneously every month or matching placebo. At randomization, mean age was 69.5 years, 27.5% were female, 92.0% had hypertension, 65.7% had diabetes, and 41.3% had heart failure. At baseline, the mean estimated glomerular filtration rate (eGFR) was 44.5 mL/min/1.73 m2, mean low-density lipoprotein cholesterol level was 77.7 mg/dL, median hsCRP level was 4.5 mg/L, and median IL-6 level was 4.9 pg/mL. At enrollment, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists were being used by 36.8% and 11.3% of the cohort, respectively. The primary outcome is 3-point major adverse cardiovascular events. Secondary cardiovascular outcomes include (1) an expanded major adverse cardiovascular event outcome including hospitalization for unstable angina requiring urgent coronary revascularization, (2) hospitalizations for heart failure or urgent heart failure visits or cardiovascular death, and (3) all-cause mortality. The secondary kidney outcome is a composite of greater than 40% decline in eGFR, eGFR less than 15 mL/min/1.73 m2, dialysis, kidney transplant, death from kidney disease, or cardiovascular death. The ZEUS randomized clinical trial will formally test the hypothesis that IL-6 inhibition with ziltivekimab will lower incident cardiovascular event rates and potentially slow kidney decline among participants with known ASCVD, CKD, and elevated hsCRP. If successful, the ZEUS 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.