Ziltivekimab, an interleukin-6 (IL-6) inhibitor, did not reduce cardiovascular events compared with placebo in patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and inflammation in the phase 3 ZEUS trial, according to results presented at the American Heart Association (AHA) Scientific Sessions 2026 and published in the New England Journal of Medicine.1
Ziltivekimab, a monoclonal antibody neutralizing the IL-6 ligand, lowered high-sensitivity C-reactive protein (hsCRP) and other inflammatory biomarkers in a phase 2 study of patients with CKD. The ZEUS rationale drew on mendelian randomization data implicating IL-6 signaling in atherosclerosis and on CANTOS, in which interleukin-1β inhibition with canakinumab lowered recurrent cardiovascular event rates.1
“The findings from ZEUS illustrate why clinical trials are so important: We don’t yet have all of the answers and science is often about trial and error,” said Paul M. Ridker, MD, Center for Cardiovascular Disease Prevention, Mass General Brigham. “We already know from prior studies that targeting inflammation can reduce rates of heart attack and stroke. The critical question is which drug works best in which patients.”2
Ziltivekimab efficacy on major adverse cardiovascular events in ZEUS
ZEUS was a double-blind, placebo-controlled, event-driven trial conducted at 757 sites in 38 countries, with enrollment from September 2021 through December 2024. Eligible adults had ASCVD, hsCRP of at least 2 mg/L, and CKD, defined as an estimated glomerular filtration rate (eGFR) of 15 to less than 60 mL/min/1.73 m².1
Patients with an eGFR of at least 60 mL/min/1.73 m² qualified with a urinary albumin-to-creatinine ratio of at least 200 mg/g.1
Patients were randomized 1:1 to subcutaneous ziltivekimab 15 mg once monthly or placebo, and the full analysis population included 6376 patients, with 3184 receiving ziltivekimab and 3192 receiving placebo.1
Mean age was 69.4 years, 27.5% were women, 65.8% had diabetes, and 42.2% had heart failure. Median baseline hsCRP was 4.5 mg/L, and mean eGFR was 44.5 mL/min/1.73 m².1
At 24 months, the between-group difference in median percent change was −76 percentage points for free IL-6 and −64 percentage points for hsCRP. Over a median follow-up of 33 months, 3-point major adverse cardiovascular events (MACE) occurred in 17.6% (561/3184) of the ziltivekimab group and 17.7% (565/3192) of the placebo group. The hazard ratio (HR) was 0.99 (95% CI, 0.88–1.11; P = .84).1
Secondary end points and safety of IL-6 inhibition with ziltivekimab
None of the confirmatory secondary end points favored ziltivekimab.1 The 4-point MACE end point occurred in 18.4% vs 18.5% of patients (HR, 0.99; 95% CI, 0.88–1.10), and death from any cause in 16.9% vs 17.0% (HR, 0.99; 95% CI, 0.88–1.12).1 The composite kidney end point occurred in 20.2% vs 19.3% (HR, 1.05; 95% CI, 0.94–1.17).1
Serious adverse events occurred in 54.6% of the ziltivekimab group and 54.8% of the placebo group.1 Serious infections were more frequent with ziltivekimab (20.4% vs 17.9%), as were deaths from infection (3.2% vs 2.5%) and cellulitis (2.9% vs 1.0%).1 Serious venous thromboembolism occurred in 1.6% vs 0.6% of patients, and platelet counts below 100×10⁹/L in 7.4% vs 3.2%.1
According to the investigators, established risk factors only partly explained the venous thromboembolism imbalance, and whether it reflects IL-6 pathway inhibition, the enrolled population, or chance remains uncertain.1 The press release from Mass General Brigham characterized safety as reassuring, with no adverse effect on total mortality.2
“Given our neutral findings, one logical next step is to move upstream, instead of downstream, to find the right target,” said Ridker. “For example, there are multiple new agents in development that can inhibit the upstream NLRP3 inflammasome. At the same time, it remains quite possible that downstream IL-6 inhibition is in fact effective, but that ZEUS targeted the wrong patient population.”2
ZEUS participants were about 10 years older than those in CANTOS and carried a heavier burden of CKD, diabetes, and heart failure.1 Placebo-group 3-point MACE incidence was 6.8 per 100 person-years in ZEUS vs 4.5 in CANTOS.1 The authors also noted genetic evidence points most consistently to IL6R variants, while ligand inhibitors such as ziltivekimab do not block the IL-6 receptor.1
Ziltivekimab remains under study in 2 additional trials: HERMES in heart failure with midrange or preserved ejection fraction and ARTEMIS in acute coronary ischemia. Ridker also described low-dose colchicine, approved by the US Food and Drug Administration to lower rates of myocardial infarction and stroke, as underused in patients with stable atherosclerosis.2
References
Ridker PM, Lincoff AM, Marx N, et al. Interleukin-6 inhibition with ziltivekimab for atherosclerotic disease. N Engl J Med. Published online November 7, 2026. doi:10.1056/NEJMoa2612126
Mass General Brigham. Heart researchers unpack neutral findings from ZEUS, an anti-inflammatory clinical trial. EurekAlert! Published November 7, 2026. Accessed November 7, 2026. https://www.eurekalert.org/news-releases/1150801
