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Patients with chronic kidney disease face a high risk of heart attack and stroke, even with well-controlled cholesterol and blood pressure. Part of this residual risk has long been attributed to chronic inflammation. CRP and interleukin-6 are often elevated in kidney disease and predict events. The idea is obvious: lower inflammation, lower risk.
The ZEUS trial, now published in the New England Journal of Medicine, put this idea to the test.
Why interleukin-6
Several lines of evidence pointed to interleukin-6. Genetic variants weakening signalling through the interleukin-6 receptor are associated with less atherosclerosis. In CANTOS, an antibody against interleukin-1β reduced cardiovascular events, and the effect grew with the reduction in downstream interleukin-6. In the phase 2 RESCUE trial, ziltivekimab substantially lowered CRP in patients with chronic kidney disease.
Study design
ZEUS was a double-blind, placebo-controlled, event-driven trial at 757 sites in 38 countries. Adults qualified with three features: established atherosclerotic disease, chronic kidney disease (eGFR 15 to below 60 ml/min/1.73 m², or eGFR of 60 or more with a urinary albumin-to-creatinine ratio of at least 200 mg/g), and high-sensitivity CRP of at least 2 mg/l. They received 15 mg ziltivekimab subcutaneously once a month or placebo.
The primary endpoint was the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. The trial was powered at 95% to detect a 20% relative reduction.
6376 patients were analysed. Mean age was 69.4 years and 27.5% were women. 65.8% had diabetes and 42.2% heart failure. Mean eGFR was 44.5, median CRP 4.5 mg/l and median LDL 71 mg/dl. 92.6% were already on lipid-lowering therapy.
Results
Biologically, ziltivekimab worked. At 24 months, the reduction in free interleukin-6 exceeded placebo by 76 percentage points and the reduction in CRP by 64 percentage points.
Clinically, there was no benefit. After a median of 33 months, the primary endpoint occurred in 561 of 3184 patients (17.6%) on ziltivekimab and 565 of 3192 (17.7%) on placebo. The hazard ratio was 0.99 (95% CI 0.88 to 1.11, p = 0.84). With 1126 events, the trial exceeded the planned 1044.
Secondary endpoints were equally balanced. Cardiovascular death 11.1% versus 11.2%, all-cause death 16.9% versus 17.0% (HR 0.99). The composite kidney endpoint of eGFR decline of at least 40%, kidney failure or cardiovascular death occurred in 20.2% versus 19.3% (HR 1.05, 95% CI 0.94 to 1.17).
Safety
Serious adverse events were equally frequent at 54.6% versus 54.8%. The details differ. Serious infections occurred in 20.4% versus 17.9%, deaths from infection in 3.2% versus 2.5%. Cellulitis was more frequent (2.9% vs 1.0%), as was sepsis (1.9% vs 1.3%). Serious venous thromboembolism occurred in 1.6% versus 0.6%, serious haemorrhage in 5.1% versus 4.0%. Platelet counts below 100,000/µl were seen in 7.4% versus 3.2%. The authors explain the excess of thromboembolism only partly by known risk factors.
How the authors interpret the result
The authors discuss four explanations. First, disease in ZEUS was more advanced than in CANTOS: patients were on average ten years older, the placebo event rate was 6.8 instead of 4.5 per 100 person-years, and mortality 6.2 instead of 3.0. Second, only inhibition further upstream, at interleukin-1β or the inflammasome, might work. Third, the genetic data point to the interleukin-6 receptor, whereas ziltivekimab binds the cytokine itself. A receptor blocker might act differently. Fourth, CRP might not be the right marker to select patients with modifiable inflammatory risk.
Limitations
A mean treatment exposure of 33 months is short for atherosclerosis, and 14% of patients did not adhere to treatment. Few women were enrolled. The findings apply to ziltivekimab in this population and do not transfer to receptor blockers or other patient groups. The manufacturer funded and ran the trial and analysed the data, with independent verification at an academic centre. Seven authors are employees of the manufacturer. Two further ziltivekimab trials are ongoing, in heart failure with preserved ejection fraction and in acute coronary syndrome.
What this means for practice
ZEUS is a clear negative result from a large, well-conducted trial. For patients with chronic kidney disease and atherosclerosis, treatment does not change.
- Elevated CRP remains a risk marker. As a treatment target in kidney patients, this trial does not support it.
- A lowered biomarker does not replace a clinical endpoint. ZEUS shows this clearly: strong effect in the lab, no effect on patients.
- Anti-inflammatory treatment comes at a price. More infections and thromboembolism weigh heavily in multimorbid kidney patients.
I am happy to discuss how you view inflammation as a target in your kidney patients on LinkedIn.
Source: Ridker PM, Lincoff AM, Marx N, et al., Perkovic V, for the ZEUS Investigators. Interleukin-6 Inhibition with Ziltivekimab for Atherosclerotic Disease. N Engl J Med, online 7 Nov 2026. doi:10.1056/NEJMoa2612126. ClinicalTrials.gov NCT05021835.
Source: DOI: 10.1056/NEJMoa2612126 · Original article