In the ZEUS trial, the antibody ziltivekimab reduced IL-6, an inflammatory signaling protein, but did not lower the risk of heart attack, stroke, or cardiovascular death
In the ZEUS trial, the antibody ziltivekimab reduced IL-6, an inflammatory signaling protein, but did not lower the risk of heart attack, stroke, or cardiovascular death
On August 14, geneticist Marios Georgakis explained why this result does not contradict genetic studies of the IL6 gene. Naturally occurring DNA variants exert their effects throughout life, whereas treatment began only after participants had already developed vascular disease.
The ZEUS trial included 6 385 people with atherosclerotic cardiovascular disease and chronic kidney disease. They received ziltivekimab or placebo once a month. The researchers measured the time to the first major cardiovascular event: death from a cardiovascular cause, nonfatal heart attack, or stroke. According to data from the company developing the drug, the antibody reduced free IL-6 and hsCRP, a blood marker of inflammation. The hazard ratio for the primary outcome was 0,99, with a 95-percent confidence interval from 0,88 to 1,11.
Genetic evidence provided another part of the rationale for the program. In a 2025 study, researchers constructed a score from 12 naturally occurring variants near the IL6 gene. Its profile across eight biomarkers resembled the effects of ziltivekimab. The resulting reduction in IL-6 signaling was associated with a lower lifetime risk of coronary artery disease, peripheral artery disease, and atherosclerotic stroke.
These variants slightly reduce IL-6 signaling from birth. They therefore help researchers assess how this pathway affects disease risk over several decades. ZEUS tested a different question: whether monthly IL-6 blockade reduces the number of severe events in people whose arteries are already affected by atherosclerosis.
hsCRP is produced in response to IL-6 signaling, so its reduction confirms that the antibody acted on this pathway. In his analysis of the trial, Georgakis writes:
“A reduction in CRP alone shows only that an IL-6 inhibitor is suppressing IL-6. It does not show whether the drug affects the blood vessels.”
Georgakis argues that early drug development should include direct measurements of the atherosclerotic plaque itself, including whether it grows and whether its inflammation or stability changes. An early Cyclarity trial is testing the removal of 7KC, an oxidized form of cholesterol. The researchers then plan to use computed tomography to measure separately whether plaque volume changes.
Such an intermediate test can show whether a drug modifies vascular disease before a phase III trial begins counting heart attacks, strokes, and deaths.