Ziltivekimab lowered inflammation but did not cut cardiovascular events

For more than a decade, one of the most influential ideas in cardiology has been that inflammation, not just cholesterol, drives the artery disease behind heart attacks and strokes. A large trial presented at the American Heart Association's 2026 Scientific Sessions and published in the New England Journal of Medicine on 7 November put a clean version of that idea to the test — and it did not hold up [s1].

The hypothesis being tested

Cholesterol-lowering is established beyond doubt, but many people keep having cardiovascular events despite well-controlled cholesterol. Residual inflammation has long been the leading candidate explanation. Interleukin-6 is a signalling molecule that sits in the middle of that inflammatory pathway, and high-sensitivity C-reactive protein (CRP) is the blood marker used to track it [s1].

Ziltivekimab is a monoclonal antibody designed to neutralise interleukin-6. The ZEUS trial, registered as NCT05021835, asked the direct question: in people who already have atherosclerotic cardiovascular disease plus chronic kidney disease and measurable inflammation, does lowering interleukin-6 reduce the rate of cardiovascular events [s1][s2]?

How the trial was built

ZEUS was a multinational, double-blind, randomised, placebo-controlled trial [s1]. Participants were adults with established atherosclerotic cardiovascular disease, chronic kidney disease, and cardiovascular inflammation, defined as a high-sensitivity CRP of at least 2 mg per litre [s1]. They were assigned in a 1:1 ratio to receive subcutaneous ziltivekimab at 15 mg once a month or matching placebo [s1].

The primary efficacy endpoint was a three-point major adverse cardiovascular event — a composite of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke [s1].

A total of 6,376 patients were included in the full analysis population: 3,184 assigned to ziltivekimab and 3,192 to placebo [s1]. Their mean age was 69.4 years, and 27.5% were women [s1].

What it found

The drug did what it was designed to do at the level of inflammation. At 24 months, the between-group difference in the median percent change in inflammatory markers favoured ziltivekimab by 76 percentage points for free interleukin-6 and by 64 percentage points for high-sensitivity CRP [s1]. These are large reductions — the biology worked.

The clinical result did not follow. Over a median follow-up of 33 months, a primary-endpoint event occurred in 561 patients (17.6%) in the ziltivekimab group and in 565 patients (17.7%) in the placebo group [s1]. The hazard ratio was 0.99, with a 95% confidence interval of 0.88 to 1.11 and a P value of 0.84 — about as flat a null result as a large cardiovascular trial produces [s1].

On safety, serious adverse events were essentially identical: 54.6% in the ziltivekimab group and 54.8% in the placebo group [s1]. Serious infections, a recognised concern when a drug dampens the immune system's signalling, were somewhat more common with the antibody: 20.4% versus 17.9% [s1].

What is, and is not, established

ZEUS establishes something important precisely because it is a null result. In this population — atherosclerosis with chronic kidney disease and raised CRP — reducing interleukin-6 with ziltivekimab, even though it drove inflammatory markers sharply down, did not reduce the rate of cardiovascular death, heart attack or stroke compared with placebo [s1]. The authors conclude as much directly [s1].

That matters for the broader inflammation hypothesis, but it does not settle it. ZEUS tested one molecule, one target, and one specific patient group chosen partly because chronic kidney disease carries a heavy inflammatory and cardiovascular burden. A null result here does not prove that inflammation is irrelevant to heart disease in general, nor that a different anti-inflammatory approach would fail. It does show that lowering a biomarker — even convincingly — is not the same as lowering risk, a lesson cardiology has learned repeatedly. The modestly higher rate of serious infections is the kind of trade-off that would weigh against a therapy that was not delivering clinical benefit [s1].

Ziltivekimab in this setting is investigational for cardiovascular prevention; this describes a trial, not an approved use. Nothing here is a reason to start or stop any treatment, which is a decision for a clinician who knows the full picture. This article describes research and is not medical advice.