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Dennis Wolf: Is ZEUS the End of Anti-Inflammatory Therapy in Atherosclerosis?

Dennis Wolf/LinkedIn

Aug 16, 2026, 06:19

Dennis Wolf: Is ZEUS the End of Anti-Inflammatory Therapy in Atherosclerosis?

Dennis Wolf, Professor of Cardiovascular Systems Immunology at University of Freiburg, shared a post on LinkedIn:

”Is ZEUS the end of anti-inflammatory therapy in atherosclerosis? I don’t think so.

ZEUS is a major setback: ziltivekimab engaged its target, yet did not reduce cardiovascular events. CANTOS provided proof-of-concept, but canakinumab never entered routine cardiovascular care.

Should we abandon anti-inflammatory therapy? I would argue the opposite. ZEUS tells us that we need to become more precise about whom, when and how we treat.

Four of my thoughts on why ZEUS may have failed:

Right population but wrong stage?

ZEUS selected patients with ASCVD, CKD and elevated hsCRP: a population at high risk, but also with advanced, often heavily calcified vascular disease. In CKD, atherothrombosis coexists with calcification, myocardial disease, arrhythmia and other cardiorenal mechanisms.

High event risk is not necessarily high IL-6-modifiable risk. Perhaps targeting inflammation at this stage is simply too late.

Did one hsCRP measurement identify persistent inflammatory risk?

ZEUS used hsCRP at or above 2 mg/L for enrichment. Yet one elevated value does not necessarily indicate persistent inflammation. POSEIDON reported elevated hsCRP in approximately 40 percentStay updated with Hemostasis Today. of patients with ASCVD and CKD. Our own serial hsCRP data suggest that classification becomes more selective with repeated measurements.

A transient elevation may therefore qualify a patient without identifying the inflammatory phenotype treatment needs to modify. CANTOS adds a clue: patients achieving on-treatment hsCRP below 2 mg/L derived greater benefit.

Future trials may need to enrich for persistent inflammation.

Genetic IL-6R modulation is different from pharmacological IL-6 blockade.

As Ziad Mallat Mallat recently pointed out, genetic evidence for the IL-6 pathway is not biologically equivalent to pharmacological IL-6 neutralisation. Genetic variants reflect lifelong modulation; ZEUS introduced blockade late in life. He also highlighted experimental work suggesting IL-6 deficiency can promote larger lesions and calcification.

Did RESCUE mainly demonstrate target engagement?

RESCUE showed profound hsCRP reductions with ziltivekimab. But CRP is directly downstream of IL-6 signalling. If IL-6 is neutralised, CRP will fall dramatically.

Thus, hsCRP becomes an excellent pharmacodynamic marker of target engagement but not necessarily evidence that the upstream biology driving cardiovascular events has disappeared. Rheumatologists know this well: under IL-6 pathway inhibition, CRP can become dissociated from inflammatory disease activity.

For me, ZEUS does not close the chapter on inflammation in atherosclerosis.

Selecting high-risk patients with one hsCRP value, blocking one pathway late in advanced disease, and monitoring a biomarker intrinsically linked to that pathway may simply not be enough.

Future trials need better inflammatory phenotyping, repeated biomarker assessment, pathway enrichment – and the right therapeutic window.

We should learn from ZEUS. But we should certainly not give up on inflammation.”

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