The received view in cardiology and a view that seems to me to pull so many disparate mechanistic and functional explanations together is that inflammation plays a causal or strongly facilitative role in ASCVD.
The ZEUS trial findings appear to run counter to that view.
ZEUS targeted patients who had elevated hsCRP, established ASCVD, and CKD. More than 6000 patients were enrolled at 500 sites in 32 countries. The primary endpoints were MI, Stroke, and CV death. The recent press release from Novo Nordisk said that its drug (ziltivekimab) did not reduce the primary endpoint vs placebo (hazard ratio, 0.99; 95% CI, 0.88-1.11). The null result occurred despite the finding that the drug did exactly what it was designed to do: reduce both IL-6 and hsCRP levels. The tight confidence intervals render a false-negative finding unlikely.
Of course, this is one study and participants were well advanced in a complex disease state but it still gives pause.
https://www.medscape.com/viewarticle/rethinking-inflammation-and-ascvd-four-lessons-zeus-trial-2026a1000rlm
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To me, this points to them targeting the wrong marker, namely il6.
The CANTOS Trial Targeting il1b led to a 15% reduction in MACE without altering cholesterol levels.
The COLCOT & LoDoCo2 Trials saw Low-dose colchicine, achieve 23% to 31% reductions in MACE in patients with coronary artery disease, leading to FDA approval for cardiovascular risk reduction. Colchicine targets NLRP3 to reduce hscrp.
So the issue is that tjetr are many ways to lower hscrp, but not all of them lead to good clinical outcomes.
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Il-6 is a sign of the presence of senescent cells. If you take the sign off the cell that does not stop it being senescent.
I think IL-10 is causative, but would not try to stop that either.
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Anoter likely explanation is that IL6 sits too much downstream. Both IL11b and NLRP3 sit upstream of IL6, and both yielded MACE reductions.