Cardiovascular inflammation has been the talk of the town in cardiology, and while Novo Nordisk was wise to pursue treating it, results from the ZEUS trial have led to a thunderous debate on whether or not it ever played a role in ASCVD.
- The ZEUS trial tested ziltivekimab, a monoclonal antibody that targets the IL-6 pathway to reduce inflammation.
- This trial design was built on the theory that lowering cardiovascular inflammation would translate into fewer CV events.
To test the inflammatory hypothesis directly, ZEUS enrolled more than 6,300 patients with ASCVD, CKD, and elevated inflammation (hs-CRP ≥2 mg/L), randomizing them to once-monthly ziltivekimab or placebo.
- The drug reduced both IL-6 and hs-CRP levels, which confirmed its ability to engage with those molecules.
- But this didn’t reduce the composite of CV death, nonfatal MI, or nonfatal stroke (HR: 0.99), which is a result about as flat as a trial can produce.
- Also, unsurprisingly, inhibiting IL-6 led to severe infections in some patients.
The result immediately reignited a running debate over whether inflammation is a treatable cause of cardiovascular events or merely a risk marker.
- Some cardiologists question whether ZEUS marks the end of the inflammatory hypothesis, while others argue lipids should have always been the MACE focus.
- Furthermore, the ACC’s October 2025 statement urging docs to factor inflammation into risk assessment looks less applicable than before.
It’s important to remember though, the broader anti-inflammatory story is mixed rather than uniformly negative.
- Colchicine, backed by the LoDoCo2 trial, became the first anti-inflammatory drug FDA-approved for CV event prevention in 2023 and is widely endorsed.
- On the other hand, the 2024 CLEAR SYNERGY trial found that colchicine failed to reduce MACE, meaning even it has an inconsistent track record.
However, Novo Nordisk isn’t abandoning the molecule. Two other ziltivekimab trials, HERMES in heart failure and ARTEMIS in post-MI patients, will continue as planned.
- Those trials test different populations, leaving open the possibility that IL-6 inhibition helps in settings other than the ASCVD/CKD group.
The Takeaway
While this trial isn’t a win for Novo, it’s a win for science. When a well-designed trial’s results are this flat, they help truly answer the hypothesis of whether or not reducing inflammation decreases MACE risk. The answer? A resounding “no.”
