Dipender Gill, Chief Executive Officer of Sequoia Genetics, shared on LinkedIn:
“Did ZEUS select patients at high cardiovascular risk, but with relatively little risk that was modifiable through IL-6 inhibition?
The ZEUS trial reported a neutral result for ziltivekimab, despite substantial reductions in free IL-6 and CRP.
The primary outcome of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke had a hazard ratio of 0.99 (95% CI 0.88–1.11).
However, the individual cardiovascular outcomes reveal an interesting pattern:
- Confirmed cardiovascular death: HR 0.88 (0.73–1.05)
- Nonfatal myocardial infarction: HR 0.97 (0.77–1.22)
- Nonfatal stroke: HR 0.92 (0.71–1.18)
All three point estimates favour treatment, although every 95% confidence interval includes no effect.
The primary outcome also included deaths from undetermined causes. These were numerically more frequent with ziltivekimab (141 versus 114; HR 1.24, 95% CI 0.97–1.59), largely offsetting the numerical reduction in confirmed cardiovascular deaths. This pattern leaves open the possibility of a modest benefit for some cardiovascular outcomes, but does not establish one.
Could the characteristics of the selected population help explain the findings?
ZEUS enrolled patients with established atherosclerotic cardiovascular disease, chronic kidney disease and elevated CRP. Mean age was 69 years and mean eGFR was 44.5 mL/min/1.73 m²; 66% had diabetes and 42% had heart failure.
The event profile was also notable. In the placebo group, cardiovascular death, including undetermined causes, occurred at 4.1 per 100 person-years, compared with 1.7 for nonfatal MI and 1.4 for nonfatal stroke.
My hypothesis is that ZEUS selected patients at particularly high cardiovascular risk, without necessarily enriching for cardiovascular events that could be prevented through IL-6 inhibition.
This could help reconcile the rationale for targeting IL-6 in atherosclerosis with the neutral overall ZEUS result, while leaving open the possibility of benefit in patients whose cardiovascular risk is more dependent on IL-6-mediated mechanisms.
Enriching a trial for cardiovascular risk is not necessarily equivalent to enriching it for cardiovascular risk that is modifiable through the intervention.”
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