Novo Nordisk Heart Drug Fails to Cut Cardiovascular Events in Full ZEUS Trial Results

Novo Nordisk’s experimental anti-inflammatory drug ziltivekimab did not significantly reduce heart attacks, strokes or cardiovascular deaths in a large clinical trial, even though it substantially lowered the biological markers it was designed to target. Full results presented Saturday at the American Heart Association’s Scientific Sessions in Chicago put detailed numbers behind a setback the Danish drugmaker first disclosed in July.

The phase 3 ZEUS trial enrolled 6,376 adults who already had atherosclerotic cardiovascular disease, chronic kidney disease and elevated inflammation. The study tested whether blocking interleukin-6, a protein involved in inflammatory signaling, could protect a group at particularly high risk of serious cardiovascular complications. Researchers found almost no difference in the primary outcome between patients receiving the drug and those given placebo.

Inflammation markers fell, but heart outcomes were nearly identical

During a median follow-up of about 33 months, the trial’s primary endpoint occurred in 561 patients assigned to ziltivekimab, compared with 565 assigned to placebo. Those totals corresponded to roughly 17.6% and 17.7% of the respective treatment groups. The primary measure combined cardiovascular death, nonfatal heart attack and nonfatal stroke, rather than treating any one of those events as the sole measure of success.

The American Heart Association’s account of the findings reported that ziltivekimab lowered high-sensitivity C-reactive protein, or hs-CRP, by 64% and free interleukin-6 by 76% relative to placebo. Both are measures associated with inflammation, but reducing their levels was not enough to produce a statistically significant improvement in the cardiovascular outcomes the trial was designed to assess.

That distinction is central to the result. A drug can affect a molecular target as intended without proving that patients live longer or avoid serious illness. The hazard ratio for the primary endpoint was 0.99, with a 95% confidence interval of 0.88 to 1.11, according to Novo Nordisk’s earlier disclosure. A figure close to 1 indicates that the observed event rates were essentially the same, while the confidence interval shows the result did not establish a meaningful reduction in risk.

Deaths from any cause were also similar: 538 in the ziltivekimab arm and 542 in the placebo arm. Investigators saw broadly comparable rates of adverse events overall, although serious infections were reported more often among patients receiving ziltivekimab, about 20% versus 18% with placebo. That safety difference is relevant because suppressing an inflammatory pathway can also change how the immune system responds to infection.

Patients received either a 15-milligram injection of ziltivekimab or placebo once a month, alongside usual care for their existing conditions. The study was double-blind, so neither participants nor investigators knew which treatment each patient had been assigned while the trial was underway. It was conducted across 757 research sites in 38 countries, giving the findings a broad geographic base, although the enrolled population was medically complex.

The trial tested patients with unusually advanced disease

The average ZEUS participant was about 69 years old. More than nine in ten had high blood pressure, almost two-thirds had type 2 diabetes and roughly 42% had heart failure. Every participant had established cardiovascular disease and chronic kidney disease, placing the study population at higher underlying risk than the patients in some earlier cardiovascular inflammation trials.

Paul Ridker, the study’s lead author and a researcher at Mass General Brigham, has cautioned against treating the neutral result as proof that inflammation is an irrelevant target for heart disease. Earlier research using different anti-inflammatory medicines found cardiovascular benefits, and the researchers said differences in drug mechanisms and patient selection could matter. The ZEUS findings do not establish which explanation, if any, accounts for the lack of benefit in this trial.

One possibility raised by investigators is that cardiovascular and kidney disease had progressed too far for this particular intervention to change clinical outcomes. Another is that blocking the interleukin-6 ligand is not the best point in the inflammatory pathway to intervene. These remain hypotheses rather than demonstrated explanations. ZEUS was designed to measure the drug’s clinical effect, not to resolve every question about why earlier studies of other treatments produced different results.

The trial therefore narrows the evidence for ziltivekimab in a specific group without settling the broader debate over anti-inflammatory treatment. It also illustrates the limits of using laboratory measurements as a substitute for hard outcomes such as heart attack, stroke and death. A marked change in a biomarker can provide evidence that a medicine is biologically active, but it is not by itself evidence that prescribing the drug would improve patients’ health.

Novo has already recorded a charge and reshaped its trial program

For Novo Nordisk, the full data add clinical detail to a setback that has already affected its development plans. The company announced in July that ZEUS had missed its main endpoint. By the time the comprehensive findings were presented in November, the consequences had extended to two other late-stage studies involving ziltivekimab in heart failure.

In its November 4 financial report, Novo said an independent data monitoring committee had recommended ending the HERMES and ATHENA studies. The company discontinued study treatment and closed HERMES. In ATHENA, the final participant had already completed treatment, and the study was being completed as planned. Novo said it expected results from both programs in the first half of 2027, with presentations at scientific meetings later that year.

The same filing showed that Novo recorded a DKK 4.6 billion non-cash impairment related to ziltivekimab during the third quarter. An impairment reduces the carrying value of an asset in the accounts; it does not mean the company paid out that amount in cash during the quarter. The charge gives the disappointing trial result a measurable financial consequence, separate from the question of whether future trials might identify another useful role for the medicine.

Novo’s broader business remains centered on diabetes and obesity medicines, including Ozempic and Wegovy. Cardiovascular treatments represent an additional research opportunity, but the ZEUS findings make clear that the success of one treatment targeting metabolic risk cannot be assumed for a different drug that works through inflammation. The company has not presented evidence from ZEUS that would support a new approved cardiovascular use for ziltivekimab.

A separate phase 3 study, ARTEMIS, is testing ziltivekimab in people following an acute heart attack. Novo’s November financial report still listed its results as expected in the first half of 2027. That readout will provide another test of the drug in a different clinical setting, but it cannot retroactively change the neutral outcome observed among patients with established cardiovascular and chronic kidney disease in ZEUS.