Novo Nordisk Reports Topline Results from Phase 3 ZEUS Trial Evaluating Ziltivekimab for Cardiovascular Risk Reduction
Novo Nordisk has announced topline findings from its pivotal Phase 3 ZEUS cardiovascular outcomes trial, providing new insights into the role of interleukin-6 (IL-6) inhibition in reducing cardiovascular risk among patients with chronic inflammatory conditions. While the investigational monoclonal antibody ziltivekimab successfully demonstrated biological activity by targeting inflammation through the IL-6 pathway, the treatment did not achieve its primary clinical objective of reducing major adverse cardiovascular events (MACE) compared with placebo.
The results represent an important scientific milestone for cardiovascular research, offering valuable evidence regarding the relationship between inflammation and cardiovascular disease progression. Although the study did not demonstrate the expected reduction in cardiovascular events, Novo Nordisk emphasized that the findings will help shape future research efforts and will not alter the company’s long-term commitment to developing innovative therapies for cardiovascular disease.
ZEUS Trial Evaluated IL-6 Inhibition in High-Risk Cardiovascular Patients
The Phase 3 ZEUS trial was designed to investigate whether selectively targeting inflammation through IL-6 inhibition could reduce cardiovascular complications in patients considered at particularly high risk.
The randomized, double-blind, placebo-controlled global study enrolled more than 6,300 participants diagnosed with:
- Atherosclerotic cardiovascular disease (ASCVD)
- Chronic kidney disease (CKD)
- Persistent systemic inflammation, defined by high-sensitivity C-reactive protein (hsCRP) levels of at least 2 mg/L
These individuals represent a population known to remain at elevated cardiovascular risk despite receiving standard therapies for cholesterol management and other cardiovascular risk factors.
Participants were randomly assigned to receive either:
- Once-monthly ziltivekimab 15 mg
- Matching placebo
The primary endpoint of the study measured the occurrence of major adverse cardiovascular events (MACE), including:
- Cardiovascular death
- Non-fatal myocardial infarction (heart attack)
- Non-fatal stroke
Researchers sought to determine whether reducing inflammation through IL-6 pathway inhibition would translate into meaningful improvements in cardiovascular outcomes.
Biological Activity Confirmed but Primary Endpoint Not Achieved
According to Novo Nordisk, ziltivekimab successfully engaged its biological target and produced the anticipated anti-inflammatory effects throughout the study.
Investigators observed expected reductions in:
- Free IL-6 levels
- High-sensitivity C-reactive protein (hsCRP), an established marker of systemic inflammation
These biomarker changes confirmed that the drug effectively inhibited the IL-6 signaling pathway as intended.
However, despite these encouraging biological effects, the improvements did not translate into fewer cardiovascular events.
The trial reported a hazard ratio of:
0.99 (95% Confidence Interval: 0.88–1.11)
This result indicates that treatment with ziltivekimab did not significantly reduce the risk of major adverse cardiovascular events compared with placebo.
Consequently, the study did not meet its primary efficacy endpoint.
Findings Provide Important Scientific Evidence
Although the primary clinical objective was not achieved, Novo Nordisk emphasized that the ZEUS study contributes important knowledge regarding inflammation biology and cardiovascular disease.
Martin Holst Lange, Executive Vice President, Chief Scientific Officer and Head of Research & Development at Novo Nordisk, explained that the trial was specifically designed to answer a long-standing scientific question.
According to Lange, researchers sought to determine whether suppressing IL-6-mediated inflammation could reduce cardiovascular events after successfully lowering inflammatory biomarkers.
While the expected reductions in inflammatory markers were achieved, the anticipated reduction in cardiovascular complications was not observed.
He noted that although the outcome was disappointing from a therapeutic standpoint, the trial generated meaningful scientific evidence that will help guide future cardiovascular research and drug development.
Novo Nordisk reiterated that cardiovascular disease remains a strategic priority and that the company continues to invest in therapies addressing significant unmet medical needs.
Safety Profile Generally Consistent with Expectations
The safety findings from ZEUS were generally consistent with the known mechanism of IL-6 inhibition.
According to the company:
- Overall adverse event rates were similar between ziltivekimab and placebo groups.
- Serious adverse events also occurred at comparable frequencies across both treatment arms.
- No increase in all-cause mortality was observed among patients receiving ziltivekimab.
However, investigators did identify one anticipated safety signal.
Because IL-6 plays an important role in immune system function, patients treated with ziltivekimab experienced a higher proportion of serious infections compared with placebo.
This finding aligns with previous experience involving therapies that suppress inflammatory immune pathways and was considered consistent with the drug’s biological mechanism.
No new unexpected safety concerns were reported during the study.
Understanding the Role of IL-6 in Cardiovascular Disease
Inflammation has increasingly been recognized as a key contributor to the development and progression of cardiovascular disease.
Beyond cholesterol accumulation, chronic vascular inflammation is believed to promote:
- Plaque formation
- Plaque instability
- Blood vessel injury
- Thrombotic events leading to heart attack or stroke
Interleukin-6 is one of the central inflammatory cytokines involved in these processes.
Ziltivekimab was specifically developed as a monoclonal antibody designed to neutralize IL-6 activity with the goal of interrupting inflammatory signaling while reducing cardiovascular risk.
Previous research had demonstrated that lowering inflammatory biomarkers such as hsCRP was associated with improved cardiovascular outcomes in some settings, leading investigators to hypothesize that direct IL-6 inhibition might provide additional clinical benefit.
Although ZEUS demonstrated successful suppression of inflammatory biomarkers, the absence of corresponding reductions in cardiovascular events suggests that lowering IL-6 alone may not be sufficient to improve outcomes in this patient population.
The findings are expected to influence future research into inflammation-targeted cardiovascular therapies.
Additional Cardiovascular Studies Continue
Despite the ZEUS outcome, Novo Nordisk confirmed that development of ziltivekimab will continue through two ongoing cardiovascular outcomes studies investigating different clinical settings.
These include:
HERMES Trial
The Phase 3 HERMES study is evaluating ziltivekimab in patients with heart failure.
Researchers are investigating whether targeting IL-6-mediated inflammation can improve outcomes among individuals living with chronic heart failure.
ARTEMIS Trial
The Phase 3 ARTEMIS study focuses on patients recovering from an acute myocardial infarction.
The trial is assessing whether IL-6 inhibition following a heart attack can reduce subsequent cardiovascular complications during recovery.
Novo Nordisk expects results from both HERMES and ARTEMIS during the first half of 2027.
The company believes these trials may provide additional insights into whether different patient populations could benefit from IL-6 inhibition despite the neutral findings observed in ZEUS.
Financial Outlook Remains Unchanged
Novo Nordisk also addressed the financial implications of the ZEUS results.
The company stated that the outcome will not affect its previously announced adjusted operating profit guidance for 2026.
However, because the trial failed to achieve its primary efficacy objective, Novo Nordisk expects to record a non-cash impairment charge during the third quarter of 2026.
The impairment reflects revised accounting assumptions regarding the commercial value of ziltivekimab following the trial results rather than any impact on the company’s day-to-day operations or cash position.
Full Results to Be Presented at Scientific Meeting
The topline announcement provides only the primary findings from the ZEUS trial.
Novo Nordisk indicated that comprehensive data—including subgroup analyses, secondary endpoints, biomarker findings, and additional safety results—will be presented at a major scientific congress later in 2026.
These detailed results are expected to provide researchers and clinicians with a deeper understanding of the study findings and their implications for future cardiovascular drug development.
Although ZEUS did not demonstrate a reduction in major cardiovascular events, the trial represents one of the largest investigations into IL-6 inhibition in cardiovascular disease. Its findings contribute valuable evidence to the growing understanding of inflammation’s role in cardiovascular health and are expected to influence future therapeutic strategies targeting inflammatory pathways.
About ziltivekimab
Ziltivekimab is an investigational, fully human monoclonal antibody that targets the IL‑6 ligand, a pro-inflammatory cytokine, to reduce cardiovascular inflammation and improve cardiovascular outcomes. It is being developed by Novo Nordisk for conditions such as cardiovascular disease, acute myocardial infarction (AMI) and heart failure with preserved ejection fraction (HFpEF).
About ZEUS
ZEUS – an event‑driven cardiovascular outcomes trial investigating efficacy and safety with once-monthly subcutaneous ziltivekimab 15 mg versus placebo on top of standard of care in people with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and CV inflammation (hsCRP ≥ 2 mg/L).
Novo Nordisk is a leading global healthcare company founded in 1923 and headquartered in Denmark. Our purpose is to drive change to defeat serious chronic diseases built upon our heritage in diabetes. We do so by pioneering scientific breakthroughs, expanding access to our medicines and working to prevent and ultimately cure disease. Novo Nordisk employs about 68,800 people in 80 countries and markets its products in around 170 countries. Novo Nordisk’s B shares are listed on Nasdaq Copenhagen (Novo-B). Its ADRs are listed on the New York Stock Exchange (NVO).