What Novo Nordisk’s Failed Heart-Drug Trial Really Tells Investors
What ZEUS means for Novo’s pipeline and how far investors should apply its result.
I usually write an article once a week. Not because there isn’t much to analyze and share with you. On the contrary - there is plenty to cover - but the fact is that each article takes considerable time and effort to knock out.
But this week, I am making an exception. The minute I read the Novo Nordisk announcement, I knew I was going to be clearing my calendar to unpack it. So here we go! I’ll give you the facts first and then get to my opinion later.
On July 31, Novo Nordisk announced that Ziltivekimab (I know its a mouthful but please bear with me), a drug it paid up to USD 2.8 billion to acquire, had failed a major clinical trial.
The trial was called ZEUS and it included 6,376 people with heart disease, kidney disease and high levels of inflammation. Half of the people received Ziltivekimab. The other half received a placebo. Researchers followed them for up to four years.
But lets talk about Ziltivekimab for a minute.
Ziltivekimab was designed to block IL-6, a protein that helps to drive inflammation in the body. This matters because inflammation can make the fatty plaques inside the arteries unstable and if one of those plaques breaks open, it can create a blood clot that causes a heart attack or stroke.
IL-6 is one of the proteins that drives this inflammatory process and when IL-6 activates the liver, the liver produces CRP (C-reactive protein). People with high hsCRP (high sensitivity C-reactive protein) levels tend to have a greater risk of heart attack and stroke, even when their cholesterol is normal.
Novo’s theory was straightforward: blocking the IL-6 inflammatory pathway would make dangerous cardiovascular events less likely.
There were good reasons to test the theory. Genetic studies had linked IL-6 signalling to coronary heart disease. An earlier trial of a different anti-inflammatory drug had reduced cardiovascular events, and in a smaller study called RESCUE, Ziltivekimab had lowered hsCRP and several other inflammatory markers by remarkable amounts.
The ZEUS trial was designed to answer the next (and much more important) question: would those biological changes actually prevent heart attacks and strokes?
The drug succeeded at the first part re - biological changes. It reduced hsCRP by as much as 92%. But regarding the second and more important part of the question re - prevent heart attacks and strokes, the results were clear. That dramatic reduction in hsCRP did not lead to fewer heart attacks, strokes or cardiovascular deaths. The results were almost identical in the drug and placebo groups.
Why the failure hit Novo so hard
For Novo Nordisk, the financial consequences were immediate. The company said it would record an impairment charge in the third quarter (basically write down the value of the asset), and its shares fell by close to 10%.
But the market reaction was about more than one failed drug. This was an important opportunity for Novo outside of its obesity and diabetes business. So investors were doing two things:
First, they were repricing their expectations for potential future revenues from Ziltivekimab and Novo’s growth trajectory. And second, they were also treating the results from ZEUS as evidence against the broader biological approach. This explains why companies like BioAge Labs who is pursuing a related inflammatory mechanism, lost 65% of its value in one day.
That broader conclusion (about the biological approach of this class of drugs) may eventually prove correct. But one detail deserves closer attention.
Only 27.5% of the people in ZEUS were women. Heart disease is the leading cause of death among women worldwide. Yet a trial now influencing how investors value a multibillion-dollar area of drug development was conducted in a population that was almost three-quarters male.
That figure is striking, but please allow me to add some context.
ZEUS did not study everyone with heart disease. It studied a narrower population with atherosclerotic cardiovascular disease, chronic kidney disease and elevated inflammation. In a recent real-world study of a similar population, women represented 25.9% of participants.
So the 27.5% figure does not prove, by itself, that ZEUS enrolled too few women relative to the population eligible for the drug but it does fit a much broader pattern in cardiovascular research.
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This is the pattern not the exception
A 2025 review examined 1,079 cardiovascular trials conducted between 2017 and 2023. Together, those trials included almost 1.4 million patients and women represented 41% of participants.
But even that figure hides the scale of the problem. Some types of trials, including those involving obesity and pulmonary hypertension, enrolled more women than men. But trials for some of the deadliest forms of heart disease included far fewer women:
Women represented only about 30.8% of participants in coronary heart disease trials.
They represented roughly 22.1% in trials for acute coronary syndrome
and heart failure trials were not much better with 37.4% female representation.
So, this is the pattern and clearly not a new problem. One study examined 60 trials of cholesterol-lowering drugs conducted between 1990 and 2018. The results are stark: in the early 1990s, women represented 19.5% of participants. By 2018, that percentage had risen to 33.6%.
In other words, it took almost 30 years for female participation in clinical trials to increase by just 14 percentage points.
Even government-funded trials show how headline numbers can hide the problem. One study examined cardiovascular trials funded by the US National Heart, Lung, and Blood Institute between 1965 and 1998. At first sight, women represented 54% of participants in trials. But that figure was pushed up by two enormous studies that enrolled only women: the Women’s Health Study and the Women’s Health Initiative. When researchers removed those two all-female studies, female participation in clinical trials actually fell to 38%.
ZEUS did not break the pattern. But whether women were underrepresented relative to its specific eligible population is a separate question.
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Why ZEUS does (and does not) tell us
ZEUS was designed to test whether Ziltivekimab reduced cardiovascular events across all 6,376 participants. Meaning the trial was large enough to detect a 20% reduction in risk if it showed up. The result was clear: the drug did not reduce cardiovascular events across the overall trial population.
That conclusion includes the women enrolled in ZEUS. It would therefore be wrong to say that the drug was not tested in women. But the topline result does not answer a different question: did women and men respond differently?
Approximately 1,750 women participated. Whether that produces a meaningful result depends on the number of events among women, the hazard ratio, the confidence interval and whether there was a credible interaction between sex and treatment. Novo has not yet published those details.
This means we do not yet know whether the negative result was entirely consistent across women and men. And even if a more favourable result appeared in one subgroup, it would need to be treated cautiously because ZEUS failed its primary endpoint (but that’s another point).
What this means for investors
or investors, three lessons stand out.
First, ZEUS provides strong negative evidence against ziltivekimab in the population studied. It is reasonable to reduce the value assigned to the drug and weaken confidence in the mechanism.
But deciding that the same conclusion applies to every patient group, clinical setting and related drug is a broader investment judgement. That should be informed by the full results and not only the headline.
Second, trial demographics are investment information, but percentages cannot be interpreted in isolation. Investors need to compare trial participants with the population that would actually be eligible for the treatment. They also need to understand whether the trial was designed to examine differences between women and men.
The drug failed overall and that is clear. Perhaps the real investment question is how much further that conclusion should travel.
These ideas are at the heart of my new book, The Billion Dollar Blindspot. You can find The Billion Dollar Blindspot on Amazon.
References
Swerdlow DI, Holmes MV, Kuchenbaecker KB, et al. “The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis.” The Lancet. 2012;379(9822):1214–1224. Full text | DOI
Ridker PM, Everett BM, Thuren T, et al. “Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.” New England Journal of Medicine. 2017;377:1119–1131. PubMed | DOI
Ridker PM, Devalaraja M, Baeres FMM, et al. “IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.” The Lancet. 2021;397(10289):2060–2069. PubMed | DOI
Rivera FB, Magalong JV, Bantayan NRB, et al. “Participation of Women in Cardiovascular Trials From 2017 to 2023: A Systematic Review.” JAMA Network Open. 2025;8(8):e2529104. Full article | Open-access version | DOI
Khan SU, Khan MZ, Raghu Subramanian C, et al. “Participation of Women and Older Participants in Randomized Clinical Trials of Lipid-Lowering Therapies: A Systematic Review.” JAMA Network Open. 2020;3(5):e205202.
Full article | Open-access version | DOIKim ESH, Carrigan TP, Menon V. “Enrollment of Women in National Heart, Lung, and Blood Institute-Funded Cardiovascular Randomized Controlled Trials Fails to Meet Current Federal Mandates for Inclusion.” Journal of the American College of Cardiology. 2008;52(8):672–673. PubMed | DOI
Disclaimer & Disclosure
This content is for informational and educational purposes only.
Thanks for the update and perspective. I've been thinking about this problem in a different way. Many drugs target one downstream consequence of disease--like CRP in this case--without addressing the underlying causes of inflammation. We spend far more on treating disease than preventing it, with too little investment in nutrition and lifestyle research. Take sleep-disordered breathing: it's common starting at midlife, underdiagnosed, drives chronic inflammation, and women's risk rises sharply after menopause. The landmark HypnoLaus Study revealed that sleep apnea is far more common than previously recognized, affecting nearly 60% of women and more than 80% of men aged 40–85. Yet we're doing very little to identify it early or figure out how to prevent it. We'll always need medications, but what's missing is an equal commitment to finding and addressing the underlying cause of disease--and I wish our healthcare system, researchers, and investors invested as much in that as they do in developing new drugs. I get that there are not the same financial incentives as with drugs, but therein lies the problem.
Thank you. Very interesting deconstruction. Didn't drug companies stick with using male prototypes because if they had a study with both men and women, they got two bell curves of responses, instead of one?
Why did this drug cost $1.2 billion?