Semaglutide’s Setback in Alzheimer Disease Trials: Commentary on Outcomes of evoke and evoke+

Novo Nordisk’s phase 3 evoke and evoke+ trials, which enrolled more than 3,800 adults with mild cognitive impairment or mild dementia due to Alzheimer disease (AD), failed to demonstrate that oral semaglutide slows disease progression compared with placebo, based on change in Clinical Dementia Rating–Sum of Boxes scores over 104 weeks. Although treatment produced improvements in AD-related biomarkers, those surrogate effects did not translate into clinical benefit.¹

UK Expert Perspectives: Themes and Takeaways

Quotes on the outcomes of evoke and evoke+ in the slide show above are based on a review of comments from experts submitted to the UK's Science Media Centre.² Across the UK scientific community, reactions to the findings emphasize that the results, while disappointing, are nonetheless scientifically valuable. Many researchers framed the trial outcome not as evidence that GLP-1–based therapies are a dead end, but as confirmation that these agents are likely being tested too late in the disease course. Several noted that semaglutide’s biomarker effects, reported in both the evoke trials, suggest meaningful engagement with Alzheimer’s-related pathways, even if that biological signal was insufficient to produce cognitive impact in symptomatic disease.²

The UK experts also underscored how challenging it is to alter the trajectory of established AD, pointing out that by the time mild cognitive impairment or early dementia is present, years of neuronal loss and circuit disruption have already occurred. In that context, even well-designed trials may struggle to show measurable clinical benefit within a 2-year period.²

A recurring theme from UK voices was the value of negative trials. Leaders in the field stressed that conducting large, rigorous studies, even the “long-shot” ones, helps close unproductive avenues, clarify hypotheses, and guide investment toward more promising strategies. Several of the quotations above reflect the position that future research may need to shift toward earlier intervention, greater exploration of alternative mechanisms, and investigation of more brain-penetrant or potent GLP-1 agents, along with entirely different therapeutic classes.

US Perspective

“While it is disappointing that the trials did not meet their primary endpoints, they show a fundamental shift in how we approach the development of new Alzheimer’s treatments," Howard Fillit, MD, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said in a statement.³ "Existing anti-amyloid drugs slow cognitive decline by around 30%, so therapies aimed at other pathways will be crucial… The completion of two phase 3 trials targeting one of these pathways represents real momentum toward the kind of combination approach that has already transformed cancer care.”³

In a statement on the topline data release, Joanne Pike, DrPH, Alzheimer's Association president and CEO said, "While these results are not what we had hoped for, they will contribute to our understanding of this devastating and fatal disease." Regardless of their nature, data from every clinical trial are "vital to accelerating our understanding of [AD] and helps inform the next generation of clinical trials. ⁴

Calling the results “a setback for the field,” international endocrinology expert Daniel Drucker, MD, professor of medicine in the division of endocrinology at University of Tornto, noted that GLP-1 agents may have limited brain penetration and that earlier or injectable formulations might yield different effects.⁵ “These are not wonder drugs that will fix everything that is wrong with us, and that’s why we have to do the clinical trials, and we need rigorous evidence,” Drucker said. He lauded Novo Nordisk, however, saying the company "deserves credit for doing the trials despite the low odds of success."⁵

Together, global expert responses suggest a strategic pivot toward preventing disease before symptoms appear, deploying multi-mechanism combinations, and continuing to probe metabolic pathways, while recognizing that semaglutide itself does not alter symptomatic AD.

References

1. Halsey G. Semaglutide fails to slow progression of Alzheimer disease compared to placebo: Novo Nordisk phase 3 trials update. Patient Care. November 24, 2025. Accessed December 3, 2025. https://www.patientcareonline.com/view/semaglutide-fails-to-slow-progression-of-alzheimer-disease-compared-to-placebo-novo-nordisk-phase-3-trial-update

2. Expert reaction to news from Novo Nordisk that semaglutide does not reduce Alzheimer’s Disease progression. Science Media Centre. November 24, 2025. Accessed December 3, 2025. https://www.sciencemediacentre.org/expert-reaction-to-news-from-novo-nordisk-that-semaglutide-does-not-reduce-alzheimers-disease-progression/

3. Readout of phase 3 semaglutide trials marks critical moment in Alzheimer’s research and suggests potential for combination therapies. News release. Alzheimer’s Drug Discovery Foundation. November 24, 2025. Accessed December 3, 2025. https://www.alzdiscovery.org/news-room/announcements/readout-of-phase-3-semaglutide-trials-marks-critical-moment-in-alzheimers-research-and-suggests-potential-for-combination-therapies

4. Alzheimer’s Association statement on oral semaglutide phase 3 topline data release. News release. Alzheimer's Association. November 24, 2025. Accessed December 3, 2025. https://www.alz.org/news/2025/alzheimers-association-statement-oral-semaglutide-phase-3-topline-data-release

5. Young LJ. GLP-1 pill fails to slow Alzheimer's progression in clinical trial. Scientific American. November 24, 2025. Accessed December 3, 2025. https://www.scientificamerican.com/article/glp-1-pill-fails-to-slow-alzheimers-progression-in-clinical-trial/