After GLP-1 drugs revolutionized the treatment of type 2 diabetes and obesity, it started to look like there was nothing they couldn’t treat. A deluge of new clinical trials popped up to test whether the new class of drugs could treat conditions that ranged from addiction, obstructive sleep apnea, and chronic kidney disease.
Yet, over the last few months, many scientists and pharma executives have been waiting to hear how GLP-1 drugs fare in treating one condition specifically: Alzheimer’s disease (AD). Last week, Novo Nordisk announced the top-line results from their Phase 3 evoke and evoke+ trials testing oral semaglutide to treat AD — but they were not what everyone had hoped for. The randomized, double-blind trials enrolled 3,808 adults with early-stage symptomatic AD and showed that semaglutide failed to slow the progression of disease over two years.
“Given the huge unmet need and major health challenges, the negative trial results are very disappointing, and a sobering reminder that GLP-1 medicines will not be helpful for every medical condition,” Daniel Drucker, an endocrinologist at the Lunenfeld-Tanenbaum Research Institute and a recent winner of the 2025 Breakthrough Prize in Life Sciences for his role in the development of GLP-1 agonists, told DDN.
Failing to slow disease
Progression of disease was measured by the change in Clinical Dementia Rating – Sum of Boxes (CDR-SB) score and compared to placebo on top of standard of care. Despite the results, Martin Holst Lange, Chief Scientific Officer and Executive Vice President of Research and Development at Novo Nordisk, said in the press release, “We are proud to have conducted two well-controlled phase 3 trials in Alzheimer’s disease that meet the highest standards of research and rigorous methodology.”
Scientists like Sally Frautschy, a neuroscientist studying AD at the University of California, Los Angeles, agreed that the trial was well-designed to answer the question, and told DDN that “Alzheimer’s involves clear deficits in insulin signaling, so GLP-1 receptor agonists were a logical target.”
However, Frautschy was not surprised by the results. “Improving insulin signaling may be necessary, but it is not sufficient to change the trajectory of Alzheimer’s,” she said. “If you target only one pathway in a disease with this level of complexity and feedback, you should not expect a dramatic clinical effect. The same issue that has limited amyloid-only approaches applies here: Correcting one disrupted system doesn’t fix the others.”
Paul Seidler, a structural biologist at the University of Southern California, also told DDN that the use of semaglutide in AD is quite limited in its ability to target the full pathology of AD, which includes the buildup of amyloid plaques, tau tangles, and neuroinflammation. “The evoke study was largely predicated on the idea that GLP‑1 agonists might reduce neuroinflammation and improve insulin signaling/glucose metabolism,” he said.
Given the huge unmet need and major health challenges, the negative trial results are very disappointing, and a sobering reminder that GLP-1 medicines will not be helpful for every medical condition.
– Daniel Drucker, Lunenfeld-Tanenbaum Research Institute
But Seidler emphasized that these factors are known to decline very early in dementia, meaning that early intervention would be critical for GLP-1s to show any efficacy. “The trial enrolled individuals with mild cognitive impairment or mild dementia due to Alzheimer’s disease. At that stage, amyloid pathology is already deeply rooted, which makes for a particularly challenging clinical study,” he said.
Designing future trials
In addition to a trial that studied a population at risk but without early-stage AD symptoms, Drucker also brought up additional factors that could have led to more positive trial results, including a different dose of semaglutide or another GLP-1 medicine that penetrates the brain better.
Unfortunately, these possible improvements won’t be studied in the evoke trials. Novo Nordisk reported in the press release that “the 1-year extension period in the evoke and evoke+ trials will be discontinued based on the efficacy results observed in the overall study population.” Further details about the topline results were presented yesterday at the Clinical Trials on Alzheimer's Disease Conference in San Diego, CA, and Novo Nordisk said in the news release that full results will be presented at the Alzheimer’s and Parkinson’s Diseases Conferences in March 2026.
For other trials testing GLP-1 drugs to treat AD in the future, Frautschy has some advice. “After so many failed trials, the evidence is overwhelming that Alzheimer’s cannot be shifted by targeting one pathway alone,” she said. “The barrier is that our trial infrastructure still isn’t built for combination approaches.”
