GLP-1 Semaglutide Fails to Outperform Placebo in Phase 3 EVOKE Trial of Alzheimer Disease

Topline results from the randomized, double-blinded phase 3 EVOKE (NCT04777396) and EVOKE+ (NCT04777409) studies showed that semaglutide (Ozempic; Novo Nordisk), a glucagon-like peptide-1 (GLP-1) receptor agonist, did not demonstrate superiority over placebo in reducing disease progression in patients with early-stage symptomatic Alzheimer disease (AD), despite improvements observed in AD-related biomarkers.^1,2

The 2 trials randomized a total of 3808 adults aged 55 to 85 years with mild cognitive impairment or mild dementia because of AD to investigate the efficacy and safety of oral semaglutide compared with placebo plus standard of care. Findings, to be presented at the upcoming 2025 Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1-4, in San Diego, California, showed that semaglutide was well tolerated and consistent with prior safety data. Based on efficacy results observed in the overall study population, Novo Nordisk noted in its announcement that the 1-year extension period in the trials will be discontinued.

“Based on the significant unmet need in Alzheimer’s disease as well as a number of indicative data points, we felt we had a responsibility to explore semaglutide’s potential, despite a low likelihood of success. We are proud to have conducted two well-controlled phase 3 trials in Alzheimer disease that meet the highest standards of research and rigorous methodology,” Martin Holst Lange, MD, PhD, chief scientific officer and executive vice president of Research and Development at Novo Nordisk, said in a statement.¹ “We sincerely thank all participants and their caregivers for their meaningful contributions. While semaglutide did not demonstrate efficacy in slowing the progression of Alzheimer disease, the extensive body of evidence supporting semaglutide continues to provide benefits for individuals with type 2 diabetes, obesity, and related comorbidities.”

With enrollment spanning nearly 40 countries, EVOKE and EVOKE+ represent the one of the largest AD trials of a GLP-1 agonist. The study also incorporated biomarker-based inclusion and planned long-term follow-up: a 104-week main treatment phase plus a 52-week extension to assess disease-modifying potential. Prior to the study, semaglutide was already approved as a treatment for diabetes/obesity, as well as for stroke prevention in the EU earlier this year.

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Researchers presented preliminary baseline characteristics of EVOKE and EVOKE+ earlier this year at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado.³ At the time, the trials enrolled 1855 and 1835 participants, respectively; data from 118 patients in EVOKE+ were not included in the analysis. The mean age was 71.8 years (SD, 7.1) in EVOKE and 72.6 years (SD, 7.1) in EVOKE+, with 53.0% and 51.8% of participants being women, respectively. Most of the participants were White (76.6%), and 59.7% and 54.5% were receiving AD–specific medication, respectively. The baseline mean CDR-SB scores were 3.7 (SD, 1.5) and 3.7 (SD, 1.6), and ADCS-ADL-MCI scores were 39.4 (SD, 7.3) and 38.9 (SD, 7.5); 72.5% and 68.7% of patients had a CDR global score of 0.5.

The decision to enter phase 3 development with semaglutide in AD was supported by data from preclinical models, real-world evidence studies, post hoc analyses of large cardiovascular outcomes trials. These findings included a previously published target trial emulation of electronic health records from over 1 million patients with type 2 diabetes mellitus, showing that treatment semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in this patient population compared with other antidiabetic medications, including other GLP-1 receptor agonists.⁴

During a 3-year follow-up in the prior study, results showed that semaglutide-treated patients had a significantly lower risk of first-time AD diagnosis, with a HR of 0.33 (95% CI, 0.21-0.51) compared with insulins and an HR of 0.59 (95% CI, 0.37-0.95) compared with other GLP-1RAs. Among older adults aged at least 60 years at the index event (average, 67.9 [±5.79]), the overall 3-year risk of first-time diagnosis of AD was twice as high as in the general population (average, 58.1 [±12.1]): 0.33% vs 0.16%).

Findings from a more recent study published in JAMA Neurology further supported the investigation of GLP-1 receptor agonists in AD. The study showed that patients with type 2 diabetes receiving GLP-1 receptor agonists or sodium-glucose co-transporter-2 inhibitors (SGLT2is) had a significantly lower risk of developing AD compared with those on other glucose-lowering therapies.⁵ Overall, the study found no difference in the risk of AD and other related dementias between both GLP-1RAs and SGLT2is.

“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 treatments, expanding beyond amyloid to target the complete pathobiology of the disease,” Howard Fillit, MD, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, said in a statment.²“Novo has noted an improvement of Alzheimer-related biomarkers in both trials. We look forward to seeing further results at CTAD, as this may suggest a path forward for semaglutide as part of a combination therapy approach.”

He added, “Existing anti-amyloid drugs slow cognitive decline by around 30%, so therapies aimed at other pathways will be crucial as we chip away at the remaining 70%. 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.”

REFERENCES
1. Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer's disease progression. News release. Novo Nordisk. November 24, 2025. Accessed November 24, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916462
2. 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 November 24, 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
3. Scheltens P, Atri A, Feldman H, et al. Baseline Characteristics from Evoke and Evoke+: Two Phase 3 Randomized Placebo-controlled Trials of Oral Semaglutide in Patients with Early Alzheimer’s Disease. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO.
4. Wang W, Wang Q, Qi X, et al. Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. Alzheimers Dement. 2024;20(12):8661-8672. doi:10.1002/alz.14313
5. Tang H, Donahoo WT, DeKosky ST, et al. GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias. JAMA Neurol. Published online April 7, 2025. doi:10.1001/jamaneurol.2025.0353