Welcome to NeurologyLive®'s Clinical Trial in Focus! Every month, an ongoing clinical trial in the landscape of neurology is featured, highlighting the design of the study, the targeted patient population, the enrollment criteria, the primary and secondary end points, and its potential implications for clinical care. This month’s spotlight is the phase 3 EVOKE trials (EVOKE, NCT04777396; and EVOKE+, NCT04777409) investigating the potential of semaglutide (Ozempic; Novo Nordisk), a glucagon-like peptide-1 (GLP-1) receptor agonist used for diabetes and weight loss, to slow cognitive decline in patients with early Alzheimer disease (AD).1,2
The design of EVOKE and EVOKE+ studies, published in Alzheimer’s Research & Therapy, potentially hold critical significance, as they are considered the first large-scale phase 3 trials testing a GLP-1 receptor agonist in early-AD, focusing on a disease-modifying approach rather than only symptom management. If approved, oral semaglutide, could be the first oral AD therapy to slow disease progression.
Design of the EVOKE Trials
These multicenter, randomized, double-blind, placebo-controlled trials, conducted by study investigator Jeffrey Cummings, MD, ScD, a research professor with the department of brain health at University of Nevada, Las Vegas Kirk Kerkorian School of Medicine, and colleagues, will have enrolled 1840 participants aged between 55 to 85 years with mild cognitive impairment or mild dementia because of AD, confirmed with amyloid positivity. Investigators randomized patients 1:1 to once-daily oral semaglutide 14 mg or placebo for an 8-week titration period, followed by 104 weeks of treatment plus a 52-week extension using change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) at week 104 as the primary end point.
EVOKE and EVOKE+ will also include several other secondary measures, such as Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Mini-Mental State Exam, and Neuropsychiatry Inventory, in addition to CDR-SB. Investigators will also collect data on MRI/CT scans, amyloid PET, and cerebrospinal fluid (CSF) biomarkers, as well as neuroinflammation markers. Additionally, there is a planned CSF substudy that will comprise around 210 patients that will assess an extensive panel of CSF biomarkers, organized into several key pathophysiological domains. Among those will include AD pathology, neuroinflammation, neurodegeneration and synaptic injury, and oxidative stress, blood-brain barrier integrity, and vascular health.
Topline Findings From EVOKE Studies
Topline results from the studies, announced days before the 2025 Clinical Trials on Alzheimer’s Disease (CTAD) Conference, showed that semaglutide did not demonstrate superiority over placebo in reducing disease progression in patients with early-stage symptomatic AD, despite improvements observed in AD-related biomarkers. Additional findings, to be presented at the upcoming meeting, held December 1-4, in San Diego, California, demonstrated 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 an announcement that the 1-year extension period in the trials will be discontinued.3
The Future Outlook for Alzheimer Disease
In this NeurologyLive Peer Exchange program, Alzhiemer disease (AD) experts Richard Isaacson, MD, Sharon Cohen, MD, FRCPC, and Marwan Sabbagh, MD, discussed the criticality of early intervention and evolving treatment strategies surrounding AD.
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 statement.4 “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.”
Researchers presented preliminary baseline characteristics of EVOKE and EVOKE+ at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado.5 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.
Supporting Data for Semaglutide in AD
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.6
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.7 Overall, the study found no difference in the risk of AD and other related dementias between both GLP-1RAs and SGLT2is.
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REFERENCES
1. Cummings JL, Atri A, Feldman HH, et al. evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease. Alz Res Therapy. 2025; 17 (14). doi:10.1186/s13195-024-01666-7
2. Novo Nordisk to enter phase 3 development in Alzheimer’s disease with oral semaglutide. News release. Novo Nordisk. December 16, 2025. Accessed November 21, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=39097
3. 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
4. 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
5. 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.
6. 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
7. 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
