Oral Semaglutide Did Not Confirm Superiority in Reduction of Alzheimer Disease Progression

Oral semaglutide (Rybelsus; Novo Nordisk) was not found to be superior to placebo in the reduction of Alzheimer disease, according to a Novo Nordisk news release. The results are from the 2-year primary analysis of EVOKE (NCT04777396) and EVOKE PLUS (NCT04777409), phase 3 clinical trials assessing the efficacy and safety of oral semaglutide with standard of care.^1-3

Semaglutide’s Hypothesized Benefits in Reducing Alzheimer Disease Risk

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist marketed under the brand names Ozempic and Rybelsus for the treatment of type 2 diabetes and Wegovy for the treatment of chronic weight management.¹ Preclinical studies suggested that semaglutide protected individuals against neurodegeneration and neuroinflammation. The need for disease-modifying therapies that specifically target Alzheimer disease’s diverse pathophysiology is important.^1,4,5

In a 2024 real-world study using US electronic health records of about 116 million patients, semaglutide use was associated with a significantly reduced risk for first-time Alzheimer disease diagnosis. This range was about 40% to 70% in patients with type 2 diabetes compared with other antidiabetic medications, such as insulin and other GLP-1 receptor agonists.⁶

What Did the EVOKE and EVOKE PLUS Phase 3 Trials Investigate?

Concurrent to this study, the EVOKE and EVOKE PLUS trials were ongoing. These trials are randomized, double-blind, placebo-controlled phase 3 trials that investigated the efficacy, safety, and tolerability of once-daily oral semaglutide compared with placebo in combination with standard of care in individuals aged 55 to 85 years with early-stage Alzheimer disease, including mild cognitive impairment (EVOKE), and in a broader population (EVOKE PLUS). Participants were enrolled between May 18, 2021, and September 8, 2023.^2-5

Each trial enrolled around 1840 patients who were randomly assigned to receive either semaglutide or placebo for a 156-week duration that consisted of a 104-week main treatment phase and a 52-week extension. Semaglutide was dosed at 3 mg during weeks 0 through 4, 7 mg during weeks 4 through 8, and 14 mg from week 8 to the end of the trials.^1-4

According to the manufacturer's news release, neither EVOKE nor EVOKE PLUS confirmed the superiority of semaglutide vs placebo in the reduction of the progression of Alzheimer disease, as measured by the change in Clinical Dementia Rating – Sum of Boxes score compared with baseline. In both trials, treatment with semaglutide resulted in the improvement of Alzheimer disease-related biomarkers, but this did not translate into a delay of disease progression.¹

Despite the lack of superiority reflected in the trials’ results, EVOKE and EVOKE PLUS were the first large-scale trials to investigate the potential of semaglutide in those with early-stage symptomatic Alzheimer disease, including the exploration of effects on Alzheimer disease–related biomarkers and neuroinflammation.⁴

Based on the efficacy results observed in the overall study populations, Novo Nordisk announced that the 1-year extension periods in the trials will be discontinued. Top-line results are slated for presentation at the upcoming Clinical Trials on Alzheimer’s Disease conference on December 3, 2025, and full results at the 2026 Alzheimer’s and Parkinson’s Disease Conferences in March 2026.¹

“Based on the significant unmet need in Alzheimer 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 2 well-controlled phase 3 trials in Alzheimer disease that meet the highest standards of research and rigorous methodology,” Martin Holst Lange, chief scientific officer and executive vice president of research and development at Novo Nordisk, said in the manufacturer’s news release. “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.”¹

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. A research study investigating semaglutide in people with early Alzheimer's disease (EVOKE). ClinicalTrials.gov. Updated October 17, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT04777396

3. A research study investigating semaglutide in people with early Alzheimer's disease (EVOKE Plus). ClinicalTrials.gov. Updated October 17, 2025. Updated November 24, 2025. https://clinicaltrials.gov/study/NCT04777409

4. 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. Alzheimers Res Ther. 2025;17(1):14. 2025;17(1):14. doi:10.1186/s13195-024-01666-7

5. GLP-1s and Alzheimer's: what you need to know. The Alzheimer’s Association. October 15, 2025. Accessed November 24, 2025. https://www.alz.org/blog/2025/glp-1s-and-alzheimer-s-what-you-need-to-know

6. Wang W, Wang QQ, 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. Alzheimer's Dement. 2024; 20: 8661–8672. doi:10.1002/alz.14313