Data Fails to Show Significant Change in Cognition and Function With Oral Semaglutide for Early Alzheimer Disease

The Evoke and Evoke+ trials of oral semaglutide for early Alzheimer disease failed to show clinically significant difference in cognition and function of participants.¹ Data were presented at the 2025 Clinical Trials on Alzheimer’s Disease conference, December 1-4, in San Diego, California.

Evoke and Evoke+ trials were randomized, placebo-controlled trials with 1855 and 1953 participants, respectively, with the goal of assessing safety and efficacy of semaglutide in early Alzheimer disease. Participants were aged 55 to 85 years, with PET or cerebrospinal fluid amyloid positivity.² For inclusion in the study, clinical dementia rating scores required were 0.5 with greater than or equal to 0.5 on 3 activities of daily living, or a Clinical Dementia Rating (CDR) global score of 1. Mini-Mental State Examination scores required were 22 or greater, along with scores 85 or lower on the Repeatable Battery for Assessment of Neurological State delayed memory index. Continuation of stable, approved Alzheimer disease treatments were allowed. Patients were excluded if they had evidence of a relevant neurological disorder or unstable psychiatric disorder, or MRI or CT scans suggesting clinically significant structural central nervous system disease or strategic infarcts. In the Evoke+ trial only, participants were still able to be included if they had significant small vessel pathology (defined as age-related white matter changes greater than 2 and/or greater than 1 lacunar infarct). In both trials, approved Alzheimer disease medications could be initiated throughout, including antiamyloid monoclonal antibodies.

Patients were randomly assigned to daily oral semaglutide 14 mg or placebo for 8 weeks of titration, then 104 of treatment, and a 52-week extension. In Evoke and Evoke+, the primary endpoint was change in CDR sum of boxes score from baseline to week 104. Secondary endpoints included change from baseline to week 104 in Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale for mild cognitive impairment score.

Adverse events occurring in 10% or greater of participants were decreased body weight, decreased appetite, nausea, diarrhea, vomiting, and COVID-19. The mean body weight change across both trials from baseline to week 104 was -5.8% for oral semaglutide and +0.6% for placebo. Safety and tolerability of oral semaglutide was consistent with the known safety profile. Adverse events leading to withdrawal or dose-reduction of the drug were driven by gastrointestinal disorders, weight decrease, and decreased appetite.

Both trials showed that oral semaglutide did not slow cognitive and functional decline in participants with early Alzheimer disease vs placebo in either trial. There were no significant differences between treatment and placebo in Evoke or Evoke+. Oral semaglutide also did not delay time to progression to dementia in participants with mild cognitive impairment in either trial. The treatment did not show beneficial effects on cognition and function either in participants with early Alzheimer disease.

References

1. Cummings J, Johannsen, Knop FK. Evoke and Evoke+: 2 randomized placebo-controlled trials of semaglutide in participants with early-stage Alzheimer’s disease (NCT04777396 and NCT04777409). Conference Proceedings of the Clinical Trials on Alzheimer’s Disease conference. December 2025;1-4. San Diego, California.

2. 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.