Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials
- Design
- Randomized trial · 3808 participants · Intermediate outcome
- Match to healthy normal-weight adults aged 55–75
- Partial matchParticipants were older adults (mean 72) not selected for obesity or diabetes, so demographically closer to the target than metabolic trials; but they had established Alzheimer's disease, so results address treatment of AD, not prevention in healthy people.
- Could weight loss explain it?
- UnlikelyNull result.
- Study tier
- Study tier 1Two large, well-powered phase 3 trials with concordant null primary results; high certainty of no clinically meaningful effect on progression in early AD over two years.
- Assessment
- Version 2 · curated · Sep 13, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
Two phase 3 trials in 3,808 people with early Alzheimer's disease found that two years of oral semaglutide did not slow cognitive or functional decline at all. This is the most important negative result for the neuroprotection hypothesis: strong observational associations did not translate into a treatment effect.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- oral 14 mg daily (flexible)
- Route
- oral
- Treatment duration
- up to 156 weeks (primary at 104)
- Comparator
- placebo
- Primary outcome
- Change in CDR-SB from baseline to week 104
- Effect
- Difference -0.08 (evoke) and +0.10 (evoke+); no effect
- 95% confidence interval
- -0.35 to 0.20; -0.17 to 0.38
- P value
- 0.57; 0.46
- Follow-up
- 104 weeks
- Adverse events
- Treatment-emergent AEs 91.2% vs 84.8%; five treatment-related deaths (1 semaglutide, 4 placebo).
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Mean age
- 72.2
- Age range
- 55-85
- Age min
- 55
- Obesity status
- not an entry criterion (not selected for weight)
- Diabetes status
- not an entry criterion
- Baseline condition
- amyloid-confirmed early Alzheimer's disease (MCI or mild dementia)
- Sample size
- 9981
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 9981
- Randomization
- yes
- Blinding
- double-blind
- Comparator
- placebo
- Follow up duration
- 85 years
- Outcome type
- intermediate
- Replication
- two identical trials, both null
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- narrow CIs around zero
- Risk of bias
- not assessed (auto)
- Funding conflicts
- yes
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- Novo Nordisk
- Industry funded
- Yes
- Manufacturer
- Novo Nordisk
- Sponsor role
- Sponsor designed, ran and analysed; trials discontinued for lack of efficacy.
- Author conflicts
- Lead author consults for numerous companies including Novo Nordisk and Lilly; sponsor co-authors.
- Independent replication
- not needed (negative); consistent with ELAD null primary
- Notes
- Authors declare relationships with the drug's manufacturer: Novo Nordisk
Funding is shown on every study and never used to score it.
03Claims
Claims this study bears on
- GLP-1 receptor agonist treatment reduces the risk of developing dementia.Contradicts
evoke/evoke+: no effect on CDR-SB at 104 weeks in 3808 people with early AD; trials discontinued for lack of efficacy.
- GLP-1 receptor agonists slow clinical progression of Alzheimer's disease.Contradicts
Primary clinical endpoint null in both trials.
04Source
The source, as retrieved
Abstract
[BACKGROUND] Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease. [METHODS] evoke and evoke+ were multicentre, randomised, double-blind, placebo-controlled phase 3 trials conducted across 566 sites in 40 countries. The trials assessed the efficacy and safety of oral semaglutide up to 14 mg once daily in participants with amyloid-confirmed Alzheimer's disease, aged 55-85 years, with mild cognitive impairment or mild dementia due to Alzheimer's disease. In evoke+, participants with significant small vessel pathology were included. Participants were randomly assigned (1:1) to once-daily semaglutide 14 mg (flexible dose) or placebo for up to 156 weeks. The primary endpoint was change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score from baseline to week 104, assessed in all randomised participants. Safety was assessed in all randomised participants and reported for those receiving at least one dose of study drug. These trials were registered at ClinicalTrials.gov (NCT04777396 and NCT04777409); both trials have been discontinued due to negative clinical outcome. [FINDINGS] Between May 18, 2021, and Sept 8, 2023, 9981 participants were screened, of whom 3808 were randomly assigned; 1855 in evoke (semaglutide, n=928; placebo, n=927) and 1953 in evoke+ (semaglutide, n=976; placebo, n=977). Mean age was 72·2 years (SD 7·1), and mean CDR-SB score was 3·7 (SD 1·6) at baseline. In evoke+, 54 (2·8%) participants had small vessel pathology. In evoke and evoke+, mean changes in CDR-SB score from baseline to week 104 were 2·3 (SE 0·1) and 2·2 (0·1) with semaglutide, compared with 2·3 (0·1) and 2·1 (0·1) with placebo (estimated difference -0·08 [95% CI -0·35 to 0·20], p=0·57 in evoke and 0·10 [-0·17 to 0·38], p=0·46 in evoke+). Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo. There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group). [INTERPRETATION] Oral semaglutide was not efficacious in slowing clinical progression in participants with early Alzheimer's disease. Safety and tolerability of semaglutide in early Alzheimer's disease is consistent with studies in other indications. [FUNDING] Novo Nordisk.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 13, 2026 | 41865758 first ingestion |