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.

Cummings JL, Atri A, Sano M, Zetterberg H, Scheltens P, Knop FK, Johannsen P, Wichmann CA, Abschneider RM, Leon T, Feldman HH

Lancet (London, England)19 Mar 2026Cited by 52 (Europe PMC)

PMID41865758DOI10.1016/s0140-6736(26)00459-9PepBankPUB-41865758

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Summary

BackgroundEvidence, 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.Methodsevoke 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.FindingsBetween 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).InterpretationOral 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.FundingNovo Nordisk.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study4

4 results from studies that gave the peptide. 4 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with early Alzheimer's disease in the evoke+ trial, oral semaglutide did not change the CDR-SB score from baseline to week 104 compared with placebo.
In plain wordsIn adults with early Alzheimer's disease, oral semaglutide did not slow worsening of dementia scores more than placebo in the evoke+ trial.
Peptide
Semaglutide
Outcome
No significant changeCDR-SB change from baseline to week 104 (evoke+)
Study
n = 1,953
Comparator
Placebo
Analysis
Primary
Outcome group
Cognition and memory · Nervous system and cognition
Studied dose
14 mg once daily (flexible dose) · oral · up to 156 weeksAs given in this study (human).
Source sentences
Summary
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+).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
Show in the study text Report a problemFND-4186575802
02HumanRandomized controlled trialEfficacy outcome
In adults with early Alzheimer's disease in the evoke trial, oral semaglutide did not change the CDR-SB score from baseline to week 104 compared with placebo.
In plain wordsIn adults with early Alzheimer's disease, oral semaglutide did not slow worsening of dementia scores more than placebo in the evoke trial.
Peptide
Semaglutide
Outcome
No significant changeCDR-SB change from baseline to week 104 (evoke)
Study
n = 1,855
Comparator
Placebo
Analysis
Primary
Outcome group
Cognition and memory · Nervous system and cognition
Studied dose
14 mg once daily (flexible dose) · oral · up to 156 weeksAs given in this study (human).
Source sentences
Summary
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+).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
Show in the study text Report a problemFND-4186575801
03HumanRandomized controlled trialSafety outcome
In adults with early Alzheimer's disease, treatment-emergent adverse events were more frequent with oral semaglutide than with placebo.
In plain wordsIn adults with early Alzheimer's disease, more people on oral semaglutide than on placebo had adverse events during treatment.
Peptide
Semaglutide
Outcome
IncreaseTreatment-emergent adverse events
Study
n = 3,798
Comparator
Placebo
Outcome group
Adverse events · Whole body
Studied dose
14 mg once daily (flexible dose) · oral · up to 156 weeksAs given in this study (human).
Measurements
Participants with TEAE
1729 participants
semaglutide
Participants with TEAE
1613 participants
placebo
Source sentences
Summary
Treatment-emergent adverse events were reported in 1729 (91·2%) of 1896 participants receiving semaglutide versus 1613 (84·8%) of 1902 receiving placebo.
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-4186575803
04HumanRandomized controlled trialSafety outcome
In adults with early Alzheimer's disease, one treatment-related fatality occurred in the semaglutide group and four in the placebo group.
In plain wordsIn adults with early Alzheimer's disease, one treatment-related death occurred with semaglutide and four with placebo.
Peptide
Semaglutide
Outcome
Not applicableTreatment-related fatalities
Study
n: not reported in source
Comparator
Placebo
Outcome group
Mortality · Whole body
Studied dose
14 mg once daily (flexible dose) · oral · up to 156 weeksAs given in this study (human).
Source sentences
Summary
There were five fatalities considered treatment-related by the investigators (one in the semaglutide group and four in the placebo group).
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-4186575804

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials2

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

2 trials · 2 completed · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3NCT04777396

A Research Study Investigating Semaglutide in People With Early Alzheimer's Disease (EVOKE)

Novo Nordisk A/Sn = 1,84018 May 2021 to 30 Jan 2026

Early Alzheimer's Disease

Trial page ClinicalTrials.govUpdated 7 Jul 2026

CompletedPhase 3NCT04777409

A Research Study Investigating Semaglutide in People With Early Alzheimer's Disease (EVOKE Plus)

Novo Nordisk A/Sn = 1,84018 May 2021 to 30 Jan 2026

Early Alzheimer´s Disease

Trial page ClinicalTrials.govUpdated 26 Jun 2026

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

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