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Randomized controlled trial

evoke and evoke+: oral semaglutide in early Alzheimer's disease

At 104 weeks, CDR-SB worsened by 2.3 and 2.2 points on semaglutide in evoke and evoke+ and by 2.3 and 2.1 on placebo, with no significant differences.

Cummings JL et al. 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. The Lancet, 2026. DOI: 10.1016/S0140-6736(26)00459-9

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Key facts

Drug
semaglutide
Design
Randomized controlled trial
Participants
3,808
Duration
104 weeks
Funding
Novo Nordisk
Registry
NCT04777396
Population
3,808 people aged 55 to 85 with amyloid-confirmed Alzheimer's disease at the stage of mild cognitive impairment or mild dementia, at 566 sites in 40 countries: 1,855 in evoke and 1,953 in evoke+, which admitted significant small vessel disease; mean age 72.2 years.
Primary outcome
Change in the CDR-SB scale (Clinical Dementia Rating-Sum of Boxes, which measures the clinical progression of dementia) from baseline to week 104 with once-daily oral semaglutide (up to 14 mg, flexible dose) versus placebo, with planned treatment of up to 156 weeks.

What it found

At 104 weeks, CDR-SB worsened by 2.3 and 2.2 points on semaglutide in evoke and evoke+ and by 2.3 and 2.1 on placebo, with no significant differences. The differences were −0.08 points in evoke (95% CI, −0.35 to 0.20; p = 0.57) and 0.10 in evoke+ (95% CI, −0.17 to 0.38; p = 0.46). Adverse effects during treatment occurred in 91.2% on semaglutide and 84.8% on placebo. Oral semaglutide did not slow clinical progression, and both trials were stopped because of that negative result.

Limitations

Funded by Novo Nordisk, which makes semaglutide. It studied oral semaglutide of up to 14 mg a day in people who already had Alzheimer's symptoms, not the injectable form or the prevention of dementia. Earlier signs of a lower dementia risk with these drugs came mainly from people with type 2 diabetes or obesity, not from people already diagnosed with Alzheimer's. It was not designed to assess weight or diabetes.

What it means for you

The evoke and evoke+ trials were negative: in people with early Alzheimer’s disease, semaglutide as a pill did not slow the clinical progression of the disease compared with placebo at 104 weeks, and both trials were stopped. They say nothing about semaglutide’s effect on weight or diabetes, which they were not designed to assess, nor about preventing dementia in people without symptoms. If someone close to you has Alzheimer’s, their doctor or neurologist can advise them on the treatments available.

Further reading

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Sources

The original paper and the records consulted for this summary, with the date they were accessed.

  1. The Lancet.Cummings JL, et al. Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+). Lancet. 2026;407(10544):2167-2179.accessed .
  2. National Library of Medicine (PubMed).PubMed record PMID 41865758 (abstract).accessed .
  3. ClinicalTrials.gov (National Library of Medicine).ClinicalTrials.gov record NCT04777396 (evoke: registration and primary outcome).accessed .
  4. ClinicalTrials.gov (National Library of Medicine).ClinicalTrials.gov record NCT04777409 (evoke+: registration and primary outcome).accessed .