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

Journal Article 1 Mention

J. R. Cummings•2026

Alireza AtriMary Sano

Top 1% · 99th Percentile

9 citations · Psychiatry and Mental health

Open Access

TLDR

Taking the diabetes drug semaglutide by mouth did not help slow down memory loss or thinking problems in people with early Alzheimer's disease.

Summary

AI Generated

This content was automatically synthesized by Credo's AI models directly from the original source text.

AI summaries can make mistakes — double-check important details against the original source.

1 Study Aim

The main goal of the evoke and evoke+ trials was to find out if taking oral semaglutide (a medicine usually used for diabetes) could safely slow down the worsening of symptoms in people with early-stage Alzheimer's disease. The researchers wanted to see if this drug could help people with mild memory and thinking problems caused by Alzheimer's disease. Simply put: The study wanted to see if a diabetes drug could help slow down early Alzheimer's symptoms.

2 Study Design

The researchers ran two large, international clinical trials called evoke and evoke+. They included people aged 55 to 85 who had early Alzheimer's disease confirmed by brain scans. Participants were randomly given either semaglutide (up to 14 mg daily) or a fake pill (placebo) for up to three years. The main thing measured was how much their memory and thinking abilities changed over two years, using a test called the Clinical Dementia Rating-Sum of Boxes (CDR-SB). Safety was also closely watched. In total, 3,808 people took part across 40 countries. Simply put: The study gave people with early Alzheimer's either the drug or a fake pill and checked their memory over two years.

3 Findings

The trials showed that people who took semaglutide did not have slower memory or thinking decline compared to those who took the placebo. The difference between the two groups was very small and not meaningful. Side effects were similar to what is seen when semaglutide is used for other health problems, and there were no new safety concerns. Because the drug did not help, the trials were stopped early. The authors suggest that semaglutide should not be used to treat early Alzheimer's disease based on these results. Simply put: The drug did not help slow down Alzheimer's, and it was about as safe as expected.

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.

Primary Link Archive Pubmed DOI Openalex Full text (OA)