Research in Context

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Oral semaglutide 14 mg did not slow clinical decline in early-stage Alzheimer's disease trials

The evoke and evoke+ phase 3 trials found no superiority of oral semaglutide 14 mg versus placebo on cognitive or global decline in biomarker-confirmed early Alzheimer's disease, with reductions in CSF biomarkers reported in a separate substudy.

  • Jeffrey L Cummings, MD; Alireza Atri, MD; Mary Sano, PhD; Henrik Zetterberg, MD; Philip Scheltens, MD; Filip K Knop, MD; et al.

  • March 19, 2024

  • The Lancet
  • The Lancet, Volume 407, Issue 10544, Pages 2167–2179
  • 10.1016/S0140-6736(26)00459-9

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Evidence before this study

We searched PubMed on May 15, 2025, with no date or language restrictions, using the search terms “glucagon-like peptide-1 receptor agonist”, “GLP-1RA”, “Alzheimer's disease”, “MCI”, “AD”, “small vessel pathology”, and “cognitive function”. In observational, longitudinal cohort studies in patients with type 2 diabetes and/or obesity, a reduced risk of dementia and clinical diagnosis of Alzheimer's disease was reported after GLP-1 receptor agonist exposure. Animal studies demonstrate that GLP-1 receptor agonist exposure reduces systemic and CNS inflammation, improves memory function, and preserves blood–brain barrier integrity. In humans, two small investigator-sponsored studies suggested GLP-1 receptor agonist treatment might prevent cognitive decline or slow disease progression in Alzheimer's disease. These studies provided the basis for the mechanistic hypotheses of the current study relating to anti-inflammatory, neuroprotective, vascular, and blood–brain barrier effects in Alzheimer's disease. The evoke(+) trials were initiated to assess the safety and efficacy of a GLP-1 receptor agonist (once-daily semaglutide up to 14 mg) on top of standard of care for slowing disease progression in individuals with early Alzheimer's disease.

Added value of this study

The evoke(+) trials were the first large-scale, multi-country, randomised clinical trials investigating the clinical efficacy and safety of semaglutide in early-stage Alzheimer's disease. Neither trial demonstrated superiority of oral semaglutide 14 mg to placebo in slowing cognitive or global decline in people with early-stage Alzheimer's disease from baseline to week 104. Prespecified pooled trial analyses did not demonstrate a delay in time to progression to dementia in participants with mild cognitive impairment (MCI) due to Alzheimer's disease from baseline up to week 156. In the cerebrospinal fluid (CSF) substudy, semaglutide led to significant reductions of up to 10% in CSF-based core biomarkers associated with Alzheimer's disease (phosphorylated-tau181 [p-tau181], p-tau217, non-phosphorylated-tau181 [np-tau181], and np-tau205) and CSF biomarkers of neuroinflammation, neurodegeneration, and synaptic function (YKL-40, total tau, and neurogranin). Semaglutide treatment was also associated with significantly reduced plasma high-sensitivity C-reactive protein concentrations.

Implications of all the available evidence

The results of the large evoke(+) trials do not support the efficacy of 14 mg/day of semaglutide given for up to 156 weeks in participants with biomarker-confirmed Alzheimer's disease in the MCI or mild dementia stage.

Source: The Lancet

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