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.
Level 2 - randomized trial
Two multicentre randomized double-blind placebo-controlled phase 3 trials
PubMed 41865758 · doi:10.1016/S0140-6736(26)00459-9
What was done
Two multicentre, randomised, double-blind, placebo-controlled phase 3 trials (evoke and evoke+) conducted across 566 sites in 40 countries assessed the efficacy and safety of oral semaglutide (flexible dose up to 14 mg once daily) versus placebo in participants aged 55–85 years with amyloid-confirmed early Alzheimer's disease (mild cognitive impairment or mild dementia; evoke+ included individuals with significant small vessel pathology). Participants were randomly assigned 1:1 to semaglutide 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 in all randomised participants.
What was found
Between May 18, 2021, and Sept 8, 2023, 9,981 individuals were screened and 3,808 were randomly assigned: 1,855 in evoke (semaglutide n=928, placebo n=927) and 1,953 in evoke+ (semaglutide n=976, placebo n=977). Baseline mean age was 72.2 years (SD 7.1) and mean CDR-SB was 3.7 (SD 1.6). In evoke+, 54 participants (2.8%) had small vessel pathology. At week 104, mean CDR-SB score changes were 2.3 (SE 0.1) with semaglutide vs 2.3 (0.1) with placebo in evoke (estimated difference -0.08, 95% CI -0.35 to 0.20, p=0.57) and 2.2 (0.1) vs 2.1 (0.1) in evoke+ (difference 0.10, 95% CI -0.17 to 0.38, p=0.46). Treatment-emergent adverse events occurred in 91.2% (1,729/1,896) of participants receiving semaglutide and 84.8% (1,613/1,902) receiving placebo. Five treatment-related deaths were reported (one semaglutide, four placebo). Both trials were discontinued early due to negative clinical outcomes.
Why it matters
Despite observational and preclinical evidence suggesting GLP-1 receptor agonists reduce dementia risk, these large phase 3 trials show that oral semaglutide does not slow cognitive or functional decline in early symptomatic Alzheimer's disease.
Limits
Both trials were discontinued early due to lack of efficacy. Only an oral formulation up to 14 mg daily was tested, so findings cannot assess higher doses, subcutaneous administration, or treatment at preclinical/asymptomatic stages. Small vessel pathology was present in only 2.8% of participants in evoke+, limiting subgroup-specific conclusions.
Cited by
- context GLP-1 receptor agonist medications are currently being evaluated in major Alzheimer's disease clinical trials in non-overweight and non-obese populations.