Oral Semaglutide Shows No Significant Cognitive Benefit in Mild Alzheimer's Disease Patients

Alzheimer's disease (AD) is a progressive neurodegenerative condition and a major global health burden, currently lacking effective disease-modifying therapies that can slow progression or prevent cognitive decline. Existing treatments offer only symptomatic relief. Glucagon-like peptide-1 (GLP-1) analogues, like semaglutide, are being investigated for their neuroprotective effects observed in AD mouse models, suggesting a potential new therapeutic avenue to address the unmet need for disease modification in AD.

This study investigated oral semaglutide in patients with mild Alzheimer's disease across two trials, evoke and evoke+. The primary objective was to assess the safety and tolerability of the oral GLP-1RA. A secondary objective included evaluating changes in synaptic density using PET imaging before and after treatment. Patients were followed for 104 weeks to observe long-term effects on cognitive and functional deterioration, with CDR-SB as a key efficacy endpoint.

In the evoke and evoke+ studies, oral semaglutide did not demonstrate a significant difference in cognitive decline compared to placebo. The primary efficacy endpoint, CDR-SB score, showed comparable changes between treatment and placebo arms.

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 in evoke and evoke+ respectively. The estimated difference for CDR-SB was -0.08 (95% CI -0.35 to 0.20) with a p=0.57 in evoke, and 0.10 (-0.17 to 0.38) with a p=0.46 in evoke+. These results indicate no statistically significant benefit of semaglutide on cognitive and functional deterioration as measured by CDR-SB over the 104-week treatment period. The abstract does not provide specific safety or tolerability data, nor results from the PET imaging for synaptic density.