GLP-1 receptor treatment in Alzheimer's disease after EVOKE: moving from one idea to targeted approaches

The phase 3 EVOKE and EVOKE+ trials of oral semaglutide in early Alzheimer's disease missed their primary endpoint and all cognitive or functional secondary endpoints.

• Extension-phase data suggest some partial separation at later timepoints, which may not be conclusive.
• Limited brain penetration is proposed as a reason for the trials' failure to meet endpoints.
• Cohorts that attrited from the studies are considered to have limited inferential weight.
• A biomarker substudy complicates interpretations regarding disease modification.
• The findings do not refute the cardiometabolic hypothesis but raise new questions about potential pathways, patient selection, and disease stages for treatment benefit.

Simplified