GLP-1 receptor agonism in Alzheimer's disease after EVOKE: From single hypothesis to stratified program.

Abstract

The phase 3 EVOKE and EVOKE + trials of oral semaglutide in early Alzheimer's disease missed their primary endpoint and every cognitive or functional secondary endpoint. A recent article by Hölscher revisits extension-phase data and reports partial separation at later timepoints, attributing the failure to limited brain penetration. We argue that attrited extension cohorts bear limited inferential weight and that the biomarker substudy, read in full, complicates a clean disease-modification reading. EVOKE does not refute the cardiometabolic hypothesis but reframes the open questions: which pathways, which patients, and which disease stages are most likely to benefit.