Dulaglutide and neurodegeneration biomarkers: REWIND post hoc analysis

INTRODUCTION: This post hoc analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial examined associations between dulaglutide, Alzheimer's disease and related dementia (ADRD) biomarkers, and substantive cognitive impairment (SCI). METHODS: Participants (dulaglutide, n = 3741; placebo, n = 3627) completed cognitive tests and provided blood samples at baseline and 2 years, with additional cognitive tests at 5-year and final visits. Analysis of covariance and Cox models tested associations between dulaglutide, SCI, and plasma neurofilament light chain (NfL), phosphorylated tau217 (p-tau217), and glial fibrillary acidic protein (GFAP) biomarkers. RESULTS: Dulaglutide-associated changes in biomarkers or SCI were nonsignificant overall. Participants with NfL ≥56 pg/mL had a dulaglutide-associated 2-year reduction in NfL (-27.4% vs -14.2%; p = 0.003). Participants with p-tau217 ≥25 pg/mL had a dulaglutide-associated SCI reduction (hazard ratio = 0.78; p = 0.0064). DISCUSSION: Dulaglutide reduced NfL and SCI in participants with select elevated plasma ADRD biomarkers, with limited 2-year effects on p-tau217 and GFAP. Future studies with longer follow-up should explore incretin-related cognitive changes. CLINICAL TRIAL REGISTRATION INFORMATION: NCT01394952, registered July 15, 2011.