Repurposing GLP-1 receptor agonists and SGLT-2 inhibitors in neurodegeneration and metabolically at-risk populations: Myth or reality? An overview of randomized clinical trials.

Neurodegenerative diseases (NDs) are increasingly recognized as multifactorial disorders in which neurometabolic dysfunction intersects with classic pathological processes, including protein misfolding, neuroinflammation, synaptic failure and neurovascular impairment. In parallel, antidiabetic drug classes, particularly glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) exert pleiotropic effects beyond glycemic control, raising interest in their potential neuroprotective properties. This review provides an in-depth overview of current clinical evidence regarding the repurposing of these agents for NDs. Clinical studies evaluating GLP-1 RAs and SGLT-2i in neurodegenerative and at-risk metabolic populations have yielded heterogeneous results. Early-phase trials and neuroimaging studies suggest potential benefits on regional brain metabolism, connectivity, and selected cognitive domains, whereas large, randomized trials have generally failed to demonstrate consistent effects. Current evidence supports biological plausibility but does not yet establish disease-modifying efficacy of GLP-1 RAs or SGLT-2i in NDs. Future studies will require longer treatment duration, earlier intervention windows, harmonized cognitive and neuroimaging endpoints, and integration of biomarker-guided patient stratification to determine whether targeting systemic and cerebral metabolic pathways can meaningfully alter neurodegenerative trajectories.