SGLT-2 Inhibitors in the Prevention and Progression of Neurodegenerative Diseases: A Narrative Review.

Neurodegenerative diseases are among the most prevalent and debilitating disorders in aging populations. Despite growing insights into their complex pathophysiology, effective disease-modifying treatments remain limited. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, primarily used in type 2 diabetes mellitus, have recently gained attention for their potential neuroprotective effects. This narrative review aims to summarize the current preclinical and clinical evidence on the impact of SGLT-2 inhibitors on neurodegenerative diseases, exploring their mechanisms of action, therapeutic potential, and limitations. The authors reviewed experimental studies, animal models, clinical trials, and observational data focusing on the potential links between SGLT-2 inhibitors and neurodegeneration. We further analyzed proposed mechanisms-including metabolic, inflammatory, and vascular factors-in the context of their potential contribution to, or consequence of, neurodegenerative processes, emphasizing their interdependence rather than treating neurodegeneration as an isolated phenomenon. Preclinical studies consistently show that SGLT-2 inhibitors reduce neuroinflammation, improve mitochondrial function, enhance insulin sensitivity in the brain, and may mitigate amyloid and tau pathology. Observational clinical data suggest a lower incidence of dementia in patients treated with SGLT-2 inhibitors. However, cognitive outcomes have not been directly assessed in major randomized trials to date. SGLT-2 inhibitors hold promise as modulators of neurodegenerative processes, but robust clinical trials with cognitive endpoints are needed to confirm their therapeutic relevance. Their potential to bridge metabolic and neurodegenerative pathways highlights a novel avenue for future research and therapeutic development.