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Dapagliflozin and cognitive impairment: pharmacological mechanisms; translational evidence; and future directions
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DOI：10.3389/fphar.2026.1895764.png)
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Abstract
En 中文
Cognitive impairment increasingly emerges at the intersection of type 2 diabetes mellitus; vascular brain injury; chronic kidney disease; heart failure; and neurodegeneration; prompting interest in therapies that modify shared metabolic and inflammatory drivers of brain vulnerability. Dapagliflozin; a sodium-glucose cotransporter 2 inhibitor widely used in type 2 diabetes and cardiorenal disease; has attracted attention as a candidate modulator of cognitive decline because its established peripheral pharmacology extends beyond glucose lowering to include natriuresis; blood pressure reduction; weight loss; improved insulin resistance; reduced oxidative and inflammatory stress; and favorable cardiorenal effects. In this review; we examine the pharmacological basis by which these systemic actions could influence the neurovascular unit; mitochondrial homeostasis; glial activation; autophagy-related signaling; and synaptic plasticity pathways implicated in cognitive impairment. We summarize preclinical evidence suggesting that dapagliflozin can improve cognitive performance and modulate pathways such as AMPK-mTOR; Wnt/β-catenin; CREB/BDNF; oxidative stress responses; and neuroinflammatory signaling in experimental models; while also critically evaluating the limitations of these models. We then assess the current human evidence; distinguishing observational studies that suggest lower dementia risk from randomized clinical evidence that has not yet established a definitive cognition-related benefit. We argue that dapagliflozin should currently be viewed not as a proven cognitive therapeutic; but as a mechanistically plausible metabolic-neurovascular intervention whose relevance may be greatest in metabolically vulnerable phenotypes. Finally; we outline key translational challenges; including uncertainty regarding direct central target engagement; the need for biomarker-enriched trial designs; and the importance of integrating pharmacological; vascular; and neurodegenerative frameworks in future studies.
Keywords:
oxidative stress
SGLT2 inhibitor
cognitive impairment
neuroinflammation
Alzheimer’s disease
mitochondrial dysfunction
dapagliflozin
neurovascular unit
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