Sodium-Glucose Cotransporter 2 Inhibitors: An Emerging Therapeutic Approach for Ischemic Stroke Management

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a cornerstone therapy for type 2 diabetes mellitus (T2DM) and heart failure, are emerging as a promising therapeutic class for the management of ischemic stroke (IS). Given that T2DM is a significant risk factor for IS, understanding the potential neuroprotective role of SGLT2i is of paramount clinical importance. This review provides a systematic and logically structured synthesis of the current evidence, beginning with foundational preclinical studies in animal models that consistently demonstrate a reduction in infarct volume and improved neurological outcomes. We then transition to the extensive clinical evidence, primarily from large-scale real-world observational studies, that has confirmed a significant reduction in stroke risk, particularly in high-risk T2DM populations. The strengths and limitations of this evidence base are critically appraised, highlighting the robustness of the findings while acknowledging the predominantly observational nature of the data and the lack of stroke-specific primary endpoints in major trials. The neuroprotective benefits of SGLT2i appear to be multifactorial; this review delves into the potential mechanisms, emphasizing a foundational, glucose-dependent pathway of ameliorating hyperglycemia-induced neurotoxicity, which is complemented by a suite of pleiotropic, glucose-independent effects, including the induction of mild ketosis, attenuation of neuroinflammation, and preservation of the neurovascular unit. Finally, we address the key clinical challenges to their application, such as the management of euglycemic ketoacidosis, and outline crucial directions for future research, underscoring the need for dedicated randomized trials.