Effects of antidiabetic medications on the relationship between type 2 diabetes mellitus and cognitive impairment

Type 2 diabetes mellitus (T2DM)-related cognitive impairment (CI) has garnered increasing attention in recent research and is emerging as a highly relevant area of study. T2DM is a chronic and globally prevalent condition characterized by insulin resistance, hyperglycemia, oxidative stress, neuroinflammation, and cerebrovascular dysfunction, factors that collectively contribute to cognitive decline. Notably, T2DM is strongly associated with neurodegenerative conditions, ranging from mild cognitive impairment (MCI) to dementia. This review explores the potential neuroprotective effects of various antidiabetic drugs, including insulin-sensitizing agents (metformin and pioglitazone), sodium-glucose co-transporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is). These medications exert their effects through multiple mechanisms, such as reducing neuroinflammation and oxidative stress, decreasing Aβ accumulation and apoptosis, enhancing cerebral glucose metabolism, and promoting neuroplasticity, processes directly implicated in the interplay between T2DM and cognitive decline. The review highlights the therapeutic potential of these agents in mitigating CI and supporting brain health in individuals with T2DM. However, given the conflicting nature of current clinical evidence, further research is needed to clarify their cognitive benefits, elucidate underlying mechanisms of action, and assess their long-term effects on cognitive outcomes in this population.