Glucose-Lowering Therapies and Cognitive Decline: From Molecular Mechanisms to Clinical Evidence and Future...

Several lines of evidence suggest the relationship between diabetes and cognitive decline. Patients with a diagnosis of type 2 diabetes (T2D) present an increased risk of Alzheimer's disease (AD) development than the general population, and it is known that brain insulin resistance (IR) plays a key role in the conversion from mild cognitive impairment (MCI) into AD. During recent years, emerging therapeutic perspectives have been proposed with the aim of targeting T2D-related cognitive impairment, and glucose-lowering drug classes, especially glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium glucose cotransporter inhibitors (SGLT2is), demonstrated neuroprotective effects and a positive effects on cognitive function acting by several molecular mechanisms including anti-inflammatory activity, modulation of insulin signaling, and promoting the neurogenesis process. Different clinical trials showed their ability in preventing neurodegenerative decline, with numerous phase II and III trials underway in populations with AD; however, although preclinical evidence is promising and some clinical data are encouraging, translating these results into established therapeutic strategies requires larger, randomized, and controlled clinical trials with extended follow-up period, standardized cognitive assessments, and inclusion of molecular and imaging biomarkers. Addressing these gaps will be essential to determine whether glucose-lowering drug classes can be introduced into clinical practice to prevent or slow cognitive decline in patients with T2D, exerting neuroprotective activity beyond their effect on glycemic control.