Glucose-Lowering Therapies, New Expectations for Brain Health: Emerging Promise and Uncertainty

As the population ages, the burden of type 2 diabetes mellitus and dementia is increasing. Type 2 diabetes is associated with a 1.5- to 2-fold increased risk of dementia through mechanisms that include hyperglycemia-induced oxidative stress, inflammation, microvascular injury, and insulin resistance. Current diabetes management targets not only glycemic control but also a reduction in cardiovascular and renal complications. This is largely attributable to novel antidiabetic agents, such as glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors, which have demonstrated cardiovascular, renal, and metabolic benefits beyond glycemic control. These pleiotropic effects have raised the possibility that these therapies may also have beneficial effects on brain health, and observational studies have suggested a reduced risk of dementia. However, the evoke and evoke+ trials of oral semaglutide in early Alzheimer’s disease did not demonstrate significant cognitive benefit. These findings appear to be inconsistent with previous observational studies; it would be premature to conclude that antidiabetic therapies have no beneficial effects on brain health or dementia prevention. Further studies are needed to evaluate the effects of these therapies across diverse dementia subtypes, including vascular dementia.