Glucose-lowering drugs, cognition, and dementia: The clinical evidence

Type 2 diabetes mellitus (T2DM) is an important risk factor for dementia. The possibility to mitigate this risk by controlling T2DM is compelling; however, different glucose-lowering drugs have different effects on the brain by virtue of their different mechanisms of action. The clinical and epidemiological data appear mixed, warranting careful critical evaluation of the human studies. Here we examine the evidence in the context of dementia prevention and treatment, both for people with and without T2DM. We discuss the evidence on this scaffold of research directions, identifying methodological complexities in the extant literature (e.g. comparator discrepancies, changes in the therapeutic landscape), and the implications of different outcome measures (e.g. neuropsychological). We consider possible implications of cerebrovascular protection vs. effects on progression of neurodegenerative proteinopathy, and we present a research roadmap for glucose-lowering drugs in cognitive neurology, including neuroimaging, and fluid biomarkers. We conclude that there is great potential to advance personalized strategies to prevent and treat dementia with glucose-lowering drugs. •Cognitive benefits of certain glucose-lowering drugs may vary by cognitive status.•Evidence of benefit remains inconclusive in people without diabetes.•Real-world epidemiological studies are needed for new drugs (GLP-1a and SGLT2i).•Neuroimaging and fluid biomarkers are needed to define specific benefits.