Sustained hyperglycemia in type 2 diabetes is associated with cognitive impairment and the progression of dementia-related conditions, including Alzheimer's disease.
Cognitive impairment is an undervalued long-term complication of type 2 diabetes.
Brain hyperglycemia and insulin resistance can disrupt insulin signaling, crucial for cognitive function.
Large-scale studies link systemic with poorer cognitive outcomes, which can be improved by managing plasma glucose levels.
Glucagon-like peptide-1 (GLP-1) receptor analogs and sodium glucose cotransporter 2 inhibitors (SGLT2is) may provide significant protection against cognitive dysfunction.
Metformin and dipeptidyl peptidase 4 inhibitors (DPP-4is) also show benefits for cognitive outcomes, while sulfonylureas and exogenous insulin may worsen cognitive function.
Simplified
The maintenance of cognitive function is essential for quality of life and health outcomes in later years. Cognitive impairment, however, remains an undervalued long-term complication of type 2 diabetes by patients and providers alike. The burden of sustained hyperglycemia includes not only cognitive deficits but also the onset and progression of dementia-related conditions, including Alzheimer's disease (AD). Recent research has shown that the brain maintains an independent glucose "microsystem"-evolved to ensure the availability of fuel for brain neurons without interruption by transient hypoglycemia. When this milieu is perturbed, brain hyperglycemia, brain glucotoxicity, and brain insulin resistance can ensue and interfere with insulin signaling, a key pathway to cognitive function and neuronal integrity. This newly understood brain homeostatic system operates semi-autonomously from the systemic glucoregulatory apparatus. Large-scale clinical studies have shown that systemic is also strongly associated with poorer cognitive outcomes, which can be mitigated through appropriate clinical management of plasma glucose levels. Moreover, these studies demonstrated that glucose-lowering agents are not equally effective at preventing cognitive dysfunction. Glucagon-like peptide-1 (GLP-1) receptor analogs and sodium glucose cotransporter 2 inhibitors (SGLT2is) appear to afford the greatest protection; metformin and dipeptidyl peptidase 4 inhibitors (DPP-4is) also significantly improved cognitive outcomes. Sulfonylureas (SUs) and exogenous insulin, on the other hand, do not provide the same protection and may actually worsen cognitive outcomes. In the creation of a treatment plan, comorbid cognitive conditions should be considered. These efficacious treatments create a new gold standard of managing hyperglycemia-one which is consistent with the "complication-centric prescribing" mandates issued in type 2 diabetes treatment guidelines. The increasing longevity enjoyed by our populace places the onus on clinical care to play the "long game" in using targeted treatments for glucose control in patients with, or at risk for, cognitive decline to maintain cognitive wellness later in life. This article reviews critical emerging data for scientists and trialists and translates new enhancements in patient care for practitioners.
Key numbers
2×
Cognitive Dysfunction Risk Increase
Increased risk of dementia for individuals with diabetes vs. those without diabetes.
0.58
Odds Ratio for Dementia with SGLT2is
Odds ratio for dementia with SGLT2 inhibitors compared to other treatments.
0.58
Odds Ratio for Dementia with GLP-1 Agonists
Odds ratio for dementia with GLP-1 receptor agonists compared to other treatments.
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Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
