Activation of Glucagon‐Like Peptide‐1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism‐Independent Pathway

BACKGROUND: Patients with hypertension and diabetes mellitus are susceptible to dementia, but regular therapy fails to reduce the risk of dementia. Glucagon‐like peptide‐1 receptor agonists have neuroprotective effects in experimental studies. We aimed to assess the effect of liraglutide, a glucagon‐like peptide‐1 receptor agonist, on cognitive function and whether its effect was associated with metabolic changes in patients with type 2 diabetes mellitus. METHODS AND RESULTS: Fifty patients with type 2 diabetes mellitus were recruited in this prospective study. All patients underwent cognitive assessment and brain activation monitoring by functional near‐infrared spectroscopy. At 12 weeks, patients in the glucagon‐like peptide‐1 group acquired better scores in all cognitive tests and showed remarkable improvement in memory and attention (P=0.040) test compared with the control group after multivariable adjustment. Compared with the control group, liraglutide significantly increased activation of the dorsolateral prefrontal cortex and orbitofrontal cortex brain regions (P=0.0038). After liraglutide treatment, cognitive scores were significantly correlated with changes in these activating brain regions (P<0.05), but no correlation was observed between the changes in cognitive function and changes of body mass index, blood pressure, and glycemic levels. CONCLUSIONS: We concluded that liraglutide improves cognitive decline in patients with type 2 diabetes mellitus. This beneficial effect is independent of its hypoglycemic effect and weight loss. The optimal intervention should be targeted to cognitive decline in the early stages of dementia. REGISTRATION: URL: https://www.ClinicalTrials.gov; Unique identifier: NCT03707171.