Enhancement of Impaired Olfactory Neural Activation and Cognitive Capacity by Liraglutide, but not Dapagliflozin or Acarbose, in Patients With Type 2 Diabetes: A 16-Week Randomized Parallel Comparative Study

<b>Objective:</b> <a></a><a>The comparative neuroprotective effects of different anti-diabetic drugs have not been characterized in randomized controlled trials. Here, </a><a>we investigated the therapeutic effects of liraglutide, dapagliflozin, or acarbose treatment on brain functional alterations and cognitive changes in patients with type 2 diabetes.</a> <p> </p> <p><b>Research design and methods: </b>Thirty-six patients with type 2 diabetes inadequately controlled with metformin monotherapy were randomized to receive liraglutide, dapagliflozin, or acarbose treatment for 16 weeks. Brain functional magnetic resonance imaging (fMRI) scan and a battery of cognitive assessments were evaluated <a>pre- and postintervention</a> in all subjects.</p> <p> </p> <p><b>Results: </b>The 16-week treatment with liraglutide significantly enhanced the impaired odor-induced left hippocampal activation with GRF correction, and improved cognitive subdomains of delayed memory, attention, and executive function (all <i>P</i> < 0.05), whereas dapagliflozin or acarbose did not. Structural equation modeling analysis demonstrated that such improvements of brain health and cognitive function could be partly ascribed to a direct effect of liraglutide on left hippocampal activation (<i>β</i> = 0.330, <i>P</i> = 0.022) and delayed memory (<i>β</i> = 0.410, <i>P</i> = 0.004), as well as to the metabolic ameliorations of reduced waist circumference, decreased body fat ratio, and elevated fasting insulin (all <i>P</i> < 0.05).</p> <p> </p> <p><b>Conclusions:</b> <a>Our head-to-head study demonstrated that liraglutide</a> enhanced impaired brain activation and restored impaired cognitive domains in patients with type 2 diabetes, whereas dapagliflozin and acarbose did not. The results expand the clinical application of liraglutide and provide <a>a novel treatment strategy for individuals with diabetes and a high risk of cognitive decline.</a><b></b></p>