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

Abstract

OBJECTIVE The comparative neuroprotective effects of different antidiabetes drugs have not been characterized in randomized controlled trials. Here, we investigated the therapeutic effects of liraglutide, dapagliflozin, or acarbose treatment on brain functional alterations and cognitive changes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS 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 MRI (fMRI) scan and a battery of cognitive assessments were evaluated pre- and postintervention in all subjects. RESULTS The 16-week treatment with liraglutide significantly enhanced the impaired odor-induced left hippocampal activation with Gaussian random field correction and improved cognitive subdomains of delayed memory, attention, and executive function (all P < 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 (β = 0.330, P = 0.022) and delayed memory (β = 0.410, P = 0.004) as well as to the metabolic ameliorations of reduced waist circumference, decreased body fat ratio, and elevated fasting insulin (all P < 0.05). CONCLUSIONS Our head-to-head study demonstrated that liraglutide 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 novel treatment strategy for individuals with diabetes and a high risk of cognitive decline.

Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomization study

“…By reviewing existing clinical trial and/or MR studies of medication treatment and/or drug repurposing on Alzheimer’s disease, we found that cholinesterase inhibitors and NMDA receptor antagonist were the two most widely used anti-dementia medications 42,43 , which were recommended by the current National Institute for Health and Care Excellence (NICE) guidance for people with Alzheimer’s disease (https://www.nice.org.uk/guidance/cg42). We also found some evidence to support the role of liraglutide (one GLP-1 inhibitor) and most of the anti-hypertensive drugs on preventing/delaying cognitive impairment 37,38,39,40,41 . The level of prevention of liraglutide was similar to the effect estimate we observed on metformin targets (14%) 37 .…”

“…By reviewing existing clinical trial and/or MR studies of drug repurposing on Alzheimer's disease, we found some evidence to support the role of liraglutide (one GLP-1 inhibitor) and most of the anti-hypertensive drugs on preventing/delaying cognitive impairment 37,38,39,40,41 .…”

Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomisation study

“…By reviewing existing clinical trial and/or MR studies of medication treatment and/or drug repurposing for Alzheimer's disease (from inception to 1 March 2021), we found some evidence to support the role of liraglutide (a GLP-1 inhibitor) and most of the antihypertensive drugs on preventing/ delaying cognitive impairment [37][38][39][40][41]. The level of prevention of dulaglutide (another GLP-1 inhibitor) was similar to the effect estimate we observed on metformin targets (14%) [37].…”

Altered brain spontaneous and synchronization activity in latent autoimmune diabetes in adults: A resting‐state functional MRI study

“…During the functional MRI scan, the individuals were asked to lie quietly with their eyes closed but not to fall asleep, not to think of anything in particular, and to avoid head movement. Structural images and functional images were obtained axially using the parameters described in our previous articles 16 . Additionally, fluid‐attenuated inversion recovery (FLAIR) scans were acquired with the following settings: repetition time/echo time (TR/TE) = 7000/120; slices = 18; thickness = 6 mm; gap = 1.3 mm; flip angle = 110°; and voxel size = 0.65 × 0.95 × 6 mm 3 .…”

“…Statistical Parametric Mapping (SPM12, Wellcome Trust Centre for Human Neuroimaging) and Data Processing and Analysis for Brain Imaging (DPABI_V4.2_190919, https://rfmri.org/dpabi) were used to preprocess fMRI data. Statistical Parametric Mapping preprocessing was undertaken in seven distinct steps in accordance with our previous study 16 . Anatomical images were processed using FreeSurfer, version 5.3 (http://surfer.nmr.mgh.harvard.edu/) with thorough manual editing to obtain cortical parcellations according to the Desikan‐Killiany Atlas.…”