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| Name | Class |
|---|---|
| Nanjing First Hospital, Nanjing Medical University | OTHER |
| The Affiliated Jiangning Hospital of Nanjing Medical University | OTHER |
| Wuxi People's Hospital | OTHER |
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This is an investigator-led prospective, randomized, open label, parallel study to explore and evaluate the therapeutic effects of Liraglutide, Empagliflozin and Linagliptin on the cognitive function in T2DM patients with mild cognitive impairment (MCI), consisting of a 48-week core study followed by a 28-week extension phase.
The LIGHT-MCI trial is an investigator-led, prospective, randomized, open label, parallel, multi-center study to explore and evaluate the therapeutic effects of Liraglutide, Empagliflozin and Linagliptin on the MCI remission in T2DM patients with MCI inadequately controlled with metformin monotherapy. The trial consists of a 48-week core study followed by an extension phase through to 76 weeks and the investigators will screen in the outpatient and inpatient departments to enroll 396 patients (132 for each arm) totally with the inclusion and exclusion criteria. The patients will be randomized at a 1:1:1 ratio into Liraglutide, Empagliflozin and Linagliptin treatment group with a computer-generated random order. All patients will also continue on their existing dose and regimen of metformin throughout the study. At the baseline, clinical information collection, 100g-steamed bread meal test, biochemical measurement, body composition analysis, cognitive assessment, olfactory test and functional magnetic resonance imaging(fMRI) scan will be conducted for all patients. During the treatment period, visits at 8-week intervals will be performed to evaluate the safety of drugs and adjust the dose of metformin if hypoglycaemia occurs; meanwhile, fasting and 2-hour postprandial plasma glucose assayed by fingerstick, physical examination, and olfactory test will be conducted. Participants who complete the 48-week core study will have the option to receive an additional 28 weeks of intervention after signing an extension consent form. At 48 and 76 weeks of treatment, all of the assessments will be performed again for all recruited subjects, including early withdrawal patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Liraglutide | Experimental | Liraglutide will be titrated from 0.6mg/day to a final dose 1.8mg/day during the first 2 weeks, if well tolerated. Meanwhile, All patients will also continue on their existing dose and regimen of metformin throughout the study. Visits at 8-week intervals will be performed to evaluate the safety of drugs. Metformin dose can be reduced in response to hypoglycaemia, but liraglutide could not be adjusted. If the plasma glucose still not achieve the target at the maximum dose, the maximum dose will be maintained until the completion of the study. |
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| Empagliflozin | Experimental | Empagliflozin will be initiated and maintained at 10mg/ day every morning until the completion of the study. Meanwhile, All patients will also continue on their existing dose and regimen of metformin throughout the study. Visits at 8-week intervals will be performed to evaluate the safety of drugs. Metformin dose can be reduced in response to hypoglycaemia, but Empagliflozin could not be adjusted. If the plasma glucose still not achieve the target at the maximum dose, the maximum dose will be maintained until the completion of the study. |
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| linagliptin | Experimental | linagliptin will be initiated at 5mg/ day every morning. Meanwhile, All patients will also continue on their existing dose and regimen of metformin throughout the study. Visits at 8-week intervals will be performed to evaluate the safety of drugs. Metformin dose can be reduced in response to hypoglycaemia, but linagliptin could not be adjusted. If the plasma glucose still not achieve the target at the maximum dose, the maximum dose will be maintained until the completion of the study. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Liraglutide | Drug | Liraglutide will be titrated from 0.6mg/day to 1.8mg/day during the first 2 weeks, if well tolerated. All patients will also continue on their existing dose and regimen of metformin throughout the study |
| Measure | Description | Time Frame |
|---|---|---|
| Mild cognitive impairment (MCI) remission rate | MCI mitigation is defined by three criteria: an education-adjusted score of the Montreal Cognitive Assessment (MoCA) ≥26, no cognitive deficits in any explored cognitive subdomain, including processing speed, executive function, immediate memory, visuospatial construction ability, language, attention and delayed memory, evaluated by Trail-Making Test, Stroop Color-Word Test and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively, and preservation of ability to perform instrumental activity of daily living (IADL) with a Functional Activities Questionnaire (FAQ) score <5. | The core study spans from baseline to 48 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in score of Mini-Mental State Examination (MMSE) | The MMSE contains a total of 30 items that assess orientation, registration, attention and calculation, recall, and language, with a score range from 0 to 30. Generally, a higher MMSE score reflects a better cognitive function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
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Inclusion criteria
Participants aged ≥40 and ≤75 years, of any gender.
Type 2 diabetes diagnosed according to the American Diabetes Association criteria
Mild cognitive impairment diagnosed according to the established criteria
Treatment with a stable glucose lowering regimen of metformin monotherapy (≥ 1,000 mg daily) or combination with sulfonylurea/glibenclamide/glycosidase inhibitor/basal insulin over the previous 3 months
Glycosylated hemoglobin (HbA1c) during screening between ≥7.0% and ≤10.0%
BMI of ≥ 19 kg/m2
Education duration of ≥6 years
Right-handed participants
Understanding of the research procedures and methods, potential benefits and risks of the trial, and sign written informed consent
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Yan Bi, MD, PhD | The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Endocrinology, Changzhou No.2 People's Hospital, the Affiliated Hospital of Nanjing Medical University | Changzhou | Jiangsu | 213000 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31221697 | Result | Zhang Z, Zhang B, Wang X, Zhang X, Yang QX, Qing Z, Zhang W, Zhu D, Bi Y. Olfactory Dysfunction Mediates Adiposity in Cognitive Impairment of Type 2 Diabetes: Insights From Clinical and Functional Neuroimaging Studies. Diabetes Care. 2019 Jul;42(7):1274-1283. doi: 10.2337/dc18-2584. Epub 2019 May 21. | |
| 29500313 | Result |
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| ID | Type | URL | Comment |
|---|---|---|---|
| 10.6084/m9.figshare.30994510 | Statistical Analysis Plan | View IPD |
Data Availability:
De-identified participant data may be shared with qualified researchers upon request, subject to review and approval.
Access Conditions:
Data requests require a valid research proposal and signed data use agreement. Approval is contingent on compliance with applicable laws and ethical guidelines.
Timing:
Data will become available after study completion and primary publication.
Restrictions:
Certain data types may be excluded due to privacy or regulatory requirements.
Contact:
Requests should be submitted to the study sponsor for consideration.
Data will become available after study completion and primary publication for 3 years.
Data requests require a valid research proposal and signed data use agreement. Approval is contingent on compliance with applicable laws and ethical guidelines.
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| Changzhou No.2 People's Hospital |
| OTHER |
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| Empagliflozin | Drug | Empagliflozin will be initiated and maintained at 10mg/ day every morning until the completion of the study. All patients will also continue on their existing dose and regimen of metformin throughout the study. |
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| Linagliptin | Drug | Iinagliptin will be initiated at 5mg/ day every morning until the completion of the study. All patients will also continue on their existing dose and regimen of metformin throughout the study. |
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| Changes in score of MoCA | The MoCA (Chinese version) is a screening instrument for MCI comprised of 30 items to assess multiple cognitive domains (memory recall, visuospatial abilities, executive functions, attention, language, and orientation to time and place; scores range from 0 to 30, with higher scores indicating better cognitive function). Participants received one additional point if they had a MoCA score < 30 and 12 years or less of formal school education. | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in total score of RBANS | The RBANS (Chinese version) is a brief neuropsychological screening battery with established test-retest reliability and age-appropriate normative data, which consists of 12 task tests assessing 5 cognitive domains, namely immediate memory, visuospatial/ constructional, language, attention and delayed memory, with a score range from 40 to 160. A higher RBANS score reflects a better global cognitive function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in the RBANS index score of immediate memory | The RBANS (Chinese version) is a brief neuropsychological screening battery with established test-retest reliability and age-appropriate normative data. The RBANS includes 12 sub-tests that generate five age-adjusted index scores and a total score. The five indices include immediate memory (consisting of list learning and story memory tests), visuospatial/constructional domain (consisting of figure copying and line orientation tests), language (consisting of picture naming and semantic fluency tests), attention (consisting of digit span and coding tests) and delayed memory (consisting of list recall, story recall, figure recall and list recognition tests). Generally, a higher index score reflects a better cognitive subdomain function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in the RBANS index score of visuospatial/constructional | Measurements and instruments are the same as the RBANS index score of immediate memory. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in the RBANS index score of language | Measurements and instruments are the same as the RBANS index score of immediate memory. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in the RBANS index score of attention | Measurements and instruments are the same as the RBANS index score of immediate memory. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in the RBANS index score of delayed memory | Measurements and instruments are the same as the RBANS index score of immediate memory. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in aggregate time to test completion for Trail Making Test (TMT) | The TMT is a validated timed measure of processing speed, which consists of part A and part B (TMT-A and TMT-B). The time limits for performing the TMT-A and TMT-B are 180 and 300 seconds, respectively. Processing speed is estimated by the aggregate time in seconds to complete TMT-A and TMT-B such that less time indicate faster processing speed. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in aggregate time to test completion for Victoria Stroop Color-Word Test | The Victoria Stroop Color-Word Test is a well-known measure of executive function. There are three indices including Stroop-dot, Stroop-word and Stroop-color word in the test. The color task consists of colored dots; the word task comprises ordinary words that are unrelated to the meaning of color; the color-word task consists of words written in color that indicate the meaning of the color, but the color of these words differs from the meaning of the word itself. The participants were asked to quickly read the color of the dots or Chinese words on the cards. The sum of consuming time taken to read the three cards is used as an index of executive function performance. Less time indicates better executive function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived total brain volume | Philips TX 3.0T superconducting clinical MRI will be used for magnetic resonance scanning (Philips Achieva 3T TX Medical Systems, Eindhoven, the Netherlands). T1 images were processed using Freesurfer software (version 8.1.0, https://surfer.nmr.mgh.harvard.edu) to calculate intracranial volume, total gray matter volume, total white matter volume, cerebrospinal fluid volume and volumes of 68 cortical and 14 subcortical regions based on the Desikan-Killiany atlas23. The total brain volume was calculated as the sum of the gray matter and white matter volumes. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived total gray matter volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived total white matter volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived cerebrospinal fluid volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived white matter hyperintensity volume (WMH) | Total white matter hyperintensity volume was measured from FLAIR images using the Lesion Segmentation Tool for Statistical Parametric Mapping (SPM) 12.0. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived frontal gray matter volume | Measurements and instruments are the same as total brain volume. Frontal gray matter volume was calculated as the sum of all frontal lobe regions parcellated by FreeSurfer (Desikan-Killiany atlas). | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived parietal gray matter volume | Measurements and instruments are the same as total brain volume. Parietal gray matter volume was calculated as the sum of all parietal lobe regions parcellated by FreeSurfer (Desikan-Killiany atlas). | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived temporal gray matter volume | Measurements and instruments are the same as total brain volume. Temporal gray matter volume was calculated as the sum of all temporal lobe regions parcellated by FreeSurfer (Desikan-Killiany atlas). | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived occipital gray matter volume | Measurements and instruments are the same as total brain volume. Occipital gray matter volume was calculated as the sum of all occipital lobe regions parcellated by FreeSurfer (Desikan-Killiany atlas). | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived insula gray matter volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived hippocampal volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived parahippocampal volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived entorhinal cortex volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived inferior parietal lobule volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived precuneus volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived cuneus volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived thalamus volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived caudate nucleus volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived putamen volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived pallidum volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived amygdala volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in MRI-derived accumbens volume | Measurements and instruments are the same as total brain volume. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in mean fractional anisotropy (FA) in white matter derived from diffusion tensor imaging (DTI) | Diffusion Toolbox in FMRIB Software Library (FSL, version 6.0.7, http://fsl.fmrib.ox.ac.uk/fsl/fslwiki) was used to process all DTI-scans, and generate FA maps. FA from DTI assessment is a global microstructural integrity measure, with higher value indicating better integrity. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in mean diffusivity (MD) in white matter derived from DTI | Measurement and instruments are the same as FA. MD describes the overall diffusion and motion of water molecules, with higher MD values reflect more water mobility. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in fractional volume of free water in white matter (FW-WM) | FW-WM maps were constructed from preprocessed diffusion-weighted images using a regularized bi-tensor model and the open-source software package Diffusion Imaging in Python (also known as Dipy) algorithm (https://dipy.org/). Elevated FW -WM suggests the stagnation of fluid drainage caused by glymphatic dysfunction. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in diffusion tensor image analysis along the perivascular space (DTI-ALPS) index | The ALPS index was analyzed on DTI images using a method developed and validated by Taoka et al. ALPS index = (mean (Dxxproj, Dxxassoc)) ∕ (mean (Dyyproj, Dzzassoc)). The ALPS indices in the bilateral hemispheres were calculated, respectively, and the mean was used in further analyses. The DTI-ALPS index is calculated from the diffusivity along the deep medullary vein at the level of the lateral ventricle body, as a measure of perivascular clearance activity in the human brain. It is validated as a non-invasive proxy for glymphatic functioning, with higher value indicating better function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in perivascular space volume fraction in white matter (PVSVF-WM) | PVSs were mapped from T2W images using an automated and highly reliable quantification method, following the pipeline of previous studies. The PVS volume fraction (PVSVF) = PVS volume/intracranial volume. The PVSVF-WM is a quantitative metric that reflects the distribution and dilatation of perivascular spaces within cerebral white matter. An elevated volume fraction may suggest impaired clearance function of brain interstitial fluid. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in functional MRI-derived odor-induced brain activation | Task-evoked activation was assessed using FSL FEAT (version 6.0.7), which use general linear modelling to estimate scent effects on brain activation. Bilateral parahippocampus, amygdala, piriform cortex, insula, orbitofrontal cortex, and hippocampus in Automated Anatomical Labeling templates and Brodmann areas 28 and 34 (entorhinal cortices) were extracted and merged as olfactory regions of interest (ROIs) (total cluster size 5,029 voxels) for further analyses. | from baseline to the 48 weeks of treatment. |
| Changes in plasma amyloid beta (Aβ)42/Aβ40 concentration | Plasma Aβ40 and Aβ42 concentration were measured using the Neurology 4-plex E assay kit from Quanterix. | from baseline to the 48 weeks of treatment. |
| Changes in plasma phosphorylated tau (p-tau)181 concentration | Plasma p-tau 181 concentration was measured using the p-Tau181 Advantage PLUS kit from Quanterix. | from baseline to the 48 weeks of treatment. |
| Changes in plasma p-tau 217 concentration | Plasma p-tau 217 concentration was measured using the ALZpath p-Tau217 Advantage PLUS kit from Quanterix. | from baseline to the 48 weeks of treatment. |
| Changes in plasma neurofilament light chain (NfL) concentration | Plasma NfL concentration was measured using the Neurology 4-plex E assay kit from Quanterix. | from baseline to the 48 weeks of treatment. |
| Changes in plasma glial fibrillary acidic protein (GFAP) concentration | Plasma GFAP concentration was measured using the Neurology 4-plex E assay kit from Quanterix. | from baseline to the 48 weeks of treatment. |
| Changes in resting-state functional MRI-derived brain network connectivity | The whole-brain network functional connectivity analysis was carried out using the CONN Toolbox (v.22.v2407). The Schaefer-Yeo 7-network functional atlas was used to parcellate the cortex into 400 volumetric functional parcels, and the Melbourne Subcortical Atlas was used to parcellate the subcortex into 54 functional nuclei, yielding a total of 454 regions. For each participant, the pre-processed resting-state fMRI time series was spatially averaged across all voxels composing each region, yielding an averaged time series for each region. The Pearson correlation coefficient was computed between all pairs of regions from the combined cortical and subcortical atlases to provide a measure of functional connectivity, yielding a 454*454 symmetric connectivity matrix for each individual. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in olfactory threshold scores | Olfactory Function Assessment by Computerized Testing (OLFACT®, Osmic Enterprises, Inc.) was administered to assess olfactory threshold, identification, and memory. The olfactory threshold test (score range, 1-14) was a forced-choice paradigm based on serial dilutions of N-butanol solutions. Higher scores indicate better olfactory function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in olfactory identification scores | Olfactory Function Assessment by Computerized Testing (OLFACT®, Osmic Enterprises, Inc.) was administered to assess olfactory threshold, identification, and memory. The olfactory identification (score 0-30) and memory (score 0-20) subtests consisted of two sequential phases separated by a 10-min interval. During task A, participants performed forced-choice identification of 10 distinct odors. In task B, they were presented with 20 odors (10 from task A and 10 novel distractors) and required to complete two tasks per odor: identify the odor, then classify it as 'old' or 'new' (relative to task A). Higher scores indicate better olfactory function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in olfactory memory scores | Olfactory Function Assessment by Computerized Testing (OLFACT®, Osmic Enterprises, Inc.) was administered to assess olfactory threshold, identification, and memory. The olfactory identification (score 0-30) and memory (score 0-20) subtests consisted of two sequential phases separated by a 10-min interval. During task A, participants performed forced-choice identification of 10 distinct odors. In task B, they were presented with 20 odors (10 from task A and 10 novel distractors) and required to complete two tasks per odor: identify the odor, then classify it as 'old' or 'new' (relative to task A). Higher scores indicate better olfactory function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in olfactory assessment total scores | The sum of the olfactory threshold, identification, and memory scores was referred to as the olfactory assessment total scores, which ranged from 0 to 64 points. Higher scores indicate better olfactory function. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in glycated haemoglobin (HbA1c) levels | Glycated haemoglobin A1c (HbA1c). | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in fasting plasma glucose levels | Fasting plasma glucose. | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in 2-hour postprandial plasma glucose levels | 2-hour postprandial plasma glucose. | from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in fasting insulin | Fasting insulin. | from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in fasting C-peptide levels | Fasting C-peptide levels. | from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in 2-hour postprandial insulin | 2-hour postprandial insulin. | from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in 2-hour postprandial C-peptide levels | 2-hour postprandial C-peptide levels. | from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in pancreatic islet function (HOMA2-β) | Pancreatic islet function (HOMA2-β) was estimated from fasting C-peptide via HOMA2 Calculator (v2.2.3, http://www.dtu.ox.ac.uk/homacalculator/) . | from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in insulin sensitivity (HOMA2-S) | Insulin sensitivity (HOMA2-S) was estimated from fasting C-peptide via HOMA2 Calculator (v2.2.3, http://www.dtu.ox.ac.uk/homacalculator/) . | from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in insulin resistance indexes (HOMA2-IR) | Insulin resistance indexes (HOMA2-IR) was estimated from fasting C-peptide via HOMA2 Calculator (v2.2.3, http://www.dtu.ox.ac.uk/homacalculator/) . | from baseline to weeks 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in fasting serum triglyceride levels | Fasting serum triglyceride levels | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in fasting serum total cholesterol levels | Fasting serum total cholesterol levels | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in fasting serum high-density lipoprotein-cholesterol levels | Fasting serum high-density lipoprotein-cholesterol levels | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in fasting serum low-density lipoprotein-cholesterol levels | Fasting serum low-density lipoprotein-cholesterol levels | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in visceral fat area | Visceral fat area was measured by Inbody 720 analyser. | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in percent body fat | Percent body fat was measured by Inbody 720 analyser. | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in liver stiffness | Liver stiffness measurement was quantified by FibroTouch® system | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in liver fat controlled attenuation parameter | Liver fat controlled attenuation parameter was quantified by FibroTouch® system | from baseline to weeks 24, 48, and 76 of treatment (the core study spans from baseline to 24, and 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Change in blood pressure | Systolic and diastolic blood pressure | from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase). |
| Change in body weight | Body weight | from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase). |
| Change in body mass index | Body mass index | from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase). |
| Change in waist circumference | Waist circumference | from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase). |
| Change in hip circumference | Hip circumference | from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase). |
| Change in waist to hip ratio | Waist circumference to hip circumference ratio | from baseline to week 48. (Measurements will be performed every 8 weeks until week 76, with data collected after week 48 will be analyzed and reported after the extension phase). |
| Changes in Barthel index | Basic activities of daily living (BADL) ability measured by the Barthel index. The Barthel Index (Chinese version) measures dependence in 10 basic personal activities of daily living such as showering, feeding, and walking. Ten items are rated, for a maximum score of 100 representing total independence. A "good" score is ≥ 60 points, which indicates that the patient is capable of basic self-care. Moderate dysfunction is defined as a score between 40 and 60, indicating that the patient needs help in daily life. Severe dysfunction is defined as a score between 20 and 40, indicating that the patient is significantly dependent on help in daily living. A score below 20 indicates a total disability in which the patient depends on help for all aspects of daily living. The measure is completed based on input from the direct care worker providing care to the participants on the day testing. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Changes in FAQ score | Instrumental activities of daily living (IADL) ability measured by FAQ scores. The Functional Activities Questionnaire (FAQ, Chinese version) is a standardized assessment of instrumental activities of daily living such as preparing balanced meals and managing personal finances. Sum scores range from 0 to 30, with higher scores indicating worse function. Functional dependence is considered with scores ≥5 points. | from baseline to week 48, and 76 of treatment (the core study spans from baseline to 48 weeks, and the week 76 assessment will be analyzed and reported after the extension phase). |
| Mild cognitive impairment (MCI) remission rate at week76 | MCI mitigation is defined by three criteria: an education-adjusted score of the Montreal Cognitive Assessment (MoCA) ≥26, no cognitive deficits in any explored cognitive subdomain, including processing speed, executive function, immediate memory, visuospatial construction ability, language, attention and delayed memory, evaluated by Trail-Making Test, Stroop Color-Word Test and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively, and preservation of ability to perform instrumental activity of daily living (IADL) with a Functional Activities Questionnaire (FAQ) score <5. | from baseline to week 76 of treatment (the week 76 assessment will be analyzed and reported after the extension phase). |
| Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University | Nanjing | Jiangsu | 210000 | China |
| Department of Endocrinology, the Affiliated Drum Tower Hospital of Nanjing University Medical School | Nanjing | Jiangsu | 210008 | China |
| Department of Endocrinology, the Affiliated Jiangning Hospital of Nanjing Medical University | Nanjing | Jiangsu | 211100 | China |
| Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University | Wuxi | Jiangsu | 214000 | China |
| Zhang Z, Zhang B, Wang X, Zhang X, Yang QX, Qing Z, Lu J, Bi Y, Zhu D. Altered Odor-Induced Brain Activity as an Early Manifestation of Cognitive Decline in Patients With Type 2 Diabetes. Diabetes. 2018 May;67(5):994-1006. doi: 10.2337/db17-1274. Epub 2018 Mar 2. |
| 35263425 | Result | Cheng H, Zhang Z, Zhang B, Zhang W, Wang J, Ni W, Miao Y, Liu J, Bi Y. 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. Diabetes Care. 2022 May 1;45(5):1201-1210. doi: 10.2337/dc21-2064. |
| 40840993 | Derived | Yu C, Yang H, Zhang B, Chen S, Yang S, Li F, Zhu W, Zhai B, Wu T, Zhao S, Zhang W, Tong X, Duan Y, Zhang L, Chao Y, Wu J, Zhu X, Wang K, Ye X, Zhang X, Xu X, Cheng H, Liu J, Zhang J, Wang Y, Zhang Z, Yan W, Bi Y. Evaluating the effects of liraglutide, empagliflozin and linagliptin on mild cognitive impairment remission in patients with type 2 diabetes (LIGHT-MCI): study protocol for a multicentre, randomised controlled trial with an extension phase. BMJ Open. 2025 Aug 21;15(8):e095382. doi: 10.1136/bmjopen-2024-095382. |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
Not provided
Not provided
| ID | Term |
|---|---|
| D000069450 | Liraglutide |
| D008687 | Metformin |
| C570240 | empagliflozin |
| D000069476 | Linagliptin |
| ID | Term |
|---|---|
| D052216 | Glucagon-Like Peptide 1 |
| D004763 | Glucagon-Like Peptides |
| D052336 | Proglucagon |
| D005768 | Gastrointestinal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D011799 | Quinazolines |
Not provided
Not provided