Effects of Liraglutide, Empagliflozin and Linagliptin on the Cognitive Function in T2DM Patients With Mild Cognitive Impairment: a Multicenter, Randomized, Parallel Controlled Clinical Trial
- Conditions
- Type 2 Diabetes MellitusMild Cognitive Impairment
- Interventions
- Registration Number
- NCT05313529
- Lead Sponsor
- The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
- Brief Summary
This is a prospective, randomized, open label, parallel, 76-week study to explore and evaluate the therapeutic effects of Liraglutide, Empagliflozin and Linagliptin on the cognitive function, olfactory function, and odor-induced brain activation in T2DM patients with mild cognitive impairment (MCI).
- Detailed Description
This is a prospective, randomized, open label, parallel, 76-week study to explore and evaluate the therapeutic effects of Liraglutide, Empagliflozin and Linagliptin on the cognitive function, olfactory function, and odor-induced brain activation in T2DM patients with MCI inadequately controlled with metformin monotherapy. The investigators will screen in the outpatient and inpatient departments to enroll 324 patients (108 for each arm) totally with the inclusion and exclusion criteria in 76 weeks. 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. At the end of the study, all of the assessments will be performed again for all recruited subjects, including early withdrawal patients.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 324
- patients with type 2 diabetes mellitus ;
- Aged:40 -75 years ;
- Cognitive function assessment suggests mild cognitive impairment;
- A stable glucose-lowering regimen include Metformin alone or in combination with sulfonylureas , glinides , glycosidase inhibitors or basic insulin for more than 3 months, and the dose of metformin≥1.0g/d;
- HbA1c 7 - 10%;
- ≥6 years education;
- Right-handed.
- Cognitive function assessment suggests normal cognition or dementia;
- Other dementia related neurological diseases or depression, Mental dysplasia, mania, schizophrenia, etc in the past 2 years; Central nervous system diseases, including brain trauma, intracranial hemorrhage, acute cerebral infarction, etc;
- Severe sinusitis, nasal cavity and sinus polyps, skull base or nasopharyngeal tumors and other space occupying lesions;
- Congenital diseases and traumatic history of nose, maxillofacial and skull base affecting olfaction. · With symptoms of upper respiratory tract infection, including nasal congestion, runny nose, fever, etc. on the day of MR examination;
- Diabetic Acute and chronic complications, including diabetic ketoacidosis, diabetic ketoacidosis; a hyperglycemic hyperosmolar state or severe hypoglycemic coma, etc.
- Severe impairment of heart, liver, kidney and other organs;
- Contraindications of MRI examination, such as implantation of metal prosthesis in vivo, claustrophobia, etc;
- Pregnant and lactating women;
- Receive other test drugs currently or within 6 months before participating in the project;
- Known or suspected allergic history to the test drug or similar drugs; GLP-1 receptor agonist, SGLT2 inhibitor and DPP4 inhibitor were used in recent 3 months.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Liraglutide Liraglutide 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. Empagliflozin Empagliflozin 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. linagliptin Linagliptin 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.
- Primary Outcome Measures
Name Time Method Mild cognitive impairment (MCI) remission rate at week48 The core study spans from baseline to 48 weeks MCI mitigation is defined by three criteria: an education-adjusted score of the Montreal Cognitive Assessment (MoCA) ≥26, no cognitive deficits in any cognitive subdomain, and preservation of ability to perform instrumental activity of daily living (IADL) with a Functional Activities Questionnaire (FAQ) score \<5. MoCA test includes attention and concentration, executive function, memory, language, visual structure skills, abstract thinking, calculation, and orientation, with a score range from 0 to 30, plus one point if the participant has 12 years or less of education. Generally, a higher MoCA score reflects a better cognitive function.
Sum scores of FAQ range from 0 to 30, with higher scores indicating worse function.
- Secondary Outcome Measures
Name Time Method Change of general cognitive function (MMSE) from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks 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.
Change of general cognitive function (MoCA) from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks evaluate changes in scores of MoCA. MoCA test includes attention and concentration, executive function, memory, language, visual structure skills, abstract thinking, calculation, and orientation, with a score range from 0 to 30, plus one point if the participant has 12 years or less of education. Generally, a higher MoCA score reflects a better cognitive function.
Change of general cognitive function (RBANS) from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks evaluate changes in total scores of Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
The Repeatable Battery for the Assessment of Neuropsychological Status (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. Generally, a higher RBANS score reflects a better cognitive function.Change of deep grey subcortical structure volumes from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks MRI-derived normalized measures of deep grey subcortical structure volumes, which include thalamus, caudate, putamen, pallidum and amygdala.
Change of lobar grey volume from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks MRI-derived normalized measures of lobar grey volume, which includes frontal, temporal, occipital and parietal.
Change of AD signature region volumes from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks MRI-derived normalized measures of AD signature region volumes, which include parahippocampal, precuneus, cuneus, entorhinal, inferior parietal lobules and hippocampus.
Change of odor-induced brain activation from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks All patients underwent odor-induced task fMRI on a 3.0T MR scanner with 222 volumes for task fMRI and 230 volumes for resting-state fMRI. The odor-induced task consisted of "fresh air" "rest" and "scent". Odor-induced brain activation was assessed by a general linear model using Statistical Parametric Mapping 12 (SPM12) software. Following extraction of the three separate conditions "fresh air," "scent," and "rest" from the whole sequence, contrasts were made for each participant between "fresh air \> rest" and "scent \> rest." Odor-induced fMRI data were analyzed in the mask of the olfactory network, including the regions of bilateral parahippocampus, amygdala, piriform cortex, insula, orbitofrontal cortex, hippocampus, and entorhinal cortices.
Change of resting-state functional connectivity from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks All patients underwent odor-induced task fMRI on a 3.0T MR scanner with 222 volumes for task fMRI and 230 volumes for resting-state fMRI. DPABI software was used to calculate the resting-state functional connectivity (FC) with a seed-based correlation analysis method. Brain areas that showed noticeably different activation of olfactory network among the three groups were selected as seed regions. Then, we extracted the time series of the signal in the seed regions and used these time series to generate voxel-wise FC maps. The parcellation scheme adopted to construct the whole-brain connectivity matrix was built upon the anatomical automatic labeling atlas, which parcellates the brain in 90 regions of interest.
Change of olfactory function from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks Whether the olfactory threshold scores of the three groups after intervention were higher than those before treatment and the difference of changes between the three groups. Olfactory testing was performed using Olfactory Function Assessment by Computerized Testing (OLFACT) (Osmic Enterprises, Inc.). Based on the University of Pennsylvania Smell Identification Test (UPSIT), OLFACT tests were computerized, standardized, and self-administered. Higher scores indicated better ability to detect odors. Threshold testing was performed by a series of binary dilutions of n-butanol solution in light mineral oil, and scores ranged from 1 to 13.5.
Change of waist circumference from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks Waist circumference
Change of hip circumference from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks Hip circumference
Change of waist to hip ratio from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks waist to hip ratio
Change of basic activities of daily living ability from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks 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.
Change of instrumental activities of daily living ability from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks 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.
Change of cognitive subdomains from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks evaluate changes in scores of each cognitive subdomain in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
Change of processing speed from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks The Trial Making Test (TMT) provides a 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 sum of the consuming time to complete TMT-A and TMT-B such that less time indicate faster processing speed.
Change of executive function from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks evaluate changes in consuming time of executive function. The Victoria Stroop Color-Word Test is a well-known measure of executive functioning. 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.
Change of total brain volume from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks MRI-derived normalized measures of total brain volume.
Change of grey matter volume from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks MRI-derived normalized measures of grey matter volume.
Change of white matter volume from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks MRI-derived normalized measures of white matter volume.
Change of cerebrospinal fluid volume from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks MRI-derived normalized measures of cerebrospinal fluid volume.
Change of white matter hyperintensity volume from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks MRI-derived normalized measures of white matter hyperintensity volume.
Change of HbA1c from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks glycated haemoglobin A1c (HbA1c)
Change of fasting and 2-hour postprandial plasma glucose from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks fasting and 2-hour postprandial plasma glucose
Change of fasting and 2-hour postprandial plasma C-peptide levels from baseline to 48 and 76 weeks Baseline, 48 and 76 weeks fasting and 2-hour postprandial plasma C-peptide levels
Change of lipid metabolism indicators from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks lipid profile (triglyceride, total cholesterol, high-density and low-density lipoprotein-cholesterol).
Change of blood pressure from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks Systolic and diastolic blood pressure
Change of body weight from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks Body weight
Change of body mass index from baseline to 24, 48 and 76 weeks Baseline, 24, 48 and 76 weeks Body mass index
Trial Locations
- Locations (5)
Department of Endocrinology, Changzhou No.2 People's Hospital, the Affiliated Hospital of Nanjing Medical University
🇨🇳Changzhou, Jiangsu, China
Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University
🇨🇳Nanjing, Jiangsu, China
Department of Endocrinology, the Affiliated Drum Tower Hospital of Nanjing University Medical School
🇨🇳Nanjing, Jiangsu, China
Department of Endocrinology, the Affiliated Jiangning Hospital of Nanjing Medical University
🇨🇳Nanjing, Jiangsu, China
Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University
🇨🇳Wuxi, Jiangsu, China
Department of Endocrinology, Changzhou No.2 People's Hospital, the Affiliated Hospital of Nanjing Medical University🇨🇳Changzhou, Jiangsu, China