Effects of Liraglutide, Empagliflozin and Linagliptin on the Cognitive Function in T2DM Patients With Mild Cognitive Impairment: a Multicenter, Randomized, Parallel Controlled Clinical Trial

Type 2 Diabetes Mellitus Clinical Trial

— LIGHT-MCI  

Official title:

A Prospective, Randomized, Open Label, Parallel, 76-week Study to Explore and Evaluate the Therapeutic Effects ofLiraglutide, Empagliflozin and Linagliptin on the Cognitive Function, Olfactory Function, and Odor-induced Brain Activation in T2DM Patients With Mild Cognitive Impairment.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05313529
• Other study ID #: ZZ2022
• Status: Recruiting
• Phase: N/A
• Start date: October 8, 2022
• Est. completion date: December 31, 2027

Study information

• Verified date: May 2024
• Source: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Contact: Yan Bi, MD, PhD
• Email: biyan[@]nju.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Recruiting
• Enrollment: 324
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 75 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Diabetes Mellitus, Type 2
• Mild Cognitive Impairment
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Liraglutide
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
• Empagliflozin
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.
• Linagliptin
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.

Locations

Country	Name	City	State
China	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

Sponsors (5)

Lead Sponsor	Collaborator
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School	Changzhou No.2 People's Hospital, Nanjing First Hospital, Nanjing Medical University, The Affiliated Jiangning Hospital of Nanjing Medical University, Wuxi People's Hospital

Country where clinical trial is conducted

China, 

References & Publications (3)

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 Par — View Citation

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 201 — View Citation

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):1274-1 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change of cognitive function	The alleviation of mild cognitive impairment in patients with type 2 diabetes (defined as a post-treatment MoCA score = 26 with no objective cognitive impairment in any cognitive domain).	from baseline to 76 weeks' follow-up
Secondary	Change of subdomains of cognitive function	whether there are differences in memory scores between the three groups before and after treatment and the difference of changes between the three groups. Memory testing was performed to let patients remember some words and stories, with a total score of 0-64. Higher scores indicated better ability.	from baseline to 76 weeks' follow-up
Secondary	Change of olfactory brain activation by fMRI	Whether the activation degree of olfactory task fMRI brain area in the three groups after intervention was different from that before treatment and the difference of changes between the three groups.; 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.	from baseline to 76 weeks' follow-up
Secondary	Olfactory function	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.	from baseline to 76 weeks' follow-up
Secondary	Change of metabolism	The changes of glycosylated hemoglobin among the three groups before and after intervention. The level of glycosylated hemoglobin <7% means better glucose metabolism.	every 12 weeks from baseline to 76 weeks' follow-up
Secondary	Change of general cognitive function	whether there are differences in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total scores between the three groups before and after treatment and the difference of changes between the three groups. The RBANS is a battery of neuropsychological tests used to assess general cognitive function, with a total score of 40-160. Higher scores indicated better ability.	from baseline to 76 weeks' follow-up