search
Back to results

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

Primary Purpose

Type 2 Diabetes Mellitus, Mild Cognitive Impairment

Status
Recruiting
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
Liraglutide
Empagliflozin
Linagliptin
Sponsored by
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus focused on measuring Functional MRI, cognition, Olfactory function, Liraglutide, Empagliflozin and Linagliptin

Eligibility Criteria

40 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • patients with type 2 diabetes mellitus ;
  • Aged:40 -75 years ;
  • Montreal Cognitive Assessment Scale (MoCA) scores 19 -25;
  • A stable glucose-lowering regimen include Metformin alone or in combination with sulfonylureas , glinides , glycosidase inhibitors, thiazolidinediones 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:

  • Mini-mental State Examination(MMSE) scores < 24;
  • 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.

Sites / Locations

  • Department of Endocrinology, Nanjing First Hospital, Nanjing Medical UniversityRecruiting
  • Division of Endocrinology, the Affiliated Drum Tower Hospital of Nanjing UniversityRecruiting
  • Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Liraglutide

Empagliflozin

linagliptin

Arm Description

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 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 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.

Outcomes

Primary Outcome Measures

Change of cognitive function
Type 2 diabetes mellitus patients with MCI were relieved of mild cognitive impairment , which means MoCA scores were not less than 26 points after treatment, or improved referring to the MoCA score or the RBANS total score increased by 0.5 standard deviation compared with baseline after treatment.

Secondary Outcome Measures

Change of other 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.
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.
Olfactory threshold test
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 metabolism
The changes of glycosylated hemoglobin among the three groups before and after intervention. The level of glycosylated hemoglobin <7% means better glucose metabolism.

Full Information

First Posted
March 19, 2022
Last Updated
May 15, 2023
Sponsor
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Collaborators
Wuxi People's Hospital, The First Affiliated Hospital with Nanjing Medical University
search

1. Study Identification

Unique Protocol Identification Number
NCT05313529
Brief Title
Effects of Liraglutide, Empagliflozin and Linagliptin on the Cognitive Function in T2DM Patients With Mild Cognitive Impairment: a Multicenter, Randomized, Parallel Controlled Clinical Trial
Official Title
A Prospective, Randomized, Open Label, Parallel, 12-month 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.
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 8, 2022 (Actual)
Primary Completion Date
August 31, 2026 (Anticipated)
Study Completion Date
August 31, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Collaborators
Wuxi People's Hospital, The First Affiliated Hospital with Nanjing Medical University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a prospective, randomized, open label, parallel, 12-month 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, 12-month 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. We have 1 principle investigator, 6 sub-investigators and 1 nurse in research centre. The sub-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 12 months. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus, Mild Cognitive Impairment
Keywords
Functional MRI, cognition, Olfactory function, Liraglutide, Empagliflozin and Linagliptin

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
324 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Liraglutide
Arm Type
Experimental
Arm Description
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.
Arm Title
Empagliflozin
Arm Type
Experimental
Arm Description
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.
Arm Title
linagliptin
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Liraglutide
Other Intervention Name(s)
metformin
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Empagliflozin
Other Intervention Name(s)
metformin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Linagliptin
Other Intervention Name(s)
metformin
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change of cognitive function
Description
Type 2 diabetes mellitus patients with MCI were relieved of mild cognitive impairment , which means MoCA scores were not less than 26 points after treatment, or improved referring to the MoCA score or the RBANS total score increased by 0.5 standard deviation compared with baseline after treatment.
Time Frame
from baseline to 1 year's follow-up
Secondary Outcome Measure Information:
Title
Change of other cognitive function
Description
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.
Time Frame
from baseline to 1 year's follow-up
Title
Change of olfactory brain activation by fMRI
Description
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.
Time Frame
from baseline to 1 year's follow-up
Title
Olfactory threshold test
Description
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.
Time Frame
from baseline to 1 year's follow-up
Title
Change of metabolism
Description
The changes of glycosylated hemoglobin among the three groups before and after intervention. The level of glycosylated hemoglobin <7% means better glucose metabolism.
Time Frame
every two months from baseline to 1 year's follow-up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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, thiazolidinediones 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.
Facility Information:
Facility Name
Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University
City
Nanjing
State/Province
Jiangsu
ZIP/Postal Code
210000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jindan Wu, MD,PhD
Phone
86-025-52271000
Email
wujindandan@sina.com
First Name & Middle Initial & Last Name & Degree
Jindan Wu, MD,PhD
First Name & Middle Initial & Last Name & Degree
Rong Huang, PhD
Facility Name
Division of Endocrinology, the Affiliated Drum Tower Hospital of Nanjing University
City
Nanjing
State/Province
Jiangsu
ZIP/Postal Code
210008
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yan Bi, MD,PhD
Phone
86-25-83-105302
Email
biyan@nju.edu.cn
First Name & Middle Initial & Last Name & Degree
PhD
First Name & Middle Initial & Last Name & Degree
YAN BI, MD,PhD
First Name & Middle Initial & Last Name & Degree
ZHOU ZHANG, MD,PhD
Facility Name
Department of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University
City
Wuxi
State/Province
Jiangsu
ZIP/Postal Code
214000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lan Xu, MD
Phone
86-0510-82700775
Email
xulan126@126.com
First Name & Middle Initial & Last Name & Degree
Lan Xu, MD
First Name & Middle Initial & Last Name & Degree
Haiyan Cheng, PhD
First Name & Middle Initial & Last Name & Degree
Xiang Xu, PhD

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
31221697
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):1274-1283. doi: 10.2337/dc18-2584. Epub 2019 May 21.
Results Reference
result
PubMed Identifier
29500313
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 2018 Mar 2.
Results Reference
result
PubMed Identifier
35263425
Citation
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.
Results Reference
result

Learn more about this trial

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

We'll reach out to this number within 24 hrs