Evaluating the Effects of Liraglutide, Empagliflozin and Linagliptin on Mild Cognitive Impairment Remission in Patients With Type 2 Diabetes: a Multi-center, Randomized, Parallel Controlled Clinical Trial With an Extension Phase

Inclusion criteria

1. Participants aged ≥40 and ≤75 years, of any gender.

2. Type 2 diabetes diagnosed according to the American Diabetes Association criteria

3. Mild cognitive impairment diagnosed according to the established criteria

4. Cognitive concern from the patient, or an informant or skilled clinicians

5. Objective evidence of cognitive impairment: education-adjusted MoCA score ≤ 25 and ≥ 18; or ≥1.0 standard deviation below the mean of age- and education-specific groups on any cognitive subdomain

6. Preservation of independence in daily living abilities: Barthel Index score ≥ 60

7. Absence of dementia

8. 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

9. Glycosylated hemoglobin (HbA1c) during screening between ≥7.0% and ≤10.0%

10. BMI of ≥ 19 kg/m2

11. Education duration of ≥6 years

12. Right-handed participants

13. Understanding of the research procedures and methods, potential benefits and risks of the trial, and sign written informed consent

Exclusion criteria

1. History of other dementia-related neurological diseases, depression within the past 2 years, developmental disorders, mania, depression, schizophrenia, etc.

2. Significant nasal sinusitis, nasal cavity and sinus polyps, cranial or nasopharyngeal tumors and other space-occupying lesions, congenital diseases and trauma of the nose, maxillofacial area, and skull base that affect olfaction. Symptoms of upper respiratory tract infection on the day of MRI examination, including nasal congestion, rhinorrhea, fever, etc.

3. Acute metabolic complications such as diabetic ketoacidosis, hyperglycemic hyperosmolar state and hypoglycemic coma within the previous 6 months

4. Severe organ dysfunction of heart, liver, kidneys, and thyroid, including unstable angina, myocardial infarction, or grade II and above cardiac insufficiency within 3 months before screening; estimated glomerular filtration rate (eGFR) by CKD-EPI formula <45 mL/min/1.73 m², alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater exceeding twice the upper limit of normal, hyperthyroidism or uncontrolled hypothyroidism

5. History of medullary thyroid carcinoma, pancreatitis, multiple endocrine neoplasia syndrome type 2, recurrent urinary tract infections, severe gastrointestinal diseases or history of gastrointestinal surgery, history of malignant tumors

6. With MRI contraindications, such as implanted metal prosthesis, claustrophobia, etc.

7. Females who are pregnant, lactating, breast feeding or of child bearing age without effective contraception

8. Participated in other clinical trials within the previous 6 months

9. Known or suspected allergy to the study drugs

10. Received treatment with GLP-1RAs, dual GLP-1R/GCGR agonist, SGLT-2 inhibitors or DPP4 inhibitors in the past 3 months

11. Known history of drug or alcohol abuse within the past 6 months