Post-stroke cognitive impairment (PSCI) increases the risk of disability and mortality in stroke patients, thereby exacerbating the disease burden of stroke. Type 2 diabetes is a major risk factor for PSCI, and stroke patients with type 2 diabetes have a higher risk of developing PSCI. Despite the high incidence and severe impact of PSCI, effective intervention methods are still lacking. Identifying safe and effective drugs to improve cognitive function in stroke patients and reduce the risk of PSCI, especially for those with type 2 diabetes, is of significant importance and could help reduce the burden of stroke.

Dipeptidyl peptidase-4 (DPP4) inhibitors are first-line antidiabetic drugs, and several studies have shown that DPP4 inhibitors provide benefits beyond glucose control, including significantly improving cognitive function in patients with type 2 diabetes or slowing the progression of cognitive impairment. Our previous research found a significant negative correlation between baseline plasma soluble DPP4 (sDPP4) levels and the 90-day PSCI risk in ischemic stroke patients. Moreover, some studies indicate that DPP4 inhibitors can increase plasma sDPP4 levels. Based on this, we hypothesize that DPP4 inhibitors could be effective for PSCI intervention and may improve cognitive function post-stroke.

This project aims to conduct a multicenter, randomized, double-blind, placebo-controlled study. We will include patients with mild ischemic stroke combined with type 2 diabetes and provide continuous intervention with DPP4 inhibitors or a placebo for 180 days. Cognitive function in both groups will be assessed before and after intervention to determine if DPP4 inhibitors can improve cognitive function and reduce the risk of PSCI in ischemic stroke patients with type 2 diabetes. Clinical blood samples and imaging data will also be used to preliminarily explore potential mechanisms.

Inclusion Criteria:

1. Mild ischemic stroke, defined as a National Institutes of Health Stroke Scale (NIHSS) score ≤ 5.
2. Coexisting type 2 diabetes with a disease duration of less than 5 years.
3. Ability to complete the MoCA, MMSE, and the NINDS-CSN-recommended 1-hour standardized neuropsychological test for VCI.
4. Age between 40 and 75 years.
5. Onset of stroke within the last 2 weeks.
6. Glycated hemoglobin (HbA1c) between 6.5% and 8.5%.
7. More than 9 years of education.
8. Informed consent signed by the patient or their family.

Exclusion Criteria:

1. Coexisting dementia or severe cognitive impairment (MoCA < 17).
2. Coexisting severe depression, defined as a Hamilton Depression Rating Scale (HAMD) score ≥ 20.
3. Prior use of cognitive-enhancing drugs, such as donepezil or memantine.
4. Allergy to DPP4 inhibitors.
5. Past or current use of DPP4 inhibitors.
6. Past or current use of GLP-1 agonists.
7. Type 1 diabetes, latent autoimmune diabetes in adults, secondary diabetes, malignant tumors, autoimmune diseases, or other endocrine-related diseases.
8. Moderate or severe liver or kidney dysfunction.
9. Chronic or acute pancreatitis.
10. Pregnancy or lactation.
11. Severe infection or severely impaired immune response.
12. Participation in other clinical trials.
13. Past or current use of insulin therapy.

Centralized network-based randomization will be used, with matching based on study center, patient age, gender, and glycated hemoglobin levels at the time of randomization. A double-blind design will be implemented, with patients randomly assigned in a 1:1 ratio to either the DPP4 inhibitor intervention group or the placebo control group, with both researchers and patients unaware of the group assignments.