DPP4 Inhibitor Intervention on Post-stroke Cognitive Impairment in Ischemic Stroke Patients With Type 2 Diabetes

Official title

DPP4 Inhibitor on Post-stroke Cognitive Impairment in Ischemic Stroke Patients With Type 2 Diabetes Mellitus (DISC-DM): Multicentre, Double Blind, Randomised, Placebo Controlled Trial

Overview

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.

Interventions

• Drug Sentagliptin Phosphate - single dose
  Sentagliptin Phosphate 50 mg, once daily, plus metformin hydrochloride extended-release tablets (50 mg, two or three times daily). If blood glucose is still not well-controlled, sulfonylurea drugs may be added as needed.
• Drug Placebo
  Placebo (identical in size, shape, color, appearance, and odor to Sentagliptin Phosphate, 50 mg, once daily) plus metformin hydrochloride extended-release tablets (50 mg, two or three times daily). If blood glucose is still not well-controlled, sulfonylurea drugs may be added as needed.

Primary outcome measures

• Change in MoCA score before and after the 180-day intervention [Time frame: 180 days]

Secondary outcome measures (4)

• PSCI incidence at 180 days [Time frame: 180 days]
• Changes in MMSE score and scores in various cognitive domains before and after the 180-day intervention [Time frame: 180 days]
• Changes in MoCA and MMSE scores before and after the 90-day intervention [Time frame: 90 days]
• Modified Rankin Scale (mRS) score and cardiovascular and cerebrovascular events at 90 and 180 days [Time frame: 90 days and 180 days]

Eligibility criteria

Inclusion criteria

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

Exclusion criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Department of Neurology, Second Affiliated Hospital of Soochow University — Suzhou

Publications

• You S, Bi Y, Miao M, Bao A, Du J, Xu T, Liu CF, Zhang Y, He J, Cao Y, Zhong C. Plasma sDPP4 (Soluble Dipeptidyl Peptidase-4) and Cognitive Impairment After Noncardioembolic Acute Ischemic Stroke. Stroke. 2023 Jan;54(1):113-121. doi: 10.1161/STROKEAHA.122.040798. Epub 2022 Dec 7. PMID 36475470
• You S, Miao M, Lu Z, Bao A, Du J, Che B, Xu T, Zhong C, Cao Y, Liu CF, Zhang Y, He J. Plasma Soluble Dipeptidyl Peptidase-4 and Risk of Major Cardiovascular Events After Ischemic Stroke: Secondary Analysis of China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Neurology. 2022 Aug 30;99(9):e925-e934. doi: 10.1212/WNL.0000000000200784. Epub 2022 Jun 2. PMID 35654589
• Baggio LL, Varin EM, Koehler JA, Cao X, Lokhnygina Y, Stevens SR, Holman RR, Drucker DJ. Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans. Nat Commun. 2020 Jul 28;11(1):3766. doi: 10.1038/s41467-020-17556-z. PMID 32724076
• Ma M, Hasegawa Y, Koibuchi N, Toyama K, Uekawa K, Nakagawa T, Lin B, Kim-Mitsuyama S. DPP-4 inhibition with linagliptin ameliorates cognitive impairment and brain atrophy induced by transient cerebral ischemia in type 2 diabetic mice. Cardiovasc Diabetol. 2015 May 20;14:54. doi: 10.1186/s12933-015-0218-z. PMID 25986579
• Chiazza F, Tammen H, Pintana H, Lietzau G, Collino M, Nystrom T, Klein T, Darsalia V, Patrone C. The effect of DPP-4 inhibition to improve functional outcome after stroke is mediated by the SDF-1alpha/CXCR4 pathway. Cardiovasc Diabetol. 2018 May 19;17(1):60. doi: 10.1186/s12933-018-0702-3. PMID 29776406
• Borzi AM, Condorelli G, Biondi A, Basile F, Vicari ESD, Buscemi C, Luca S, Vacante M. Effects of vildagliptin, a DPP-4 inhibitor, in elderly diabetic patients with mild cognitive impairment. Arch Gerontol Geriatr. 2019 Sep-Oct;84:103896. doi: 10.1016/j.archger.2019.06.001. Epub 2019 Jun 3. PMID 31204117
• Jeong SH, Kim HR, Kim J, Kim H, Hong N, Jung JH, Baik K, Cho H, Lyoo CH, Ye BS, Sohn YH, Seong JK, Lee PH. Association of Dipeptidyl Peptidase-4 Inhibitor Use and Amyloid Burden in Patients With Diabetes and AD-Related Cognitive Impairment. Neurology. 2021 Sep 14;97(11):e1110-e1122. doi: 10.1212/WNL.0000000000012534. Epub 2021 Aug 11. PMID 34380754
• Sun C, Xiao Y, Li J, Ge B, Chen X, Liu H, Zheng T. Nonenzymatic function of DPP4 in diabetes-associated mitochondrial dysfunction and cognitive impairment. Alzheimers Dement. 2022 May;18(5):966-987. doi: 10.1002/alz.12437. Epub 2021 Aug 10. PMID 34374497

Identifiers

NCT: NCT07241897 · LC2024019 · 82471226

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗