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

Summary

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.

Timeline

Start

2025-12-15

Primary completion

2027-12-31

Completion

2028-04-30

Publications

• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.
• Results Zhong J, Maiseyeu A, Davis SN, Rajagopalan S. DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ Res. 2015 Apr 10;116(8):1491-504. doi: 10.1161/CIRCRESAHA.116.305665.
• Results Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014 Dec;35(6):992-1019. doi: 10.1210/er.2014-1035. Epub 2014 Sep 12.
• Results Levine DA, Wadley VG, Langa KM, Unverzagt FW, Kabeto MU, Giordani B, Howard G, Howard VJ, Cushman M, Judd SE, Galecki AT. Risk Factors for Poststroke Cognitive Decline: The REGARDS Study (Reasons for Geographic and Racial Differences in Stroke). Stroke. 2018 Apr;49(4):987-994. doi: 10.1161/STROKEAHA.117.018529. Epub 2018 Mar 16.
• Results Rost NS, Brodtmann A, Pase MP, van Veluw SJ, Biffi A, Duering M, Hinman JD, Dichgans M. Post-Stroke Cognitive Impairment and Dementia. Circ Res. 2022 Apr 15;130(8):1252-1271. doi: 10.1161/CIRCRESAHA.122.319951. Epub 2022 Apr 14.

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