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. 2021 Jan;41(1):14-30.
doi: 10.1177/0271678X20952011. Epub 2020 Sep 20.

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Mark P Maskery  1   2 , Christian Holscher  3 , Stephanie P Jones  4 , Christopher I Price  5 , W David Strain  6 , Caroline L Watkins  4 , David J Werring  7 , Hedley Ca Emsley  1   2
Affiliations

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Mark P Maskery et al. J Cereb Blood Flow Metab. 2021 Jan.

Abstract

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.

Keywords: Acute stroke; animal models; clinical trials; neuroprotection; reperfusion.

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Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CH is a named inventor on several patent applications that cover the use of GLP-1RAs for the treatment of neurodegenerative disorders. WDS has received speaker honoraria, conference sponsorship by Astra-Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Colgate Palmolive, Eli Lilly, GlaxoSmithKline, Lundbeck, Menarini, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, and Takeda. He holds research grants from Astra-Zeneca, Novo Nordisk and Novartis.

Figures

Figure 1.
Figure 1.
PRISMA flow chart demonstrating the selection of studies.
Figure 2.
Figure 2.
Proposed neuroprotective mechanism of action for GLP-1RAs in AIS.1. Direct GLP-1R activation by GLP-1RA. 2. Potential indirect receptor activation by GLP-1RA. 3. GLP-1 sub-units are cell permeable and may affect mitochondrial function, or act on extra-cellular receptors. 4. GLP-1RAs reduce excitotoxicity.
See this image and copyright information in PMC

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