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

Maskery, M.P. and Holscher, C. and Jones, S.P. and Price, C.I. and Strain, W.D. and Watkins, C.L. and Werring, D.J. and Emsley, H.C.A. (2021) Glucagon like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke:a systematic scoping review. Journal of Cerebral Blood Flow and Metabolism, 41 (1). pp. 14-30. ISSN 0271-678X

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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.