exenatide and Ischemic-Stroke

Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia.. The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event.. From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88];. Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered.. URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Topics: Adult; Aged; Exenatide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Ischemic Stroke; Prospective Studies; Stroke; Treatment Outcome

Tissue plasminogen activator (tPA) is recommended by the FDA to dissolve intravascular clots after acute ischemic stroke (AIS). However, it may contribute to hemorrhagic transformation (HT). The Wnt/β-catenin signaling pathway plays an important role in regulating the blood-brain barrier (BBB) formation in the central nervous system. We explored whether glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4) reduces the risk of HT after rtPA treatment via the Wnt/β-catenin pathway by using a rat transient middle cerebral artery occlusion (MCAO) model in vivo and an oxygen-glucose deprivation plus reoxygenation (OGD/R) model in vitro. Our results showed that EX-4 attenuated neurological deficits, brain edema, infarct volume, BBB disruption, and rtPA-induced HT in ischemic stroke. EX-4 suppressed the production of ROS and the activation of MMP-9 to protect the integrity of the BBB by activating the Wnt/β-catenin signaling pathway. PRI-724, a selective inhibitor of β-catenin, was able to reverse the therapeutic effect of EX-4 in vivo and in vitro. Therefore, our results indicate that the GLP-1R agonist may be a potential therapeutic agent to decrease the risk of rtPA-induced HT after ischemic stroke via the Wnt/β-catenin signaling pathway.

Topics: Animals; beta Catenin; Exenatide; Hemorrhage; Ischemic Stroke; Rats; Stroke; Tissue Plasminogen Activator; Wnt Signaling Pathway