Diabetes Mellitus/Poststroke Hyperglycemia: a Detrimental Factor for tPA Thrombolytic Stroke Therapy

Abstract

Intravenous administration of tissue-type plasminogen activator (IV tPA) therapy has long been considered a mainstay in ischemic stroke management. However, patients respond to IV tPA therapy unequally with some subsets of patients having worsened outcomes after treatment. In particular, diabetes mellitus (DM) is recognized as a clinically important vascular comorbidity that leads to lower recanalization rates and increased risks of hemorrhagic transformation (HT). In this short-review, we summarize the recent advances in understanding of the underlying mechanisms involved in post-IV tPA worsening of outcome in diabetic stroke. Potential pathologic factors that are related to the suboptimal tPA recanalization in diabetic stroke include higher plasma plasminogen activator inhibitor (PAI)-1 level, diabetic atherogenic vascular damage, glycation of the tPA receptor annexin A2, and alterations in fibrin clot density. While factors contributing to the exacerbation of HT in diabetic stroke include hyperglycemia, vascular oxidative stress, and inflammation, tPA neurovascular toxicity and imbalance in extracellular proteolysis are discussed. Besides, impaired collaterals in DM also compromise the efficacy of IV tPA therapy. Additionally, several tPA combination approaches developed from experimental studies that may help to optimize IV tPA therapy are also briefly summarized. In summary, more research efforts are needed to improve the safety and efficacy of IV tPA therapy in ischemic stroke patients with DM/poststroke hyperglycemia.

NmFGF1-Regulated Glucolipid Metabolism and Angiogenesis Improves Functional Recovery in a Mouse Model of Diabetic Stroke and Acts via the AMPK Signaling Pathway

“…According to statistics, the incidence of ischemic stroke in diabetic patients is significantly higher (by 2-to 6-fold) than non-diabetic stroke patients, and about 40% of patients with cerebral ischemia are associated with type 2 diabetes mellitus (Jouihan et al, 2013;Suda et al, 2015;Li et al, 2017;Jackson et al, 2020). Tissue plasminogen activator (tPA), the food and drug administration (FDA)-approved drug for stroke, is associated with a higher risk of hemorrhagic transformation (Jiang et al, 2020). Therefore, there is a critical need for explorative research aimed at discovering effective drugs to improve glucose and lipid metabolism as well as ameliorate cerebral ischemic injury in diabetic stroke.…”

The Impact of Diabetes Mellitus and Admission Hyperglycemia on Clinical Outcomes after Recanalization Therapies for Acute Ischemic Stroke: STAY ALIVE National Prospective Registry

“…Previously, observational studies demonstrated the independent correlation between elevated serum glucose levels, diabetes, and lower recanalization rates in patients treated with IVT alone [ 9 , 10 , 11 ]. Jiang et al found precipitating factors leading to impaired fibrinolytic response after tPA treatment including diabetic vasculopathy, elevated plasminogen activator inhibitor (PAI-1) value, glycation of tPA receptor annexin A2, and increased density of fibrin clot [ 26 ]. However, the post hoc analysis of the SWIFT trial found that aHG was not correlated with the rate of recanalization in thrombectomized patients.…”

The Stress Hyperglycemia Ratio is Associated with Hemorrhagic Transformation in Patients with Acute Ischemic Stroke

“… 34–37 Persistent hyperglycemia is an independent risk factor of infarct expansion 38 and induces early neurological deterioration as well as impairment of cerebral collateral flow. 35 , 39 And patients with dyslipidemia may have an increased risk of incident stroke and recurrent ischemic events, which can worsen the condition of AIS. 40–42 Several studies have investigated acute hyperglycemia predicts increased risk of in-hospital mortality and long-term prognosis after ischemic stroke in non-diabetic patients.…”