Potential Therapeutic Effects of Sodium Glucose-linked Cotransporter 2 Inhibitors in Stroke

Abstract

Purpose: Stroke is the second leading cause of death and the third leading cause of disability worldwide. Diabetes mellitus and the associated hyperglycemia are important risk factors for acute ischemic stroke and are associated with poor prognosis. Neurovascular protection is an important therapeutic target to achieve in patients with stroke, especially in those receiving thrombolytic reperfusion therapy. Sodium glucose-linked cotransporter 2 (SGLT2) inhibitors are a novel class of antidiabetic agents that target SGLT2. Hyperglycemia exacerbates the neuronal damage through the SGLT2 transporter. The purpose of this narrative review is to discuss the pleiotropic effects of SGLT2 inhibitors and their role in the treatment and prevention of ischemic stroke in experimental and clinical studies. Methods: We searched the PubMed database using different term combinations from the date of inception to May 2019. Deselection methods were followed to exclude unrelated articles. The total number of articles included was 14. Findings: In experimental models, SGLT2 inhibitors have a protective mechanism against neuronal dysfunction and damage through various mechanisms. From a clinical perspective and based on current evidence, SGLT2 inhibitors reduce the risk of cardiovascular events, especially in patients with heart failure. Implications: SGLT inhibitors may have neurologic and/or vascular protective effect after acute ischemic stroke based on experimental studies. However, getting an accurate judgment of this effect is hard to achieve because only a few animal studies are available. Furthermore, and unlike animale studies, clinical studies provided uncertain answers on whether SGLT2 inhibitors would provide neuroprotective effect. In addition, several studies used combination of drugs along with SGLT2 inhibitors. Conclusions: It is unlikely that SGLT inhibitors have a positive or negative effect on stroke risk, but the question that remains unanswered is whether SGLT inhibitors can yield a protective effect after acute ischemic stroke. Future observational studies and registries may be the first step to help answer this question.

Neuroprotective Effect of SGLT2 Inhibitors

“…Cerebrovascular dysfunction is a pathological condition of the brain related to vascular pathology. A hyperglycemic state impairs the microvascular structure of the brain causing neurovascular remodeling, including loss of endothelial integrity, basement membrane thickening, loss of myelin and neurons, astrocytes and pericytes disturbance [ 107 ]. Such ultrastructural changes are associated with cognitive decline [ 108 ].…”

Diabetes and stroke: An important complication

“…Certainly, the effects of GLP‐1RA are highly encouraging, and one wonders whether there might be a role of such treatment in post‐stroke management. The SGLT2i have anti‐inflammatory, antioxidant, and potentially neuroprotective effects 59 . PGZ may mediate changes in miRNA in diabetes with stroke, suggesting a potential mechanism of benefit, 60 in addition to its role in reducing insulin resistance.…”

“…The SGLT2i have anti-inflammatory, antioxidant, and potentially neuroprotective effects. 59 PGZ may mediate changes in miRNA in diabetes with stroke, suggesting a potential mechanism of benefit, 60 in addition to its role in reducing insulin resistance. We know that diabetes is associated with vitamin D deficiency, which has a variety of effects both on insulin secretion and on insulin action, 61 and that vitamin D deficiency is associated with decreased endothelial function, with prothrombotic and proinflammatory effects, and with reduction in neuronal survival.…”

Sodium-glucose cotransporter 2 inhibitors and neurological disorders: a scoping review

“…First, SGLT2i play an important role in mitigating common risk factors for these disorders at the organism level, such as persistent hyperglycaemia, insulin resistance, high triglyceride levels, visceral fat and hypertension. 66 SGLT2i lower blood pressure possibly through the osmotic and diuretic effects and reduction in sodium reabsorption by the kidneys. Hypertension is a well-known risk factor for stroke and dementia as it leads to endothelial dysfunction, atherosclerosis and small vessel disease, and reduced blood pressure is associated with lower risk of stroke and TIA.…”