Cerebrovascular safety of sulfonylureas : the role of katp channels in neuroprotection and stroke risk in sulfonylurea treatment of type 2 diabetes

Sulfonylureas are the oldest class of anti-diabetic drugs and are currently the most widely used due to effectiveness and low cost. Sulfonylureas target insulin secretion by blocking ATPsensitive potassium (KATP) channels, depolarizing pancreatic β-cells and triggering the release of insulin. Sulfonylureas (SU) binds to the SUR subunit of the Kir/SUR hetero-octamer reducing mgADP’s binding and efficacy of ADP induced opening, ultimately results in closure of KATP whilst masking ATP inhibition of the channel . This becomes problematic, as KATP channel activity have demonstrated neuroprotection against ischemic brain injury . Diabetes mellitus type 2 (T2DM) is a metabolic disease where hyperglycemia persists and common comorbidities including hypertension, high blood cholesterol, atherosclerosis and obesity contribute to increasing risk for stroke. Not surprisingly, T2DM is a major independent risk factor for stroke as consistently observed in multiple racial backgrounds . Diabetes and stroke are leading causes of death and disability worldwide therefore risk modification and preventing more severe strokes in diabetic patients is crucial. Adequate glycemic control can lower risk for stroke and improve stroke outcomes but because SUs prevent KATP channel activation, which is neuroprotective, their use may increase incidence of stroke in diabetic patients. Many studies are focused on the cardiovascular safety of SUs however very few address stroke risk associated with SU diabetes treatment. Thus, we investigated in role of KATP channels in neuroprotection against ischemic insult and the stroke risk associated with treatment of diabetes, particularly with KATP blocker SU. We present our in vivo findings from animal models as well as a systematic metaanalysis of randomized clinical trials.