Abstract
The authors hypothesized that despite similar cardiovascular event rates, the improved cardiovascular survival from sodium glucose transporter 2 (SGLT2) inhibition, seen clinically, could be via a direct cytoprotective effect, including protection against myocardial ischemia/reperfusion injury. Langendorff-perfused hearts, from diabetic and nondiabetic rats, fed long-term for 4 weeks with canagliflozin, had lower infarct sizes; this being the first demonstration of canagliflozin's cardioprotective effect against ischemia/reperfusion injury in both diabetic and nondiabetic animals. By contrast, direct treatment of isolated nondiabetic rat hearts with canagliflozin, solubilized in the isolated Langendorff perfusion buffer, had no impact on infarct size. This latter study demonstrates that the infarct-sparing effect of long-term treatment with canagliflozin results from either aglucose-independent effect or up-regulation of cardiac prosurvival pathways. These results further suggestthat SGLT2 inhibitors could be repurposed as novel cardioprotective interventions in high-risk cardiovascular patients irrespective of diabetic status.
Highlights
The remarkable cardiovascular benefits of sodium/glucose co-transporter 2 (SGLT2) inhibitors are well recognized in highrisk type 2 diabetic patients following the landmark clinical trials, EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus) [1] and CANVAS (CANagliflozin CardioVAScular Assessment Study) [2], and is further supported by positive outcome data from DECLARETIMI 58 trial (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events-Thrombolysis In Myocardial Infarction 58) announced at the recent European Society of Cardiology World Congress
We found that diabetic rats treated with canagliflozin were heavier than untreated diabetic rats; the expected weight loss from the calorific depletion associated with SGLT2-dependent glycosuria was, observed in the canagliflozin-treated nondiabetic Zucker Lean (ZL) rats
The pattern and rate of weight gain seen in nondiabetic rats were mirrored in diabetic Zucker Diabetic Fatty (ZDF) rats fed with canagliflozin, suggesting a healthier animal concomitant with better-controlled diabetes, an interpretation fitting with empirical observations of these animals’ physical condition
Summary
The remarkable cardiovascular benefits of sodium/glucose co-transporter 2 (SGLT2) inhibitors are well recognized in highrisk type 2 diabetic patients following the landmark clinical trials, EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus) [1] and CANVAS (CANagliflozin CardioVAScular Assessment Study) [2], and is further supported by positive outcome data from DECLARETIMI 58 trial (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events-Thrombolysis In Myocardial Infarction 58) announced at the recent European Society of Cardiology World Congress These studies, both designed as noninferiority investigations mandated by the regulatory authorities, revealed an unexpected benefit and superiority over existing standard diabetic care, with a significant reduction of cardiovascular mortality. Many, including ourselves, have speculated a potential pleiotropic beneficial effect for this class of glucose-lowering therapy [3,4,5]
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