Lim, Ven Gee; (2021) The role of Sodium Glucose Cotransporter 2 (SGLT2) inhibitors in cardioprotection. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: Despite the effectiveness of primary coronary angioplasty in reducing myocardial infarct size, ischaemia/reperfusion injury (IRI) accounts for a significant proportion of the final infarct size and there is a need to identify therapies that can mitigate the deleterious effects of myocardial IRI. Sodium glucose cotransporter 2 (SGLT2) inhibitors were initially designed to treat diabetes but recent landmark cardiovascular outcome trials (CVOT) have revealed an unexpected cardiovascular mortality benefit from SGLT2 inhibition in type 2 diabetes mellitus (T2DM) patients. As SGLT2 receptors are predominantly found in the kidneys rather than the heart, it is likely that the cardioprotection conferred by SLGT2 inhibitors occurs in an off-target manner. This research hypothesised that attenuation of myocardial IRI may account for the cardioprotection observed in the trials. Methods and Results: Firstly, two rat models of T2DM were characterised: The high fat diet/streptozotocin (HFD/STZ) and the Zucker Diabetic Fatty (ZDF) rat. For the HFD/STZ rat model, the optimal hyperglycaemic response and survival rates were subsequently established after 5 batches of serial experiments but this model had multiple disadvantages. As the HFD/STZ rat phenotype appeared to be more suggestive of type 1 diabetes mellitus (T1DM), the ZDF rat model, which reflected the obese T2DM phenotype more closely, became the model of choice. Neither subcutaneous nor oral administration of Phlorizin (an SGLT1 and SGLT2 inhibitor) to diabetic rats conferred adequate glycaemic control. In contrast, diabetic rats exposed to oral Canagliflozin (an SGLT2 inhibitor) showed sustained and improved glycaemic profiles without any adverse events. Hence, Canagliflozin became the drug of choice for subsequent experiments. ZDF and non-diabetic Zucker Lean (ZL) rats were then fed either high-fat or standard chow respectively, with or without fortification with Canagliflozin for 4 weeks. As expected, ZDF rats were markedly diabetic with evidence of end-organ renal injury. Canagliflozin improved the blood glucose of ZDF rats and did not cause hypoglycaemia in ZL rats. After 4 weeks, the hearts were harvested, Langendorff- perfused and subjected to 35 minutes regional ischemia and 2 hours reperfusion. Canagliflozin pre-treatment led to robust attenuation of myocardial infarct size in both diabetic ZDF and non-diabetic ZL rat hearts. In contrast, short- term Langendorff-perfusion of non-diabetic (Sprague-Dawley) rat hearts with Canagliflozin had no impact on myocardial infarct size - suggesting that the reduction in myocardial infarct size by SGLT2 inhibitors occurred independent of blood glucose levels and via an in vivo mediated hormone signaling mechanism. Langendorff-perfused hearts of non-diabetic rats pre-treated with oral Canagliflozin for 24 hours also demonstrated a significant reduction in myocardial infarct size compared to that of placebo-treated rats. The cardioprotection occurred independent of blood glucose, insulin, glucagon and ketone levels. Western blot analysis of these protected hearts showed an association between SGLT2 inhibition and increased Akt phosphorylation. Conclusion: The reduction in myocardial size in diabetic rats by SGLT2 inhibition may explain the improved cardiovascular outcomes amongst T2DM patients in the SGLT2 inhibitor CVOTs. Importantly, this is the first demonstration of SGLT2 inhibitor-mediated cardioprotection in non-diabetic animals by mitigation of myocardial IRI. The reduction in myocardial infarct size could be seen within 24 hours and was independent of circulating blood glucose, insulin, glucagon and ketone levels. The association between SGLT2 inhibition and increased Akt phosphorylation suggests that involvement of the anti-apoptotic Reperfusion Injury Salvage Kinase (RISK) pathway of ischaemic conditioning. This thesis therefore provides new insight into the potential cardiovascular benefits of SGLT2 inhibition regardless of diabetes status and strengthens the belief that one day, this novel class of anti-diabetic drugs may be repurposed into highly effective therapies for heart failure, ischaemic heart disease and arrhythmia patients.

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