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Correspondence on "Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure" by Joshi et al

To the Editor Sodiumglucose cotransporter 2 (SGLT2) inhibitor therapy is a specific mode of antidiabetic strategy that significantly improves cardiovascular outcomes. The recently published article by Joshi et al has focused on beneficial effects of SGLT2 inhibitors in the setting of heart failure (HF). We fully agree that complex cellular mechanisms, beyond diuresis, seem to underlie pleitrophic actions of these agents. More specifically, it also seems likely that SGLT2 inhibitors might potentiate favourable effects of certain metabolic agents including cellular antiischaemics (and vice versa) in patients with diabetes with cardiovascular disease. Accordingly, combination of SGLT2 inhibitors with cellular antiischaemic regimens might have important implications in these patients. It is well known that free fatty acids (FFAs) serve as the major energy source in myocardium under physiological conditions. However, a significant shift to oxidation of more energyefficient substrates (including glucose and ketone bodies) usually takes place in the setting of myocardial ischaemia and/or failure. Moreover, this shift is expected to be even more pronounced under certain medications including cellular antiischaemics (trimetazidine, etc) that exert their actions largely through inhibition of FFA oxidation. In a recent metaanalysis comprising patients with diabetes, trimetazidine was demonstrated to exert favourable effects including improvement in left ventricular systolic functions, myocardial ischaemic episodes, serum glucose parameters (fasting glucose and HbA1C), etc largely attributable to its metabolic, antioxidant and antihyperglycaemic effects in these patients. However, impaired myocardial uptake of glucose in patients with diabetes potentially hinders maximum therapeutic benefits of cellular antiischaemics during periods of heightened metabolic demand. This signifies the need for alternative energyefficient substrates (including ketone bodies) in patients with diabetes receiving cellular antiischaemics. In this context, SGLT2 inhibitors provide sufficient amounts of circulating ketone bodies that seem to maximise actions of cellular antiischaemics on myocardial energetics in patients with diabetes. Moreover, hyperketonaemia associated with SGLT2 inhibitors might also prevent excessive uptake of FFAs (a reactive phenomenon predisposing to diabetic cardiomyopathy due to lipotoxicity) potentially associated with the use of cellular antiischaemics in patients with diabetes. On the other hand, cellular antiischaemics might possibly heighten favourable impact of SGLT2 inhibitors mostly through their metabolic actions (increased insulin sensitivity due to translocation of GLUT4, etc) and antioxidant features (that might reverse myocardial remodelling). Accordingly, combined use of certain metabolic agents, including SGLT2 inhibitors, dichloroacetate, perhexiline, trimetazidine, etc, was previously suggested as a potential strategy to combat failing myocardium (yet, with no recommendation of a particular combination). In this regard, combination of SGLT2 inhibitors and trimetazidine seems to be a promising option (due to the mutually complementary actions of these agents). In summary, concomitant use of cellular antiischaemics and SGLT2 inhibitors might result in a synergistic therapeutic benefit in patients with diabetes with cardiovascular disease (HF and coronary syndromes). However, this needs to be tested in clinical trials. Kenan Yalta , Ugur Ozkan, Tulin Yalta Cardiology, University of Trakya, Edirne, Turkey Pathology, University of Trakya, Edirne, Turkey