Heart | 2021
Response to: Correspondence on “Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure” by Yalta et al
Abstract
The Authors’ reply We would like to thank Yalta et al for their interest in our review. We share their enthusiasm for the potential metabolic benefits of sodiumglucose cotransporter 2 (SGLT2) inhibition. We agree with Yalta et al that in patients with type 2 diabetes or heart failure, there is dysregulated fatty acid oxidation and impaired glucose uptake causing myocardial dysfunction. In this setting of restricted fuel selection and low energetic reserve, ketone bodies are a superfuel producing Adenosine triphosphate (ATP) more efficiently than free fatty acids or glucose, which usually serve as fuels for cardiac energy under physiological conditions. SGLT2 inhibition increases hepatic synthesis and decreases urinary excretion of ketones, providing a more energyefficient substrate for cardiac metabolism. The cardiovascular benefits of SGLT2 inhibitor therapy may therefore be related to a shift in cardiac metabolism away from fatty acid and glucose oxidation towards more energyefficient ketone bodies. Several small randomised clinical trials have confirmed the efficacy of trimetazidine in patients with heart failure. These beneficial effects include an improvement in New York Heart Association functional class, exercise tolerance, quality of life, left ventricular ejection fraction and cardiac volumes. 4 However, recent evidence suggests that trimetazidine does not improve outcomes or symptoms after successful percutaneous coronary intervention in patients with acute and chronic coronary syndromes. The best known mechanism of action of trimetazidine appears to be its capacity to inhibit betaoxidation of free fatty acids, which in turn leads to an enhancement in glucose oxidation, thereby preserving energy metabolism in states like heart failure. Therefore, we agree that trimetazidine potentially offers metabolic modulation as a mechanism of benefit in heart failure, and its combination with SGLT2 inhibitor therapy could, in theory, have a synergistic therapeutic benefit in patients with type 2 diabetes and heart failure. However, the added value of combination therapy needs to be established and it will be important to determine whether there is additive or synergistic benefit to the powerful effects of SGLT2 inhibitor therapy. Although combination of trimetazidine and SGLT2 inhibitor therapy offers a potentially attractive therapeutic approach in patients with type 2 diabetes and heart failure, trimetazidine is associated with an increased risk of development of parkinsonism and worsening of symptoms in patients with preexisting Parkinson’s disease. Further studies are needed to assess the risk–benefit ratio of trimetazidine, especially in susceptible or elderly populations.