The effects of SGLT2i on cardiac metabolism in patients with HFpEF: Fact or fiction?

The rising prevalence of Type 2 diabetes (T2D) has been closely associated with an increased incidence of cardiovascular diseases, particularly heart failure with preserved ejection fraction (HFpEF). Cardiometabolic disturbances in T2D, such as insulin resistance, hyperglycemia, and dyslipidemia, contribute to both microvascular and macrovascular complications, thereby intensifying the risk of heart failure. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed as glucose-lowering agents for T2D, have demonstrated promising cardiovascular benefits in patients with heart failure, including those with preserved ejection fraction (HFpEF), regardless of T2D status. These benefits include reduced heart failure hospitalization rates and improvements in various metabolic parameters. This review aims to critically examine the effects of SGLT2i on cardiac metabolism in HFpEF, evaluating whether the observed benefits can truly be attributed to their impact on myocardial energy regulation or whether they represent other, potentially confounding, mechanisms. We will focus on the key metabolic processes possibly modulated by SGLT2i, including myocardial glucose utilization, fatty acid oxidation, and mitochondrial function, and explore their effects on heart failure pathophysiology. Additionally, we will address the role of SGLT2i in other pathogenetic factors involved in HFpEF, such as sodium and fluid balance, inflammation, and fibrosis, and question the extent to which these mechanisms contribute to the observed clinical benefits. By synthesizing the current evidence, this review will provide an in-depth analysis of the mechanisms through which SGLT2i may influence cardiac metabolism in HFpEF, assessing whether their effects are supported by robust scientific data or remain speculative. We will also discuss the potential for personalized treatment strategies, based on individual patient characteristics, to optimize the therapeutic benefits of SGLT2i in managing both T2D and cardiovascular risk. This review seeks to clarify the true clinical utility of SGLT2i in the management of cardiometabolic diseases and HFpEF, offering insights into their role in improving long-term cardiovascular outcomes.