Proving SGLT2 Inhibitor-Mediated Improvement in Cardiomyocyte Energetics: Beyond a Reasonable Doubt?
Abstract
Cardiometabolic heart failure (HF) with preserved ejection fraction (HFpEF) is associated with systemic metabolic disease, including obesity, diabetes, dyslipidemia, and hypertension.Despite its high morbidity and mortality, the list of effective therapeutics for HFpEF remains short.Sodium glucose cotransporter 2 (SGLT2) inhibitors have gained US Food and Drug Administration approval for targeting hyperglycemia by inhibiting renal reabsorption of glucose and sodium.Recent clinical trials have revealed the benefit of empagliflozin and dapagliflozin in reducing HF hospitalizations in patients with HFpEF even in the absence of diabetes, leading to the approval of SGLT2 inhibitors as a foundational treatment for HF across the ejection fraction spectrum.1,2 The reduction in HF hospitalizations in these trials occurs as early as approximately 2 weeks after randomization, suggesting that the SGLT2 inhibitor-mediated reductions in cardiac filling pressures are paramount to their beneficial effects in HF.SGLT2 inhibitors have also been shown to reduce systemic, cardiac, and adipose tissue inflammation.3,4 However, it remains unclear how SGLT2 inhibition is mechanistically mediating these cardiovascular and inflammatory benefits-especially in the absence of diabetes-as there is no evidence of myocardial or immune expression of SGLT2.5 In this issue of Circulation: Heart Failure, Schauer et al begin to explore how SGLT2 inhibitors may be modulating cardiac metabolism and function in a…
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