Potential Mechanisms of SGLT2 Inhibitors for the Treatment of Heart Failure With Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is an unsolved and growing concern in cardiovascular medicine. While no treatment options that improve prognosis in HFpEF patients has been established so far, SGLT2 inhibitors (SGLT2i) are currently being investigated for the treatment of HFpEF patients. SGLT2i have already been shown to mitigate comorbidities associated with HFpEF such as type 2 diabetes and chronic renal disease, however, more recently there has been evidence that they may also directly improve diastolic function. In this article, we discuss some potential beneficial mechanisms of SGLT2i in the pathophysiology of HFpEF with focus on contractile function.

A pilot clinical trial of cell therapy in heart failure with preserved ejection fraction

“…2 Although the underlying mechanisms for these findings are not clearly defined, they may be related to the empagliflozin-induced reduction in inflammation-dependent endothelial dysfunction resulting in improved cardiomyocyte contractility. 19 In our study, no patients were receiving empagliflozin, and the optimization of other medical therapy was not associated with improvement in left ventricular systolic and diastolic function, NT-proBNP levels, or exercise capacity. In contrast, 6 months after cell therapy, we found a significant improvement in E/e ′ , NT-proBNP, exercise capacity, deceleration time, and maximal tricuspid regurgitation velocity.…”

“…However, recent data demonstrate that empagliflozin therapy reduces the combined risk of cardiovascular death or hospitalization for heart failure in HFpEF patients, regardless of the presence or absence of diabetes 2 . Although the underlying mechanisms for these findings are not clearly defined, they may be related to the empagliflozin‐induced reduction in inflammation‐dependent endothelial dysfunction resulting in improved cardiomyocyte contractility 19 …”

Emerging concepts in heart failure treatment and management: focus on SGLT2 inhibitors in heart failure with preserved ejection fraction

“… 5 , 6 In a HF setting, SGLT2 inhibition results in a clear positive haemodynamic effect since both ventricular preload (via natriuresis and osmotic diuresis) and afterload (via blood pressure reduction and vascular function improvement) are reduced. 60 In addition, SGLT2i act independently on metabolic, molecular and biological pathways known to be involved in the development of HF and are thus able to prevent cardiac functional derangement through direct cytoplasmic sodium and calcium lowering actions, attenuate the remodelling process (fibrosis, necrosis, apoptosis), mitigate involved pro-inflammatory and oxidative stress processes, improve myocardial energetic supply, enhance myocardial mitochondrial turnover and myofilament function, 1 , 84 and improve renal outcomes. 70 The relevance of these direct cardiac effects may justify the important clinical benefit provided by SGLT2i since, despite being volume depleting, they did not substantially modify (pre/post) haematocrit, body weight, or NT-proBNP levels in patients with HFrEF, 80 , 85 , 86 whilst, on the other hand, patients with HFpEF had lower baseline NT-proBNP values ( versus HFrEF) with similar positive results post SGLT2i introduction.…”

Pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction

“…Moreover, we only generally analyzed the mechanisms of SGLT2is for HFpEF, but we still need to further study the single SGT2i, because the action mechanisms of different SGLT2is may not be completely consistent. In addition, the pathophysiology of HFpEF manifestations is highly heterogeneous [ 84 , 85 ], more current and future endeavors are underway to evaluate the optimal methods to classify patients into phenotypically homogeneous subpopulations to facilitate better individualization of treatment [ 86 ]. Finally, this study is based on computer and biological information mining, these reliable results we obtained here still need to be verified by molecular biology experiments in the later stage.…”