A mechanistic rationale for the investigation of sodium–glucose co‐transporter 2 inhibitors in heart failure with preserved ejection fraction. Letter regarding the article ‘Baseline characteristics of patients with heart failure with preserved ejection fraction in the <scp>EMPEROR‐Preserved</scp> trial’

Pabel, Steffen; Hamdani, Nazha; Sossalla, Samuel

doi:10.1002/ejhf.2091

Cited by 6 publications

(7 citation statements)

References 4 publications

(6 reference statements)

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“…Recently, in pigs with myocardial infarction induced HFrEF 2 months of treatment with empagliflozin also resulted in an improved diastolic function in invasive and non-invasive analyses, which was associated with increased NO availability and PKG signaling (Santos-Gallego et al, 2021). As PKG is centrally involved in HFpEF pathophysiology, the impact of SGLT2i on PKG signaling and myofilament function could therefore be a key-stone effect in improving diastolic function in HFpEF hearts (Figure 2), thereby resulting in material change the disease trajectory (Pabel et al, 2020a).…”

Section: Effects Of Sodium-glucose-cotransporter 2 Inhibitors On Myofilament Functionmentioning

confidence: 99%

“…As empagliflozin reduced oxidative stress and inflammation in human HFpEF myocardium, NO bioavailability and PKG signaling were improved upon exposure to empagliflozin leading to lower myofilament stiffness and thereby improved diastolic function in human myocardium (Pabel et al, 2018;Kolijn et al, 2021). Thus, the attenuation of oxidative stress and inflammation due to SGLT2i treatment could be potentially helpful in HFpEF patients (Figure 3) at least via an improvement of contractility (Pabel et al, 2020a). Also, other potential secondary effects of SGLT2i driven by a reduction of oxidative stress and inflammation are conceivable.…”

Section: Effects Of Sodium-glucose-cotransporter 2 Inhibitors On Cardiomyocyte Na + and Ca 2+ Homeostasismentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Effects Of Sodium-glucose-cotransporter 2 Inhibitors On Myofilament Functionmentioning

confidence: 99%

Section: Effects Of Sodium-glucose-cotransporter 2 Inhibitors On Cardiomyocyte Na + and Ca 2+ Homeostasismentioning

confidence: 99%

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

et al. 2021

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“…Also, in studies of diabetic mice, empagliflozin beneficially impacted cardiac function via NO-sGC-PKG pathway after 8 weeks of treatment [98]. As altered NO-sGC-PKG signalling is a key mechanism of diastolic dysfunction and HFpEF [99,100], further investigations of this pathway upon SGLT2i in HFpEF appear promising [101]. Moreover, the reduced fibrotic content upon SGLT2i or changes in cardiomyocyte ion-homeostasis (see below) could also favourably affect HFpEF patients.…”

Section: Myocardial Contraction and Relaxationmentioning

confidence: 99%

“…In general, it can be assumed that a not insignificant number of HFpEF patients were included in the studies due to the inclusion criteria and the patient risk profile. Moreover, preclinical data on the effects of SGLT2i on diastolic function and pathways involved in HFpEF pathophysiology might also provide a rationale for the efficacy of these drugs in this complex disease [101]. The DELIVER trial (NCT03619213) investigates the effects of dapagliflozin in patients with HFpEF (EF >40%, structural heart disease, elevated NT-pro BNP levels, NYHA II-IV) on cardiovascular death or HF events.…”

Section: What To Expect From Sglt2 Inhibitors In Hfpefmentioning

confidence: 99%

SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled?

Pabel

Hamdani

Luedde

et al. 2021

Curr Heart Fail Rep

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Purpose of review SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. Recent findings Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Summary Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.

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“…This showed a significant reduction in the combined endpoint of hospitalization for HF and cardiovascular death among these patients. In this trial, the benefit of reduced heart failure hospitalization was attenuated in higher left ventricular ejection fractions (LVEF ≥ 65%) 6 .…”

Section: Introductionmentioning

confidence: 97%

DELIVER: Extending the benefits of SGLT-2 inhibitors

Samaan

Wagdy

2023

gcsp

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The DELIVER trial investigated the efficacy and safety of dapagliflozin in patients with heart failure and preserved or mildly reduced ejection fraction. The trial demonstrated that dapagliflozin significantly reduced the risk of worsening heart failure or cardiovascular death compared to placebo. The benefit was mainly driven by a decrease in heart failure hospitalizations, with no significant impact on mortality. Patients with different ejection fractions and diabetes status showed similar treatment effects. Dapagliflozin also improved functional capacity and quality of life. These findings support the use of SGLT-2 inhibitors in HFpEF and HFmrEF, potentially influencing clinical practice and future guidelines.

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Cited by 6 publications

References 4 publications

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

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

SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled?

DELIVER: Extending the benefits of SGLT-2 inhibitors

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