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Review
. 2021 Oct;18(5):315-328.
doi: 10.1007/s11897-021-00529-8. Epub 2021 Sep 15.

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

Steffen Pabel  1 , Nazha Hamdani  2 , Mark Luedde  3 , Samuel Sossalla  4   5
Affiliations
Review

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

Steffen Pabel et al. Curr Heart Fail Rep. 2021 Oct.

Abstract

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. 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.

Keywords: HFpEF; HFrEF; Heart failure; SGLT2 inhibitors.

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Conflict of interest statement

N. Hamdani has nothing to report. S. Pabel receive speakers/consultancy honoraria from AstraZeneca. S. Sossalla and M. Luedde receive speaker’s/consultancy honoraria from Boehringer Ingelheim Pharma GmbH and AstraZeneca.

Figures

Fig. 1
Fig. 1
Possible mechanisms of SGLT2 inhibitors (SGLT2i) on the heart with respect to rather systemic (left panel), combined (middle panel) or myocardial effects (right panel). Image heart: © Shutterstock/Vasif Maharov; Image human: © Shutterstock/10topvector
Fig. 2
Fig. 2
Contractility of isolatedhuman HFrEF trabecula upon empagliflozin treatment. A Original twitches of stimulated human trabecula before and after wash-in of increasing concentrations of empagliflozin. B Normalised developed (systolic) force (Tdev) and C normalised diastolic tension (Tdia). Raw data before and after wash-in of empagliflozin are provided in the inlay scatter. With permission from Pabel et al. [90]
Fig. 3
Fig. 3
Effects of empagliflozin on the passive stiffness of (skinned) cardiomyocytes from HFpEF patients and from healthy donors. A The original recordings of force response during stepwise cell stretches. B Normalised passive stiffness of HFpEF and non-failing (NF) cardiomyocytes upon empagliflozin measured at different sarcomere lengths. With permission from Pabel et al. [90]
Fig. 4
Fig. 4
Proposed myocardial mechanisms of Gliflozins (SGLT2 inhibitors) in HF. PKG, Proteinkinase G. Image heart: ©AdobeStock/Rogatnev
See this image and copyright information in PMC

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