SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms

Abstract

This paper highlights the cardioprotective potential of sodium-glucose cotransporter 2 inhibitors (SLGT2i), as well as several most discussed mechanisms responsible for their cardioprotection. Cardiovascular diseases are considered a primary cause of death in nearly 80% of type 2 diabetes mellitus (T2DM) patients, with a 2–4-fold greater incidence of heart failure (HF) among diabetics. As novel hypoglycemics, SGLT2i showed exceptional cardiovascular benefits, reflected through robust reductions of cardiovascular mortality and hospitalization for HF in T2DM patients. Recently, those effects have been reported even in patients with HF and reduced ejection fraction irrespectively of diabetic status, suggesting that cardioprotective effects of SGLT2i are driven independently of their hypoglycemic actions. SGLT2i exerted hemodynamic and metabolic effects, partially driven by natriuresis and osmotic diuresis. However, those systemic effects are modest, and therefore cannot be completely related to the cardiac benefits of these agents in T2DM patients. Hence, increased circulating ketone levels during SGLT2i administration have brought out another hypothesis of a cardiac metabolic switch. Moreover, SGLT2i influence ion homeostasis and exert anti-inflammatory and antifibrotic effects. Their enviable influence on oxidative stress markers, as well as anti- and pro-apoptotic factors, have also been reported. However, since the main mechanistical contributor of their cardioprotection has not been elucidated yet, a joint action of systemic and molecular mechanisms has been suggested. In the light of ongoing trials evaluating the effects of SGLT2i in patients with HF and preserved ejection fraction, a new chapter of beneficial SGLT2i mechanisms is expected, which might resolve their main underlying action.

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Funding

This work was supported by Faculty of Medical Sciences, University of Kragujevac (Junior project No. 03/18 and No. 03/20).

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Maja Nikolic—collecting literature data, writing a manuscript and table design; Vladimir Zivkovic—text supervising and research the literature; Jovana Joksimovic Jovic—text supervising and editing; Jasmina Sretenovic—text supervising and editing; Goran Davidovic—design of the topic; Stefan Simovic—text supervising and editing; Danijela Djokovic—text supervising and final approval; Nemanja Muric—text supervising; Sergey Bolevich—text supervising and final approval; Vladimir Jakovljevic—text supervising and final approval.

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Correspondence to Vladimir Jakovljevic.

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Nikolic, M., Zivkovic, V., Jovic, J.J. et al. SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms. Heart Fail Rev (2021). https://doi.org/10.1007/s10741-021-10079-9

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Keywords

  • SGLT2 inhibitors
  • Type 2 diabetes mellitus
  • Heart failure
  • Cardioprotective mechanisms