Metabolism of the failing heart and the impact of SGLT2 inhibitors

ABSTRACT

Introduction: Cardiac metabolism represents a complex network of numerous pathways responsible for an adequate supply of ATP to the incessant contractile apparatus. Impairments of such pathways are associated with myocardial dysfunction. The newest antidiabetic drugs, the SGLT2 inhibitors, have been demonstrated to reduce cardiovascular mortality and heart failure hospitalizations. The mechanisms underlying these benefits are still uncertain; however, they may play a decisive role in restoring energy efficiency to the damaged heart.

Areas covered: This article reviews normal cardiac metabolism and contribution of different substrates to fuel supply. Specific attention is devoted to alterations of these pathways and their association with myocardial dysfunction. In addition, the impact of the novel SGLT2 inhibitors on cardiac mortality and heart failure hospitalizations is discussed. Various postulated mechanisms responsible for such benefits are also discussed.

Expert opinion: Metabolic alterations seem to play a crucial role in etiology and progression of heart failure. The cardiovascular benefits of the novel SGLT2 inhibitors have attracted more attention to this field. With effects beyond lowering glucose levels, these agents have been reported to induce changes in cardiac metabolism and to exert anti-inflammatory properties that may contribute to their large cardiovascular beneficial effects by improving contractile bioenergetics. Therefore, SGLT2 inhibitors may become an alternative drug to treat heart failure patients, regardless of diabetic status.

KEYWORDS:

• Cardiac metabolism
• heart failure
• diabetic cardiomyopathy
• SGLT2 inhibitors
• ketone bodies
• NHE1
• anti-inflammatory effects

Article highlights

• Cardiac function is regulated by a complex network of metabolic pathways.

• These pathways rely on substrate ‘flexibility’ to ensure adequate ATP supply to the myocardial contractile apparatus.

• Alterations in this refined biochemical structure are associated with cardiac damage and contractile dysfunction.

• Interestingly, the novel SGLT2 inhibitors have demonstrated to significantly reduced mortality and HF hospitalizations, in diabetic patients.

• The cardiac benefits of these antidiabetic agents appear to be independent of their glucose-lowering effect. They also exert anti-inflammatory properties and they improve cardiac bioenergetics.

• Although there is still a lack of proper knowledge about mechanisms responsible for such surprising cardiac benefits of the SGLT2 inhibitors, they may represent an alternative for HF patients regardless of their diabetic status.

This box summarizes the key points contained in the article.

Declaration of interest

J Badimon has been awarded an Investigator-Initiated Grant funded by Boehringer-Ingelheim to investigate the mechanism of action of the cardiac benefits of empagliflozin. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.