Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure

Abstract

Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor-mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.

Keywords: heart failure; heart failure with reduced ejection fraction; pharmacology; systemic review.

Figure 1

Schematic diagram showing conventional mechanisms of action of SGLT2 inhibitors. SGLT, sodium-glucose co-transporter.

Figure 2

Schematic diagram showing proposed novel mechanisms of action of SGLT2 inhibitors in heart failure. AMPK, adenosine monophosphate-activated protein kinase; HIF, hypoxia-inducible factor; NHE, sodium-hydrogen exchanger; SGLT, sodium-glucose co-transporter; SIRT, sirtuin.