Sodium-glucose co-transporter 2 inhibitors in 2022: mechanisms of cardiorenal benefit

The use of sodium-glucose co-transporter 2 (SGLT2) inhibitors has evolved over the past decade, from their initial indication as an adjunctive oral medication to treat hyperglycaemia in diabetics, to becoming part of guideline-directed therapy for the treatment of chronic kidney disease, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. This transition was driven by data from large cardiovascular and renal outcome trials, which repeatedly demonstrated that SGLT2 inhibitors improve important endpoints in chronic kidney disease and heart failure. In chronic kidney disease, SGLT2 inhibition reduces decline in glomerular filtration rate, risk of progression to end-stage renal disease and death from renal causes. With respect to their use in heart failure, SGLT2 inhibitors decrease risk of major adverse cardiac events, hospitalisation for heart failure and death from cardiovascular causes. While the benefits of these medications have been demonstrated, the mechanisms by which they are conferred are less clear. Extensive investigation into potential mechanisms of benefits has been pursued internationally and current hypotheses include increased natriuresis and osmotic diuresis, improved glomerular haemodynamic, reduced body mass and reduced adipose tissue mediated inflammation, in addition to others. This review discusses the physiology underlying the therapeutic benefit of SGLT2 inhibition in chronic kidney disease and heart failure.