Cardiometabolic and renal benefits of sodium–glucose cotransporter 2 inhibitors

The therapeutic scope of sodium–glucose cotransporter 2 (SGLT2) inhibitors has expanded beyond glycaemic regulation in the management of diabetes mellitus. Studies published in the past few years highlight their substantial effect on cardiovascular outcomes, notably in decreasing mortality and the need for heart failure-related hospitalization. These agents also lead to pronounced improvements in a range of renal outcomes. The primary actions of SGLT2 inhibition, glycosuria and natriuresis, are pivotal in enhancing glucose control, promoting weight loss and lowering blood pressure. These effects initiate a series of beneficial mechanisms: facilitating haemodynamic improvement by reducing interstitial volume, enhancing cardiac function, boosting energy efficiency through altered ketone body metabolism and mitigating inflammation and oxidative stress. Additional effects include heightened erythropoiesis, reduced hyperuricaemia and increased levels of angiotensin-converting enzyme 2 and angiotensin (1–7). SGLT2 inhibitors also attenuate sympathetic overactivity by modulating neurohumoral activation and renal afferent signalling, contributing to their cardioprotective and renoprotective profiles. This Review provides a comprehensive overview of the diverse mechanisms underpinning the cardiometabolic and renal effects of SGLT2 inhibitors, emphasizing their clinical relevance and therapeutic potential.