Applications of SGLT2 inhibitors beyond glycaemic control

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed for their glucose-lowering effects and have shown a modest glycaemic benefit in people with type 2 diabetes mellitus (T2DM). In the past decade, a series of large, robust clinical trials of these therapies have demonstrated striking beneficial effects for various care goals, transforming the chronic disease therapeutic landscape. Cardiovascular safety studies in people with T2DM demonstrated that SGLT2 inhibitors reduce cardiovascular death and hospitalization for heart failure. Subsequent trials in participants with heart failure with reduced or preserved left ventricular ejection fraction demonstrated that SGLT2 inhibitors have beneficial effects on heart failure outcomes. In dedicated kidney outcome studies, SGLT2 inhibitors reduced the incidence of kidney failure among participants with or without diabetes. Post hoc analyses have suggested a range of other benefits of these drugs in conditions as diverse as metabolic dysfunction-associated steatotic liver disease, kidney stone prevention and anaemia. SGLT2 inhibitors have a generally favourable adverse effect profile, although patient selection and medication counselling remain important. Concerted efforts are needed to better integrate these agents into routine care and support long-term medication adherence to close the gap between clinical trial outcomes and those achieved in the real world. Here, the authors discuss the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors for a range of clinical outcomes beyond glucose lowering, including kidney and cardiovascular protection. They also discuss the need for implementation and adherence initiatives to help translate the benefits of these agents into real-world clinical outcomes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of kidney disease progression in people with or without diabetes as well as the risk of acute kidney injury and hyperkalaemia.SGLT2 inhibitors reduce the risk of cardiovascular death and heart failure hospitalization among people with type 2 diabetes mellitus and have beneficial effects on key heart failure outcomes irrespective of diabetes status or left ventricular ejection fraction.SGLT2 inhibitors modestly lower systolic and diastolic blood pressure without a significant increase in risk of hypotensive episodes and have modest benefits for weight loss.Other benefits of SGLT2 inhibitors include improvements in liver outcomes in people with metabolic dysfunction-associated steatotic liver disease, reduced risk of symptomatic kidney stone events, improvements in anaemia outcomes and potential reductions in the risk of new-onset atrial fibrillation and new-onset diabetes.SGLT2 inhibitors have a generally favourable adverse effect profile but are associated with increased risk of genital mycotic infections and a small increased risk of diabetic ketoacidosis; they should be used with caution in people with unstable volume status owing to the risk of hypovolaemia.Prescription of SGLT2 by clinicians and patient adherence are suboptimal despite strong evidence for the efficacy and cost-effectiveness of these therapies.