In 2015, the first large-scale placebo-controlled trial designed to assess cardiovascular safety of glucose-lowering with sodium-glucose co-transporter 2 (SGLT2) inhibition in type 2 diabetes mellitus raised hypotheses that the class could favourably modify not only risk of atherosclerotic cardiovascular disease, but also hospitalization for heart failure, and the development or worsening of nephropathy. By the start of 2021, results from 10 large SGLT2 inhibitor placebo-controlled clinical outcome trials randomizing ∼71 000 individuals have confirmed that SGLT2 inhibitors can provide clinical benefits for each of these types of outcome in a range of different populations. The cardiovascular and renal benefits of SGLT2 inhibitors appear to be larger than their comparatively modest effect on glycaemic control or glycosuria alone would predict, with three trials recently reporting that clinical benefits extend to individuals without diabetes mellitus who are at risk due to established heart failure, or albuminuric chronic kidney disease. This European Society of Cardiology position paper summarizes reported results from these 10 large clinical outcome trials considering separately each of the different types of cardiorenal benefit, summarizes key molecular and pathophysiological mechanisms, and provides a synopsis of metabolic effects and safety. We also describe ongoing placebo-controlled trials among individuals with heart failure with preserved ejection fraction and among individuals with chronic kidney disease.