Cardiovascular (CV) disease (CVD) is the main cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Despite optimal glycaemic control, standard antihyperglycaemic therapy failed to impact CV events in intervention trials; therefore, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued a guidance to the pharmaceutical industry to specifically assess the CV outcomes and safety of new glucose-lowering drugs. Amongst them, sodium-glucose transporter 2 (SGLT2) inhibitors proved to not only provide good tolerance, few adverse effects, and good glycometabolic control, but also striking reduction in the risk of CV events. In this review, data from the main randomised controlled trials are presented, including post-hoc analyses looking into several aspects of CV protection. Moreover, the main findings from observational real-world studies to date are described, overall reassuring as regards to CV safety and efficacy of SGLT2 inhibitors. Finally, several mechanisms which might contribute to the cardioprotective effect of SGLT2 inhibition are depicted, including findings from recent mechanistic studies.

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