In the EMPA-REG OUTCOME trial, therapy with the sodium/glucose co-transporter (SGLT) 2 inhibitor empagliflozin over just 2.6 years was associated with a 14% reduction in the risk of major cardiovascular events, driven by a marked and unexpected reduction in cardiovascular mortality (38%) in patients with type 2 diabetes and established cardiovascular disease [1]. The drug also reduced the incidence of heart failure hospitalisation (HFH) by 35%.

The magnitude of these benefits and their rapid emergence after only a few months from randomisation make it unlikely that the modest benefits on HbA1c (− 0.4% compared with placebo), body weight (− 2 kg) and systolic/diastolic blood pressure (4/2 mmHg) were responsible [1]. Moreover, the divergence in the HRs for non-fatal myocardial infarction (HR 0.87 [95% CI 0.70, 1.09]) vs non-fatal stroke (HR 1.24 [0.92, 1.67]) makes it unlikely that the benefits of empagliflozin involved classical effects on atherosclerosis. Accordingly, additional mechanisms and mediators need to be considered to better understand why empagliflozin had such important benefits in this trial [2–5]. Based on their mode of action, SGLT2 inhibitors induce natriuresis and osmotic diuresis, associated with significant reductions in systolic and diastolic blood pressure. The resultant decrease in plasma volume and both cardiac preload and afterload may have obvious benefits for the heart, particularly in patients with impaired left ventricular function. However, it should be noted that only 10% of trial participants had recognised heart failure at baseline [6]. In addition, in clinical trials, anti-hypertensive agents and, specifically, diuretics, have not been demonstrated to have such strong protective cardiovascular effects, particularly on cardiovascular death and HFH. Only a recent trial involving eplerenone in patients with heart failure (but not necessarily diabetes) has demonstrated a similarly rapid improvement in heart failure outcomes [7]. Thus, it is conceivable that empagliflozin’s diuretic activity contributed at least partially to the improved cardiovascular outcomes observed in EMPA-REG OUTCOME via an improvement in haemodynamics, decreasing myocardial stretch and the risk of developing potentially lethal arrhythmias. Yet, the results of this trial remain surprising, leading investigators to propose other mediators.