EMPA-REG: Empagliflozin’s benefits were not driven by participants with pre-existing heart failure

Heart failure is a highly prevalent comorbidity with diabetes, occurring in more than one in five people with the condition aged over 65 years (Bertoni et al, 2004). Furthermore, it is associated with a very poor prognosis, with a median survival time of around 4 years. Recently, there has been considerable debate around the effects of different blood glucose-lowering therapies on heart failure outcomes in type 2 diabetes, while intensive glucose control has failed to demonstrate any benefit with respect to heart failure outcomes.

Empagliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor and as such reduces renal glucose reabsorption, thus increasing urinary glucose excretion. The recently published EMPA-REG OUTCOME study demonstrated that treatment with empagliflozin added to standard care reduced the risk of the primary composite outcome of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke; cardiovascular mortality; hospitalisation for heart failure; and overall mortality compared with placebo in 7020 people with type 2 diabetes and high cardiovascular risk (Zinman et al, 2015).

This particular subanalysis of EMPA-REG (summarised alongside) focussed on heart failure and hospitalisation outcomes in the overall study population and in subgroups defined according to baseline characteristics. Participants were randomised to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo. Of the 7020 participants, 706 (10.1%) had heart failure at baseline. The composite outcome of heart failure hospitalisation or cardiovascular death occurred in a significantly lower proportion of empagliflozin recipients compared with placebo (5.7% vs 8.5%; hazard ratio [HR], 0.66). This corresponded to a number needed to treat of 35 to prevent one heart failure hospitalisation or cardiovascular death over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including people with or without heart failure, and across categories of medications to treat diabetes and/or heart failure.

Empagliflozin improved other heart failure outcomes, including hospitalisation for or death from heart failure (2.8% vs 4.5%; HR, 0.61) and was associated with a reduction in all-cause hospitalisation (36.8% vs 39.6%; HR, 0.89). In both treatment groups, serious adverse events and adverse events leading to discontinuation were more common in people with heart failure at baseline than in those without it, but they were no more common with empagliflozin than with placebo. Empagliflozin appeared to reduce the risk of the primary outcome to the same extent in people with heart failure at baseline – who had high use of medications used to treat heart failure – as in those without pre-existing heart failure. Thus, the positive outcomes associated with empagliflozin do not appear to have been predominantly driven by this patient group.

The effects of empagliflozin on heart failure hospitalisation or cardiovascular death and on all-cause hospitalisation was observed very early in the study and was sustained throughout the trial. This suggests that the benefit was not driven by an effect on atherosclerosis; however, the mechanisms behind these observations remain unknown. Potential contributors include osmotic diuresis; effects on plasma volume and sodium retention; reductions in arterial stiffness and rate pressure product; reductions in weight and blood pressure without increases in sympathetic nervous activity; reductions in hyperglycaemia and insulin levels; and reductions in uric acid.

There are some limitations to these data, primarily concerning the validity of the diagnosis of heart failure at baseline and the absence of objective measures of ventricular function. Nevertheless, the data provide further evidence in support of the potential cardiovascular benefits of SGLT2 inhibitor therapy, although the generalisability to wider patient populations remains the focus of ongoing studies of these agents.

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