Heart failure

EMPEROR-Reduced increases rationale for SGLT2 inhibitors as standard of care in HFrEF


A second major trial has strengthened the case for using SGLT2 inhibitors in patients with heart failure and a reduced ejection fraction (HFrEF) regardless of diabetes status.

Results seen with empagliflozin in the EMPEROR-Reduced trial show that those seen previously with dapagliflozin in the DAPA-HF were no fluke, according to cardiologists presenting findings at European Society of Cardiology Congress (ESC 2020).

The trial enrolled 3,730 patients with heart failure and a left ventricular ejection fraction of 40% or less with or without diabetes, and about half had type 2 diabetes. It found that empagliflozin reduced the primary endpoint of risk of cardiovascular death or hospitalisation for heart failure by 25% compared to placebo in who were already receiving all appropriate treatments for heart failure.

During a median follow-up of 16 months, the primary endpoint occurred in 361 patients in the empagliflozin group and 462 patients in the placebo group (hazard ratio 0.75; 95% confidence interval [CI] 0.65–0.86; p<0.0001).

Empagliflozin reduced total hospitalisations for heart failure by 30% compared to placebo (HR 0.70; 95% CI 0.58–0.85; p<0.001).

The study investigators noted that the benefits were seen in patients receiving any of the currently recommended drugs for heart failure, including sacubitril–valsartan, and were seen regardless of the presence or absence of diabetes.

Empagliflozin was also associated  with a slower rate of decline in the estimated GFR and a 50% reduction in adverse renal outcomes, which occurred in 30 patients in the empagliflozin group and 58 patients in the placebo group (HR 0.50; 95% CI 0.32–0.77; p<0.01).

Uncomplicated genitourinary tract infections were more common in the empagliflozin group (1.3% vs. 0.4%), but the frequency of hypotension, volume depletion and hypoglycaemia were similar in the two groups.

The trial results published simultaneously in NEJM, extends the benefits of SGLT2 inhibitors to higher-risk patients and shows a meaningful benefit on renal outcomes in patients with heart failure for the first time, according to principal investigator  Dr Milton Packer of Baylor University Medical Centre, Dallas, Texas.

“Based on the combined results of our trial (together with the earlier trial with dapagliflozin), we believe that SGLT2 inhibition with empagliflozin and dapagliflozin will now become a new standard of care for patients with heart failure and a reduced ejection fraction,” he said.

An accompanying editorial in NEJM noted that reductions cardiovascular death rates were smaller with empagliflozin than dapagliflozin (HR 0.92 vs 0.82). But author Dr John Jarcho, a cardiologist from Harvard Medical School, said that conversely the effects on mortality in patients with diabetes were greater for empagliflozin, suggesting there was heterogenous effect with SGLT2 inhibitors.

He concluded that the evidence was now strong enough to persuade guideline committees – such as those in Canada – to recommend the use of SGLT2 inhibitors in patients with mild or moderate heart failure who have an ejection fraction of 40% or less to improve symptoms and quality of life and to reduce the risk of hospitalisation and cardiovascular mortality.

“The EMPEROR-Reduced data will provide further impetus for other groups to address this question,” he wrote.

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