EMPEROR-Reduced: SGLT2 inhibitor empagliflozin also effective for heart failure

The previously-released trial results were presented with additional current data, supporting the inhibitor’s use as a further pillar for heart failure treatment in patients with reduced ejection fraction.

Could it be a new therapy standard?

The results of the EMPEROR-Reduced trial with empagliflozin, which were presented for the first time at the virtual ESC Congress 2020, were presented once again at the virtual Annual Meeting of the European Association for the Study of Diabetes in September 2020, with additional updated and current data. For Milton Packer, Baylor University Medical Center, Dallas, the now available data on the use of SGLT2 inhibitors in heart failure are so convincing that they should be used as a new therapy standard and as a further pillar in the therapy of heart failure in patients with reduced ejection fraction.

The randomized, double-blind EMPEROR-Reduced study (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction) included 3,730 patients with heart failure and reduced ejection fraction. Compared to the DAPA-HF study with dapagliflozin (Forxiga®), more patients with an ejection fraction ≤ 30% were enrolled. Patients with an ejection fraction above 30% had to have very high NT-proBNP levels or had been hospitalized for heart failure in the last 12 months.

In addition to their standard therapy, the test subjects were randomly given 10 mg empagliflozin (n = 1863) or placebo (n = 1867) once a day.

Only three endpoints were assessed, with primary and first and second secondary endpoints being tested in a hierarchical procedure. The primary endpoint was the combination of cardiovascular death and hospitalization for heart failure. The first secondary endpoint included all hospitalizations for heart failure and the second secondary endpoint included the decrease in glomerular filtration rate (GFR) over time.

The demographic parameters of the subjects were comparable in both groups. About 50% suffered from diabetes, 73% had an ejection fraction below 30% and 79% had an NT-proBNP value of at least 1000 pg/ml. In 48% the GFR was below 60 ml/min per 1.73 m². About 20% took an angiotensin receptor neprilysin inhibitor (ARNI).

Compared to the DAPA-HF study, the patients had a lower ejection fraction (27.7 vs. 31.2%), higher NT-proBNP values (1900 pg/ml vs. 1428 pg/ml), and a lower GFR (62 vs. 66 ml/min per 1.73m²).

Primary endpoint reduced by 25%

The EMPEROR-Reduced study achieved the study objective of significantly reducing the risk of cardiovascular death and hospitalization due to heart failure by 25% (p < 0.0001) when compared to placebo. During the 16-month median follow-up period, 361 of 1,863 patients (19.4%) in the empagliflozin group and 462/1,867 patients (24.7%) in the placebo group met the primary endpoint.

The event rate was thus 40% higher than in the DAPA-HF study, which can be attributed to the higher risk of patients in the EMPEROR study. This result was driven by a 31% reduction in the risk of first hospital admissions for heart failure. The risk of cardiovascular death decreased by 8%.

The events of the combined primary endpoint were similarly reduced in all 12 subgroups by empagliflozin.

Fewer hospitalizations, fewer renal complications

The total number of all hospital stays was reduced from 553 to 388 by empagliflozin, a relative risk reduction of 30% (p = 0.0003).

In the empagliflozin group, the decrease in GFR slowed to -0.9 ml/min per 1.73² compared to the placebo group, where GFR decreased by 4.2 ml/min per 1.73m² over 16 months.

Events of a combined renal endpoint such as dialysis, transplantation, or significant sustained decrease in GFR occurred in 30 patients (1.6%) on empagliflozin and 58 patients (3.1%) on placebo, representing a 50% risk reduction.

Overall, the SGLT2 inhibitor was well tolerated, with uncomplicated infections of the genital tract occurring more frequently than with placebo.

Effectiveness in diabetics and non-diabetics comparably good

Stefan Anker (Department of Cardiology, Charité, Berlin, Germany) showed in a recent evaluation that all effects of empagliflozin were comparably good in diabetics and non-diabetics as well as in test subjects with and without ARNI therapy. Increased hypoglycaemic episodes were not observed. Empagliflozin did not - as expected - reduce the HbA1c value in non-diabetics. Anker concluded that "the decision to use empagliflozin in heart failure with reduced ejection fraction should be made independently of the patient's glycaemic status".

A meta-analysis of the DAPA-HF and EMPEROR-Reduced Study

A meta-analysis of the EMPEROR-Reduced and DAPA-HF studies was possible, according to Faiez Zannad (University Hospital Nancy, France) because the design of both studies was similar. Based on data from 8,474 patients, it was found that treatment with an SGLT2 inhibitor reduced the risk of all-cause mortality by 13% (p = 0.018), cardiovascular mortality by 14% (p = 0.027), cardiovascular mortality plus initial hospitalisation for heart failure by 26% (p < 0.0001) and the composite renal endpoint by 48% (p = 0.013).

The effects of SGLT2 inhibitors are independent of age, gender, and the presence or absence of diabetes or treatment with a neprilysin inhibitor.