Empagliflozin: Another SGLT-2i in HFrEF armamentarium

Adding empagliflozin to recommended therapy in patients with heart failure with reduced ejection fraction (HFrEF) reduced the risk of HF hospitalization and slowed renal function decline, the EMPEROR-Reduced* trial showed.

The trial involved 3,730 patients with NYHA** class II–IV HF and left ventricular ejection fraction (LVEF) ≤40 percent*** who were randomized 1:1 to receive empagliflozin (10 mg once/day) or placebo plus usual therapy.

The risk of the primary composite outcome of CV death or hospitalization for HF at a median 16 months was lower among patients on empagliflozin than placebo (19.4 percent vs 24.7 percent; hazard ratio [HR], 0.75, 95 percent confidence interval [CI], 0.65–0.86; p<0.0001). [ESC 2020, Hot Line session; N Engl J Med 2020;383:1413-1424]

This reduction occurred regardless of baseline diabetes status (HR, 0.72 and HR, 0.78 in patients with and without diabetes, respectively). Similar findings were observed with other subgroups including the use vs non-use of angiotensin receptor neprilysin inhibitors (ARNIs; HR, 0.64 and HR, 0.77, respectively). 

The risk reduction was driven primarily by fewer incidents of first hospitalizations for HF in the empagliflozin vs placebo group (13.2 percent vs 18.3 percent; HR, 0.69), with a smaller effect on the risk of CV death (10.0 percent vs 10.8 percent; HR, 0.92, 95 percent CI, 0.75–1.12). 

There was also a 30 percent reduction in total number of hospitalizations for HF (first and recurrent; HR, 0.70, 95 percent CI, 0.58–0.85; p=0.0003) and a 50 percent improvement in the composite renal endpoint^# (HR, 0.50, 95 percent CI, 0.32–0.77; p=0.0019) with empagliflozin vs placebo.

Mean eGFR change from baseline during the double-blind period was smaller with empagliflozin vs placebo (difference in slope, 2.1 mL/min/1.73 m²; p<0.0001), with a slower annual rate of eGFR decline (-0.55 vs -2.28 mL/min/1.73 m² per year; p<0.001).

Assessment of eGFR 23–42 days following withdrawal of double-blind therapy in 966 patients showed significantly less eGFR deterioration with empagliflozin vs placebo (-0.9 vs -4.2 mL/min/1.73 m²; p<0.0001).

All-cause mortality was similar between groups (HR, 0.92, 95 percent CI, 0.77–1.10). Serious adverse events related to cardiac disorders (26.8 percent vs 34.0 percent) or worsening renal function (3.2 percent vs 5.1 percent) occurred less frequently in empagliflozin than placebo recipients. Hypoglycaemia, hypotension, and volume depletion rates were comparable between groups.

 

Different trials, different results?

Comparing the DAPA-HF^## and EMPEROR-Reduced trials, the results for the primary composite endpoint (HR, 0.75 in both trials) and first hospitalization for HF (HR, 0.69 in EMPEROR-Reduced and HR, 0.70 in DAPA-HF) are “virtually superimposable”, said principal investigator Dr Milton Packer from Baylor University Medical Center, Dallas, Texas, US.

“Although the effect on CV death in EMPEROR-Reduced was smaller than that seen in DAPA-HF [HR, 0.92 and HR, 0.82, respectively], the reverse was true when the effects of dapagliflozin and empagliflozin on CV death were assessed in comparable patients in trials of type 2 diabetes [DECLARE-TIMI58 and EMPA-REG OUTCOME, respectively]. Accordingly, the effects of these drugs on survival is characterized by significant heterogeneity,” he said.

With regard to CV death, one possibility is that SGLT-2^### inhibitors may not be as effective in patients with more severe HF, such as in EMPEROR-Reduced, said Assistant Professor John Jarcho from Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, US, in an editorial. However, this may be a chance finding. [N Engl J Med 2020;doi:10.1056/NEJMe2027915]

As Packer noted, compared with DAPA-HF patients, those in EMPEROR-Reduced had lower LVEF, higher NT-proBNP levels, and worse renal function.

Subgroup analysis by EF, baseline NT-proBNP level, or NYHA class may help elucidate this finding, while a randomized head-to-head trial would provide definitive answers, said Jarcho.

There could be other reasons for the divergent CV death outcomes in the two trials, noted Professor Marco Metra from the University of Brescia in Brescia, Italy, who discussed the findings at ESC 2020.

“It may be that there are differences between the two drugs, [though] such heterogeneity has not been shown with other outcomes.” The drugs may also be more effective if administered earlier in the clinical course of the disease, he added.

DAPA-HF had relatively low renal dysfunction rates, and as such, there was no significant reduction in the main renal endpoint with dapagliflozin (HR, 0.71), he continued.

Metra also noted that the number of patients on ARNIs in EMPEROR-Reduced was approximately twofold that in DAPA-HF (18.3 and 20.7 percent of empagliflozin and placebo recipients, respectively, in EMPEROR-Reduced, and 10.5 percent in DAPA-HF).

Among patients treated with ARNIs (sacubitril/valsartan), the addition of SGLT-2 inhibitors was associated with a significant reduction in the primary outcome in EMPEROR-Reduced (HR, 0.64 [empagliflozin vs placebo]) but not in DAPA-HF (HR, 0.75 [dapagliflozin vs placebo]), he said.

 

Definitive role for SGLT-2 inhibitors in HFrEF

“The results of the EMPEROR-Reduced trial confirm that the findings in DAPA-HF were no fluke and substantially strengthen the rationale for the use of SGLT-2 inhibitors in patients with HFrEF,” said Jarcho.

“We now have new drugs for the treatment of HF and these drugs may consistently improve the outcome of our patients compared to traditional therapy,” added Metra.

“They should probably be started [as soon as possible] to improve the outcome of our patients,” he said. [https://www.youtube.com/watch?v=HOYGg7nf4CI, accessed 6 October 2020]

 

An expert’s opinion

 

Dr Anggia Chairuddin Lubis

Cardiologist

Head of Cardiac Centre, Rumah Sakit Umum Pusat H. Adam Malik

Faculty of Medicine, Universitas Sumatera Utara,

Indonesia

 

How many patients do you tend to see with HF with/without diabetes in your practice?

In routine practice I usually see about 50 HF cases per week, though this has reduced during the COVID-19 pandemic.

 

How would SGLT-2 inhibitors fit into the treatment algorithm for your patients with HF with/without diabetes?

Looking at the latest evidence, SGLT-2 inhibitors will fit perfectly into treatment for patients with symptomatic HF who are using standard medication. As the EMPEROR-Reduced study was conducted in patients with NYHA class II–IV, I would use SGLT-2 inhibitors the way they were used in the study.

 

How would you say the EMPEROR-Reduced results apply to patients with HF and chronic kidney disease?

Compared to the DAPA-HF trial, the EMPEROR-Reduced trial was conducted in a sicker HF population. The results were consistent and identical with those of the DAPA-HF trial. Looking at these results, patients with HFrEF will derive benefits from SGLT-2 inhibitors which impressively, also had kidney benefits in EMPEROR-Reduced.

From EMPEROR-Reduced, we have confirmation of an SGLT-2 inhibitor subclass effect. On top of that, we also have convincing evidence of this class in sicker HFrEF patients.

 

How would the trial results influence your practice?

The EMPEROR-Reduced results will without a doubt influence my practice. EMPEROR-Reduced confirmed the subclass effect of SGLT-2 inhibitors. The advantages of SGLT-2 inhibitors are ease of use (once-daily dose, no need for titration) and an acceptable safety profile (no effect on blood pressure or heart rate and protective of kidney function). I would use SGLT-2 inhibitors early if the patient remained symptomatic after standard medication.

 

How would you select which SGLT-2 inhibitor to prescribe to your patient?

I do believe that both dapagliflozin and empagliflozin provide solid evidence of the effects of SGLT-2 inhibitors in the HFrEF population. Therefore, selection of SGLT-2 inhibitor will depend on cost.

 

What other information would you say is pertinent in this patient population?

Beyond its efficacy, I will underline the safety profile of empagliflozin. It is, thus far, the only HFrEF medication with no effect on heart rate, blood pressure, and kidney function.