Empagliflozin reduces CV death/HHF and renal events in HFrEF patients with or without DM
The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin significantly reduces the risk of cardiovascular (CV) death or hospitalization for heart failure (HHF) as well as renal events vs placebo in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes mellitus (DM), according to results of the EMPEROR-Reduced trial presented at the European Society of Cardiology Congress 2020 (ESC 2020). These results, taken together with results of an earlier SGLT2 inhibitor trial in HFrEF patients with or without DM, suggest that SGLT2 inhibitors may be considered as a new standard of care (SoC) in HFrEF treatment.
In the double-blind phase III EMPEROR-Reduced trial, 3,730 adult patients with class II–IV HFrEF (left ventricular ejection fraction [LVEF] ≤40 percent), with or without DM, were randomized to receive empagliflozin 10 mg once daily (n=1,863; mean age, 67.2 years; female, 23.5 percent; Asian, 18.1 percent) or placebo (n=1,867; mean age, 66.5 years; female, 24.4 percent; Asian, 17.9 percent) in addition to recommended therapy for heart failure (HF). [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
At baseline, 73 percent of patients had LVEF ≤30 percent, and 79 percent had N-terminal pro-brain natriuretic peptide (NT-proBNP) level ≥1,000 pg/mL. Mean LVEF was 27.7 percent in the empagliflozin group vs 27.2 percent in the placebo group (LVEF ≤30 percent in 71.8 percent vs 74.6 percent of patients), while median NT-proBNP level was 1,887 pg/mL vs 1,926 pg/mL (NT-proBNP ≥1,000 pg/mL in 78.6 percent vs 79.7 percent of patients).
The trial recruited patients with estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2. [Eur J Heart Fail 2019;21:1270-1278] Mean eGFR at baseline was 61.8 mL/min/1.73 m2 in the empagliflozin group vs 62.2 mL/min/1.73 m2 in the placebo group. DM was present in 49.8 percent of patients in each arm, while 18.3 percent vs 20.7 percent of patients were on an angiotensin receptor-neprilysin inhibitor (ARNI).
“EMPEROR-Reduced was conducted in a sicker population of patients with lower LVEF, higher NT-proBNP level and poorer renal function than HFrEF patients in the DAPA-HF trial of dapagliflozin,” said investigator Dr Milton Packer of the Baylor University Medical Center, Dallas, Texas, US. “At DAPA-HF baseline, patients in the dapagliflozin group had a mean LVEF of 31.2 percent, median NT-proBNP level of 1,428 pg/mL, and mean eGFR of 66 mL/min/1.73 m2. In addition, a lower proportion [10.5 percent] of patients in the dapagliflozin group were on an ARNI or had had DM [41.8 percent] at baseline.” [N Engl J Med 2019;381:1995-2008]
Empagliflozin reduces CV death or HHF
After a median follow-up of 16 months, empagliflozin 10 mg once daily, on top of recommended therapy for HF, demonstrated a 25 percent relative reduction in risk of the primary composite endpoint of CV death or HHF vs placebo (19.4 percent vs 24.7 percent; hazard ratio [HR], 0.75; 95 percent confidence interval [CI], 0.65 to 0.86; p<0.001). (Figure 1) [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
“Empagliflozin’s benefit in the primary composite endpoint was driven by a 31 percent reduction in risk of first HHF vs placebo [13.2 percent vs 18.3 percent; HR, 0.69; 95 percent CI, 0.59 to 0.81],” said Packer. “The risk of CV death was 8 percent lower with empagliflozin vs placebo [10 percent vs 10.8 percent; HR, 0.92; 95 percent CI, 0.75 to 1.12].”
“The benefit of empagliflozin on the primary composite endpoint was consistent in 12 prespecified subgroups of patients,” he pointed out. “Of note, the magnitude of benefit was similar between patients with DM [HR, 0.72; 95 percent CI, 0.60 to 0.87] and those without DM [HR, 0.78; 95 percent CI, 0.64 to 0.97] at baseline. A significant benefit was also observed in patients who used an ARNI [HR, 0.64; 95 percent CI, 0.45 to 0.89] and in those who did not [HR, 0.77; 95 percent CI, 0.66 to 0.90].”
The secondary endpoint of total (first and recurrent) HHFs also saw a 30 percent reduction with empagliflozin vs placebo (HR, 0.70; 95 percent CI, 0.58 to 0.85; p<0.001). (Figure 2)
Empagliflozin slows eGFR decline, reduces adverse renal outcomes
The rate of on-treatment eGFR decline, which served as one of the secondary endpoints, was significantly slower in the empagliflozin vs placebo group (-0.55 mL/min/1.73 m2/year vs -2.28 mL/min/1.73 m2/year; difference in eGFR slope, +1.73 mL/min/1.73 m2/year; p<0.001). (Figure 3) [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
Furthermore, patients treated with empagliflozin had a 50 percent reduction in risk of a composite renal outcome that included chronic dialysis, renal transplantation, a sustained ≥40 percent reduction in eGFR, sustained eGFR <15 mL/min/1.73 m2 in patients with baseline eGFR ≥30 mL/min/1.73 m2, or sustained eGFR <10 mL/min/1.73 m2 in patients with baseline eGFR <30 mL/min/1.73 m2 (1.6 percent vs 3.1 percent; HR, 0.50; 95 percent CI, 0.32 to 0.77).
Safety and tolerability
“Empagliflozin was well tolerated in the trial,” said Packer. “Serious adverse events [AEs] occurred in 41.4 percent of patients on empagliflozin vs 48.1 percent of those on placebo, with 26.8 percent vs 34 percent of events being related to cardiac disorder and 3.2 percent vs 5.1 percent being related to worsening of renal function.” [Packer M, et al, ESC 2020]
No significant differences were seen between empagliflozin and placebo in rates of volume depletion (10.6 percent vs 9.9 percent), hypotension (9.4 percent vs 8.7 percent; symptomatic hypotension, 5.7 percent vs 5.5 percent), and hypoglycaemia (1.4 percent vs 1.5 percent). Uncomplicated genital tract infection was reported more frequently with empagliflozin vs placebo (1.7 percent vs 0.6 percent).
“Safety concerns seen with other drugs for HF, such as hypotension, volume depletion, renal dysfunction, bradycardia and hyperkalaemia, were not evident with empagliflozin in the current trial,” the investigators noted. [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
SGLT2 inhibitors as new SoC in HFrEF?
“The 25 percent risk reduction in CV death or HHF demonstrated in the EMPEROR-Reduced trial was comparable to the risk reduction in the primary composite endpoint seen in the DAPA-HF trial,” highlighted Packer.
In the DAPA-HF trial, dapagliflozin reduced the risk of the primary composite outcome of worsening HF (HHF or an urgent visit resulting in intravenous therapy for HF) or CV death by 26 percent vs placebo (HR, 0.74; 95 percent CI, 0.65 to 0.85; p<0.001). [N Engl J Med 2019;381:1995-2008]
The number needed to treat to prevent one primary event was 19 for empagliflozin in the EMPEROR-Reduced trial, and 21 for dapagliflozin in the DAPA-HF trial. [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190; N Engl J Med 2019;381:1995-2008]
“The 31 percent reduction in first HHF seen with empagliflozin in EMPEROR-Reduced was also similar to the reduction in risk of first worsening HF event reported with dapagliflozin in DAPA-HF [HR, 0.70; 95 percent CI, 0.59 to 0.83],” said Packer.
In addition, empagliflozin demonstrated a 30 percent reduction in the secondary outcome of total HHFs in the EMPEROR-Reduced trial. In the DAPA-HF trial, the secondary composite outcome of total HHFs and CV deaths was reduced by 25 percent with dapagliflozin (HR, 0.75; 95 percent CI, 0.65 to 0.88; p<0.001).
“Taken together, we believe that the concordant results of EMPEROR-Reduced and DAPA-HF should be sufficient to establish SGLT2 inhibitors as a new SoC for patients with HFrEF,” Packer concluded.