The SGLT-2 inhibitors were initially developed for diabetes but eventually noted to have significant effects on outcomes in patients with heart failure in addition to diabetes. The DAPA-HF trial established the usefulness of dapagliflozin in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. After that the EMPEROR-Reduced trial was announced to evaluate the efficacy of empagliflozin in similar population.
The EMPEROR Reduced trial evaluated the safety and efficacy of a empagliflozin in patients with HFrEF (<40%) with or without diabetes.
Similar to the results of the DAPA HF trial, empagliflozin group had a lower risk of CV death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes.
Randomized, double-blind, parallel-group, placebo-controlled, event-driven trial
In total, 3730 patients were included and were randomized to empagliflozin (N=1863) or placebo (N=1867)
- Adults (≥18 years of age) who had chronic heart failure (functional class II, III, or IV) with a LVEF of 40% or less.
- All the patients were receiving appropriate treatments for heart failure, including diuretics, RAAS and neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and, if indicated, cardiac devices.
- HF hospitalization within 12 months
- N-terminal pro–B-type natriuretic peptide (NT-proBNP ≥600 pg/ml if EF ≤30%; ≥1000 pg/ml if EF 31-35%; ≥2500 pg/ml if EF >35%.
- Composite outcome of death from cardiovascular causes or hospitalization for heart failure %
19.4% patients in the empagliflozin had primary endpoint event compared to 24.7% in the placebo group.
HR 0.75; 95% CI, 0.65 to 0.86; P<0.001, NNT = 19
Key Secondary Outcomes:
1. Hospitalizations for heart failure (events)
388 (empagliflozin) vs 553 (placebo) hospitalizations.
HR 0.70; 95% CI, 0.58 to 0.85; P<0.001
2. Rate of the decline in the estimated GFR
–0.55 ml/min/per year (empagliflozin) vs. –2.28 (placebo)
Difference 1.73 (95% CI, 1.10 to 2.37; P<0.001)
3. Composite renal outcome (chronic hemodialysis, renal transplantation, profound sustained reduction in eGFR)
1.6% vs. 3.1% (HR 0.50, 95% CI 0.32-0.77, p < 0.01)
Take Home Point:
Empagliflozin was initially tested in EMPA-REG OUTCOME trial which highlighted its usefulness in reducing CV mortality. The DAPA-HF and EMPEROR-Reduced trials have now established the efficacy of SGLT2 inhibitors in HF without DM. FDA has already approved dapagliflozin for HF treatment and empagliflozin will likely going to follow suit. The EMPEROR-Preserved trial is the next trial to look forward to which is evaluating empagliflozin in patients with HF and preserved EF.