EMPEROR-Reduced Trial: Overall Results for patients with HFrEF

Heart failure (HF) is a debilitating, devastating, and fatal condition that has affected 64 million people worldwide.1,2 It is a significant global health problem with a mortality rate of 20% and 53% at one and five years from its initial diagnosis.3 An earlier trial, the DAPA-HF trial, showed that dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces the risk of cardiovascular death or hospitalization for heart failure regardless of the presence or absence of diabetes. Compared with the DAPA-HF trial, which includes patients with milder HF, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure (EMPEROR-Reduced) trial was conducted among patients diagnosed with more severe disease.  

The EMPEROR-Reduced study is a phase III randomized, double-blinded, placebo-controlled, and event-driven trial. The trial was performed in 20 countries and was conducted on 3,730 patients diagnosed with class II, III, or IV HF and left ventricular EF of ≤40% with or without diabetes. This trial's participants were further limited to patients with an EF of >30% with a history of hospitalization due to HF within 12 months or had a high level of N-terminal prohormone of brain natriuretic peptide. The patients were randomized 1:1 and were followed up every 2 to 3 months.^4,5  

The trial was designed to evaluate the efficacy and safety of empagliflozin (10 mg once daily), and its primary endpoint was the composite outcome of cardiovascular (CV) death or hospitalization for HF (hHF). The secondary endpoints included first and recurrent hHF and slope of decline in estimated glomerular filtration rate (eGFR) over time.5   During a median follow-up of 16 months, the trial revealed that the combined risk of CV death and hHF was 25% lower for patients receiving empagliflozin. Results also showed that the first and recurrent hHF was reduced by 30% (HR 0.70, 95% CI 0.58–0.85, p<0.001) in the empagliflozin group. These findings also revealed that the annual rate of decline in eGFR was slower in the empagliflozin group (-0.55 vs. 0.28 mL/minute/1.73m2 of body surface area/year, p<0.001).5 These results were consistent with previous trials using the SGLT2 inhibitors in different aspects of the cardiovascular disease spectrum.⁴  

The safety profile that was seen in EMPEROR-Reduced supports the currently available safety profile of empagliflozin. There was no clinically meaningful difference in adverse events between empagliflozin and placebo groups in hypoglycemia, hypotension, and hypovolemia. It is also important to note that there are no cases of ketoacidosis that was noted in EMPEROR-Reduced.⁵  

Overall, the EMPEROR-Reduced Trial supports the use of SGLT2 inhibitors as part of the foundational treatment among patients with HF with reduced ejection fraction (HFrEF). This result is especially helpful in the Asian population, where there is a continuous rise in the prevalence of diabetes with HF. As Asian patients diagnosed with HFrEF have an increased burden of diabetes at a young age, higher prevalence of other comorbidities, and association with worse outcomes, this trial provides a basis for a much-needed treatment option that targets not only diabetes with mild HF but also diabetes with severe HF.<sup>5,6

References:
1. Lam CSP, et al. J Am Heart Assoc 2019;8:e013389. 2. Lippi G, Sanchis-Gomar F. AME Med J 2020;5:15. 3. Chen YT, et al. Cells. 2019 December 16;8:1651. 4. Pina IL. E SGLT2 Inhibitors in HFrEF: Putting EMPEROR-Reduced in Context. Medscape resource page. Available at: https://www.medscape.com/viewarticle/936525. Accessed September 25, 2020. 5. Packer M, et al. N Engl J Med 2020.
6. Chandramouli C, Lam CSP. Heart Metab. 2019;80:8–12.</sup>