Ten Lessons from the EMPEROR-Reduced Trial

The pace of research has accelerated for chronic diseases like heart failure (HF), kidney disease, and diabetes. Multiple trials showing benefits provide a robust evidence base for the treatment of these diseases. This also challenges, however, the clinicians on how to incorporate learnings from multiple trials into effective clinical decision-making. For HF with reduced ejection fraction (HFrEF), four large positive outcomes trials have come out in ∼5 years. PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and morbidity in Heart Failure), DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure),2 and EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic Heart Failure With Reduced Ejection Fraction) trials1-3 enrolled chronic HFrEF patients in the outpatient setting, whereas the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial4 focused on worsening HF. A simple comparison of the relative risk reductions across these trials may not be fully informative as they differed with respect to their eligibility criteria, trial design, and follow-up. In this respect, comparison of both absolute and relative risk reduction in the context of trial eligibility provides a more comprehensive approach to understanding the implications of multiple trials.5 Sodium–glucose co-transporter 2 (SGLT2) inhibitors were developed to treat diabetes but also prevented HF hospitalizations, which led to their evaluation in HF. DAPA-HF was the first trial with an SGLT2 inhibitor that showed improved HFrEF outcomes in both patients with and without diabetes.2 Further data confirming the role of SGLT2 inhibitors in patients with HFrEF, especially in those without diabetes, were needed to solidify their role as foundational HFrEF therapy. Also, EMPEROR-Reduced included overlapping patient population with DAPA-HF but enriched for sicker patients.3 The DAPA-HF excluded patients with estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 and EMPEROR-Reduced extended the enrolment to eGFR >20 mL/min/1.73 m2. The EMPEROR-Reduced trial randomized 3730 patients to empagliflozin or placebo and followed them for a median of ∼16 months. The primary endpoint of time to cardiovascular death or HF hospitalization was improved with empagliflozin [hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.65–0.86]. The effect of empagliflozin on the two component of the primary endpoint was 0.92 (95% CI 0.75–1.12) for cardiovascular death and 0.69 (95% CI 0.59–0.81) for first hospitalization for HF. Results were consistent in patients with and without diabetes, and among those that were or were not on ARNI therapy. The rate of decline in eGFR (−0.5 mL/min/1.73 m2/year with empagliflozin vs. −2.3 mL/min/1.73 m2/year with placebo, P < 0.0001) and the frequency of serious renal outcomes (HR 0.50, 95% CI 0.32–0.77) were both improved. Table 1 compares the baseline characteristics and outcomes between the four contemporary HFrEF trials. 1910 25 Class effect vs. drug effect: Only empagliflozin and dapagliflozin have been assessed for outcomes in HFrEF. It is not known whether other SGLT2 inhibitors have beneficial effects in HFrEF. Experience has shown that not all agents within a class improve outcomes in HFrEF, e.g. beta-blockers. The evidence base for the management of patients with HFrEF continues to grow and brings needed promise for patients who suffer greatly from the risk of morbidity, mortality, and poor quality of life. While implementation and cost challenges lay ahead, these recent trials provide options to change the natural history of HFrEF. Currently five targets (angiotensin II, aldosterone, norepinephrine, neprilysin, and SGLT2) modified with four drugs (ARNI, evidence-based beta-blockers, mineralocorticoid receptor antagonists, and evidence-based SGLT2 inhibitors) should be considered as foundational standard of care for HFrEF.6 The consistency of results from the DAPA-HF and the EMPEROR-Reduced trials has confirmed the role for dapagliflozin and empagliflozin as an additional cornerstone of the treatment of HFrEF.7 Conflict of interest: The authors of this paper were members of the Executive Committee for the EMPEROR-Reduced trial with empagliflozin, which was sponsored by Boehringer Ingelheim and Eli Lilly and Company.