Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction - EMPEROR-Reduced
Contribution To Literature:
Highlighted text has been updated as of August 25, 2023.
The EMPEROR-Reduced trial showed that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤40%) on excellent baseline GDMT, irrespective of diabetes status.
The goal of the trial was to assess the safety and efficacy of empagliflozin in patients with symptomatic heart failure with reduced ejection fraction (HFrEF), irrespective of diabetes status.
Patients were randomized in a 1:1 fashion to either empagliflozin 10 mg (n = 1,863) or matching placebo (n = 1,867). All the patients were receiving appropriate treatments for heart failure.
- Total screened: 7,220
- Total number of enrollees: 3730
- Duration of follow-up: 16 months (median)
- Mean patient age: 67 years
- Percentage female: 24%
- Age ≥18 years
- Chronic HF, New York Heart Association (NYHA) functional class II/III/IV
- Left ventricular EF (LVEF) ≤40%
- 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%
- If concomitant atrial fibrillation, then above thresholds were doubled)
- Acute coronary syndrome, stroke, or transient ischemic attack (TIA) within 90 days
- Listed for orthotopic heart transplantation, currently implanted LV assist device (LVAD)
- Cardiomyopathy based on infiltrative/accumulation diseases, muscular dystrophies, reversible causes, hypertrophic cardiomyopathy, pericardial restriction, peripartum, cardiomyopathy caused by chemotherapy within 12 months
- Severe valvular heart disease
- Acute decompensated HF
- Implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT) within 3 months
Other salient features/characteristics:
- White 70%, Asian 18%
- North America: 11%, Europe: 36%, Asia: 13%, Latin America: 34%
- NYHA functional class II: 75%
- Mean LVEF: 27%
- Type 2 diabetes: 50%
- Estimated glomerular filtration rate (eGFR) <60: 48%
- Medications: angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker: 70%, angiotensin receptor-neprilysin inhibitor: 19%, mineralocorticoid receptor antagonist (MRA): 71%, beta-blocker: 94%
- ICD: 31%, CRT 12%
The primary outcome, cardiovascular death or HF hospitalization, for empagliflozin vs. placebo, was 19.4% vs. 24.7% (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.65-0.86, p < 0.001)
- Cardiovascular death: 10% vs. 10.8% (HR 0.92, 95% CI 0.75-1.12)
- HF hospitalization: 13.2% vs. 18.3% (HR 0.69, 95% CI 0.59-0.81)
- Total hospitalizations: 388 vs. 553 (p < 0.001)
- 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)
- All-cause mortality: 13.4% vs. 14.2% (HR 0.92, 95% CI 0.77-1.10, p > 0.05)
- New-onset type 2 diabetes among patients with prediabetes: 11.2% vs. 12.6% (p > 0.05)
- Change in hemoglobin A1c between baseline and week 52 (patients with diabetes): -0.28 vs. -0.12% (p < 0.05)
- Systolic blood pressure -2.4 vs. -1.7 mm Hg (p > 0.05)
- Confirmed hypoglycemic event: 1.4% vs. 1.5%
- Death/HF hospitalization/emergent or urgent HF visit requiring intravenous treatment or diuretic intensification/deterioration of NYHA class: 32.7% vs. 43% (p < 0.0001)
- Intensification of diuretics: 15.9% vs. 22.2% (p < 0.0001)
- Emergent or urgent HF visit requiring intravenous treatment: 6.8% vs. 9.9% (p = 0.0004)
- Hospitalization for HF requiring cardiac care unit/intensive care unit care: 4.8% vs. 5.7% (p = 0.002)
Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS): Benefit of empagliflozin vs. placebo was maintained across tertiles of baseline KCCQ-CSS for the primary endpoint, total HF hospitalizations and eGFR slope. In addition, benefit of empagliflozin vs. placebo for mean KCCQ-CSS was noted as early as 3 months, and noted to be sustained over 12 months.
Patients with volume overload within 4 weeks of enrollment: Primary endpoint for empagliflozin vs. placebo among patients with recent volume overload: 28.4% vs. 24.8% (p = 0.035); without volume overload: 16.0% vs. 22.2% (p = 0.0004; p for interaction = 0.34). Similarly, no difference was noted for the endpoint of total HF hospitalizations by volume overload status (p for interaction = 0.09). Intensification of diuretics was also similar between the two subgroups of patients (p for interaction = 0.88). Similarly, there was no difference in NT-proBNP, systolic blood pressure, or body weight for empagliflozin vs. placebo between patients with and without recent volume overload.
Influence of MRAs: 71% on MRAs in this trial. Composite endpoint for empagliflozin vs. placebo among MRA users: 18.6% vs. 24.4%; among nonusers: 21.2% vs. 25.8% (p for interaction = 0.83). Similarly, no interaction was observed for secondary endpoints and adverse events (including hyperkalemia) by MRA use as well.
Influence of region and race/ethnicity: Regional distribution: 36.3% Europe, 34.5% Latin America, 11.4% in North America, and 13.2% in Asia; 70.5% were White, 6.9% Black, and 18.0% Asian. Important differences were noted in baseline characteristics. Placebo arm event rate (per 100 person-years) for the primary outcome of cardiovascular death or HF hospitalization was highest in Asia (27.7) and North America (26.4) and lowest in Europe (17.5). Event rate (per 100 person-years) for the primary composite outcome of cardiovascular death or HF hospitalization in the placebo group was highest among Black patients (34.4) and lowest in White patients (18.7). The magnitude of the effect of empagliflozin on the primary composite outcome and total hospitalizations for HF was most pronounced in Asia (hazard ratios of 0.55 and 0.41, respectively); intermediate in North America (hazard ratios of 0.69 and 0.71, respectively) and Latin America (hazard ratios of 0.73 and 0.65, respectively); and least pronounced in Europe (hazard ratios of 0.94 and 0.96, respectively) (p for interaction = 0.1). The magnitude of the effect of empagliflozin on the primary composite outcome and on total hospitalizations for HF was most pronounced in Black patients (hazard ratios of 0.46 and 0.39, respectively) and Asian patients (hazard ratios of 0.57 and 0.45, respectively) and least pronounced in White patients (hazard ratios of 0.88 and 0.90, respectively) (p for interaction = 0.008).
Pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved:
Renal outcomes (profound and sustained decreases in eGFR or renal replacement therapy), total n = 9,718: 2.8% vs. 3.5% for empagliflozin vs. placebo, with significant heterogeneity between both trials (p = 0.016 for interaction).
Potassium balance (n = 9,583): Patients with hyperkalemia (potassium >5 mmol/L) were more likely to have lower EF, diabetes, and lower mean eGFR; they were also more likely to be treated with sacubitril/valsartan and an MRA. Empagliflozin reduced the composite of investigator-reported hyperkalemia or initiation of potassium binders compared with placebo (6.5% vs. 7.7%, HR 0.82, 95% CI 0.71-0.95, p = 0.01). Composite of investigator-reported hypokalemia or initiation of potassium supplements was similar compared with placebo (6.4% vs. 6.7%, p > 0.05).
Uric acid balance: The prevalence of hyperuricemia at baseline was 51.6 vs. 55.3% (empagliflozin vs. placebo, p = 0.03). Elevated serum uric acid was associated with advanced severity of HF and with worst outcome (composite outcome, HR 1.64 [95% CI 1.28-2.10]; cardiovascular mortality, HR 1.98 [95% CI 1.35-2.91]; all-cause mortality, HR 1.8 [95% CI 1.29-2.49], all p < 0.001) in multivariable adjusted analyses, as compared with the lowest tertile. Serum uric acid was reduced following treatment with empagliflozin at 4 weeks (vs. placebo: −1.12 ± 0.04 mg/dL, p < 0.0001) and remained lower throughout follow-up. Treatment with empagliflozin reduced the risk of clinically relevant hyperuricemic events by 32% (HR 0.68 [95% CI 0.52-0.89], p = 0.004). The effect of empagliflozin on the primary composite endpoint and on the risk of hospitalization for HF was not influenced by serum uric acid.
Proteomics substudy (n = 1,134): Using Olink® Explore 1536 platform, 1,283 circulating proteins were measured at baseline, week 12, and week 52. Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyl transferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney, or endothelium, a feature of six proteins.
Blinded withdrawal of long-term randomized patients: At the end of the trials, 6,799 patients (placebo 3,381, empagliflozin 3,418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3,981 patients (placebo 2,020, empagliflozin 1,961) underwent prespecified in-person assessments after 30 days off treatment. From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or HF hospitalization was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 vs. 13.5 events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI 0.60–0.96]). When the study drugs were withdrawn for ~30 days, the annualized risk of cardiovascular death or HF hospitalization increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 vs. 14.1 events per 100 patient-years for empagliflozin and placebo, respectively). After withdrawal, the KCCQ-CSS declined by 1.6 in patients withdrawn from empagliflozin versus placebo (p < 0.0001).
The results of this trial indicate that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFrEF (EF ≤40%) on excellent baseline guideline-directed medical therapy (GDMT), irrespective of diabetes status. Benefit is primarily driven by a reduction in HF hospitalizations, not mortality. There was an early and sustained benefit on KCCQ-CSS. There was also a benefit in renal outcomes. The use of MRAs did not influence the effect of empagliflozin on clinical outcomes. Some regional and racial differences in efficacy were noted. This is a very important trial, and mirrors similar findings from the DAPA-HF trial for dapagliflozin. Even patients with severe LV dysfunction appeared to benefit. Of note, the DAPA-HF trial was larger, and did show a benefit in cardiovascular and all-cause mortality with dapagliflozin use. The proteomics substudy suggests that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signaling, and transmembrane sodium transport. Benefit of SGLT2 inhibitors disappears rapidly after withdrawal of the drug.
Even though the SGLT2 inhibitors were introduced as type 2 diabetes management drugs, the results of the EMPA-REG OUTCOME trial and others indicated a clear benefit in HF management. This trial enrolled a dedicated HF population, and conclusively shows a benefit in this patient population, irrespective of diabetes status. These drugs will likely have a prominent role in future HF management guidelines. The mechanism of benefit is unclear. The subgroup analysis of this trial suggests that this benefit may not necessarily be driven by a diuretic effect alone (as noted among patients with and without recent volume overload), but further studies are needed to clarify this and other potential mechanisms of benefit. The pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved suggests that the renal benefit is primarily among patients with HFrEF, and eGFR slope analysis may not be predictive of renal outcomes among patients with HF. In both groups, empagliflozin reduced the incidence of hyperkalemia without a significant increase in hypokalemia.
Presented by Dr. Milton Packer at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 25, 2023.
Presented by Dr. Faiez Zannad at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 26, 2022.
Doehner W, Anker SD, Butler J, et al. Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J 2022;43:3435-46.
Presented by Dr. Milton Packer at the European Society of Cardiology Virtual Congress, August 27, 2021.
Lam CS, Ferreira JP, Pfarr E, et al. Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur Heart J 2021;42:4442-51.
Butler J, Anker SD, Filippatos G, et al. Empagliflozin and Health-Related Quality of Life Outcomes in Patients With Heart Failure With Reduced Ejection Fraction: The EMPEROR-Reduced trial. Eur Heart J 2021;42:1203-12.
Editorial Comment: Spertus JA. Quality of Life in EMPEROR-Reduced: Emphasizing What Is Important to Patients While Identifying Strategies to Support More Patient-Centered Care. Eur Heart J 2021;42:1213-15.
Packer M, Anker SD, Butler J, et al., on behalf of the EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial. J Am Coll Cardiol 2021;77:1381-92.
Editorial Comment: Kosiborod MN, Vaduganathan M. SGLT-2 Inhibitors in Heart Failure: Volume or Value? J Am Coll Cardiol 2021;77:1393-6.
Ferreira JP, Zannad F, Pocock SJ, et al. Interplay of Mineralocorticoid Receptor Antagonists and Empagliflozin in Heart Failure: EMPEROR-Reduced. J Am Coll Cardiol 2021;77:1397-407.
Editorial Comment: Greene SJ, Khan MS. Quadruple Medical Therapy for Heart Failure: Medications Working Together to Provide the Best Care. J Am Coll Cardiol 2021;77:1408-11.
Presented by Dr. Javed Butler at the American Heart Association Virtual Scientific Sessions, November 13, 2020.
Packer M, Anker SD, Butler J, et al., on behalf of the EMPEROR-Reduced Trial Committees and Investigators. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation 2021;143:326-36.
Packer M, Anker SD, Butler J, et al., on behalf of the EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes With Empagliflozin in Heart Failure. N Engl J Med 2020;383:1413-24.
Editorial: Jarcho JA. More Evidence for SGLT2 Inhibitors in Heart Failure. N Engl J Med 2020;383:1481-2.
Presented by Dr. Milton Packer at the European Society of Cardiology Virtual Congress, August 29, 2020.
Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: ESC21, ESC22, ESC23, ESC Congress, AHA20, AHA Annual Scientific Sessions, ESC20, Atrial Fibrillation, Blood Pressure, Cardiac Resynchronization Therapy, Diabetes Mellitus, Type 2, Heart Failure, Defibrillators, Implantable, Ethnic Groups, Metabolic Syndrome, Natriuretic Peptide, Brain, Potassium, Proteomics, Renal Insufficiency, Secondary Prevention, Stroke Volume, Uric Acid
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