Principal Findings:

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)

Secondary outcomes:

• 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).