Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction - EMPEROR-Preserved

Nov 07, 2024
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC; Kim A. Eagle, MD, MACC
Trial Sponsor:
Boehringer Ingelheim and Eli Lilly
Date Presented:
08/25/2023
Date Published:
10/23/2024
Date Updated:
11/07/2024
Original Posted Date:
08/27/2021
References

Contribution To Literature:

Highlighted text has been updated as of November 7, 2024.

The EMPEROR-Preserved trial showed that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFpEF on excellent baseline GDMT, irrespective of diabetes status.

Description:

The goal of the trial was to assess the safety and efficacy of empagliflozin in patients with symptomatic heart failure with preserved ejection fraction (HFpEF), irrespective of diabetes status.

Study Design

Patients were randomized in a 1:1 fashion to either empagliflozin 10 mg (n = 2,997) or matching placebo (n = 2,991). The trial was stratified by geographic region, diabetes status, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF; <50%/≥50%). All the patients were receiving appropriate treatments for HF.

  • Total screened: 11,583
  • Total number of enrollees: 5,988
  • Duration of follow-up: 26.2 months (median)
  • Mean patient age: 72 years
  • Percentage female: 45%

Inclusion criteria:

  • Age ≥18 years
  • Chronic HF, New York Heart Association (NYHA) functional class II/III/IV
  • Preserved LVEF (EF >40%)
  • HF hospitalization within 12 months
  • N-terminal pro–B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml without atrial fibrillation (AF), >900 pg/ml with AF
  • Structural heart disease within 6 months or documented HF hospitalization within 12 months
  • Stable dose of oral diuretics, if prescribed

Exclusion criteria:

  • Acute coronary syndrome, stroke, or transient ischemic attack within 90 days
  • Listed for orthotopic heart transplantation (OHT) or OHT recipient
  • Acute decompensated HF
  • Systolic blood pressure (SBP) ≥180 mm Hg
  • Symptomatic hypotension or SBP ≤100 mm Hg
  • Liver or kidney disease (eGFR <20 ml/min/1.73 m2)
  • Current use or prior use of a sodium-glucose co-transporter (SGLT)-2 inhibitor or combined SGLT-1 and -2 inhibitor

Other salient features/characteristics:

  • White 76%, Asian 14%
  • North America: 12%, Europe: 45%, Asia: 11%, Latin America: 25%
  • NYHA class II: 82%
  • Mean LVEF: 54.3%
  • Type 2 diabetes mellitus: 49%
  • eGFR <60 ml/min/1.73 m2: 50%
  • AF: 51%

Principal Findings:

The primary outcome, cardiovascular (CV) death or HF hospitalization, for empagliflozin vs. placebo, was 13.8% vs. 17.1% (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.69-0.90, p < 0.001).

  • CV death: 7.3% vs. 8.2% (HR 0.91, 95% CI 0.76-1.09)
  • HF hospitalization: 8.6% vs. 11.8% (HR 0.71, 95% CI 0.60-0.83)
  • For the primary outcome, the benefit was similar among patients with or without type 2 diabetes. The benefit appeared somewhat attenuated among patients with EF ≥60%.

Secondary outcomes for empagliflozin vs. placebo:

  • Total hospitalizations: 407 vs. 541 (p < 0.001)
  • Change in mean eGFR slope/year: -1.25 vs. -2.62 (p < 0.001)
  • Composite renal outcome 3.6% vs. 3.7% (p > 0.05)
  • 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: 12.0% vs. 14.0% (p > 0.05)

Patients with and without type 2 diabetes: Type 2 diabetes was present in 49% of patients. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (with diabetes: HR 0.79 [95% CI 0.67-0.94]; without diabetes: HR 0.78 [95% CI 0.64-0.95]; p for interaction = 0.92). The effect of empagliflozin to attenuate eGFR decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes vs. 0.98 mL/min/1.73 m2 in patients without diabetes; p for interaction = 0.01).

Pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved on 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).

Outcomes based on EF (33% had EF 41-49%; remainder had EF ≥50%):

  • Primary endpoint for empagliflozin vs. placebo for EF ≥50%: 6.7% vs. 8.0% (p = 0.024); for EF 41-49%: 7.2% vs. 10% (p = 0.002; p for interaction = 0.27)
  • Total HF hospitalizations for EF ≥50%: 4.5% vs. 5.7% (p = 0.013); for EF 41-49%: 3.8% vs. 6.5% (p < 0.001; p for interaction = 0.06)
  • All-cause mortality for EF ≥50%: 6.1% vs. 6.1% (p = 0.84); EF 41-49%: 7.7% vs. 8.0% (p = 0.72; p for interaction > 0.05)
  • Change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) quality of life at week 52 for EF ≥50%: 4.24 vs. 2.78 (p = 0.006); EF 41-49%: 4.86 vs. 3.3 (p = 0.043; p for interaction = 0.92)

Health-related quality of life: Patients treated with empagliflozin had significant improvement in KCCQ-Clinical Summary Score (KCCQ-CSS) versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively; p < 0.01); similar results were seen for total symptom score and overall summary score. At 12 weeks, patients in the empagliflozin arm were more likely to show meaningful improvements (≥5 points [51.6% vs. 46.5]; ≥10 points [45.0% vs. 41.8%]; ≥15 points [44.0% vs.41.3%]) and less likely to show deterioration (≥5 points [21.6% vs. 24.4%]) in KCCQ-CSS.

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).

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.

Effect of age: Patients were grouped based on baseline age (<65 years [n = 1,199], 65-74 years [n = 2,214], 75-79 years [n = 1,276], ≥80 years [n = 1,299]). Event rates increased with increasing age. Empagliflozin reduced primary outcomes (p for trend = 0.33), first HF hospitalization (p for trend = 0.22), and first and recurrent HF hospitalization (p for trend = 0.11) across all age groups. Effects were also similar at ≥75 years (p for interaction = 0.22) or ≥80 years (p for interaction = 0.51).

Effect of sex: 44.7% of enrolled patients were women. Compared with placebo, empagliflozin reduced the risk of CV death or HF hospitalization to a similar degree in both sexes (HR 0.81, 95% CI 0.69-0.96 for men; HR 0.75, 95% CI 0.61-0.92 for women; p for interaction = 0.54). Similar results were seen for secondary outcomes, quality of life, and physiological measures.

Effect of baseline BP: Patients were categorized into three groups based on baseline SBP: <110, 110-130, and >130 mm Hg. Among these three groups, no significant interaction in the effect of empagliflozin vs. placebo was noted for the primary endpoint (p for interaction = 0.69), first HF hospitalization (p for interaction = 0.46), or recurrent HF hospitalization (p for interaction = 0.55). SBP did not meaningfully associate with adverse events such as hypotension, volume depletion, and acute renal failure.

Concomitant diuretic use: At baseline, 20.3% were not on diuretics, 29.7% were taking furosemide (or equivalent) <40 mg, 30.5% were taking furosemide (or equivalent) 40 mg, and 19.6% were taking furosemide (or equivalent) >40 mg daily. The impact of empagliflozin vs. placebo was similar irrespective of baseline diuretic use for CV death or first HF hospitalization (p for interaction = 0.58), total HF hospitalization (p for interaction = 0.94), first HF hospitalization (p for interaction = 0.68), CV death (p for interaction = 0.31), all-cause mortality (p for interaction = 0.94), and the composite kidney endpoint (p for interaction = N/A). Empagliflozin was associated with a higher incidence of volume depletion events in the diuretic group (7.5 vs 5.6 events per 100 patient-years; HR, 1.34; 95% CI, 1.13-1.59) but not the nondiuretic group (4.3 vs 4.1 events per 100 patient-years; HR, 1.06; 95% CI, 0.70-1.61; p for interaction = 0.32). Among patients who were not taking diuretics at baseline, empagliflozin was associated with a lesser likelihood of diuretic initiation (HR, 0.73; 95% CI, 0.59-0.90; p = 0.004) compared with placebo. In those who were treated with diuretics at baseline, empagliflozin use was associated with a significantly greater probability of diuretic discontinuation (HR, 1.43; 95% CI, 1.15-1.78; p = 0.002) and de-escalation (HR, 1.15; 95% CI, 1.02-1.30; p = 0.02).

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 CV 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; HR 0.76 [95% CI 0.60–0.96]). When the study drugs were withdrawn for ~30 days, the annualized risk of CV 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 Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) declined by 1.6 in patients withdrawn from empagliflozin versus placebo (p < 0.0001).

Uric acid and SGLT2 inhibition: Hyperuricemia (serum uric acid >5.7 mg/dL for women, >7.0 mg/dL for men) was prevalent in 49% of patients. Patients with hyperuricemia had a higher risk of adverse outcomes. Uric acid was reduced early (after 4 weeks vs. placebo -0.99 mg/dL; p < 0.0001) and throughout follow-up, with reduction in all prespecified subgroups. Empagliflozin reduced clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of antigout therapy) by 38% (HR 0.62 [95% CI 0.51-0.76]; p < 0.0001). The treatment benefit of empagliflozin compared with placebo on the primary endpoint was not influenced by baseline serum uric acid levels and the magnitude of benefit was comparable across baseline serum uric acid tertiles.

Interpretation:

The results of this trial indicate that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFpEF (EF >40%), irrespective of diabetes status, baseline SBP, or sex. The benefit is primarily driven by a reduction in HF hospitalizations, not mortality. There was also a benefit in eGFR, but not in renal outcomes per se. Outcomes appeared robust irrespective of baseline EF, including among patients with EF ≥50%. Empagliflozin improved quality of life measures, and the improvement was seen early and was sustained for 1 year. Effects were similar among patients already on diuretics at baseline. Diuretic requirement was lower among patients on empagliflozin, but patients on empagliflozin had a higher incidence of volume depletion events, especially if they were already on diuretics at baseline. 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. An improvement in serum uric acid was also noted with empagliflozin with a reduction in hyperuricemic events compared with placebo.

Even though the SGLT-2 inhibitors were introduced as type 2 diabetes management drugs, the results of EMPA-REG OUTCOME, EMPEROR-Reduced, and others indicated a clear benefit in HF management. This trial enrolled a dedicated HFpEF population, and shows a benefit in this patient population, irrespective of diabetes status. Most routinely used drugs for HFrEF have not shown to be effective among patients with HFpEF, and some drugs such as candesartan, spironolactone, and sacubitril/valsartan appear to mostly have a benefit among patients with EF between 40-49% rather than true HFpEF. The exact mechanism of benefit is unclear. 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.

References:

Doehner W, Anker SD, Butler J, et al. Uric Acid and SGLT2 Inhibition With Empagliflozin in Heart Failure With Preserved Ejection Fraction: The EMPEROR-Preserved Trial. JACC Heart Fail 2024;Oct 23:[Epublished].

Packer M, Butler J, Zeller C, et al. Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure. Circulation 2023;148:1011-22.

Presented by Dr. Milton Packer at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 25, 2023.

Butler J, Usman MS, Filippatos G, et al. Safety and Efficacy of Empagliflozin and Diuretic Use in Patients With Heart Failure and Preserved Ejection Fraction: A Post Hoc Analysis of the EMPEROR-Preserved Trial. JAMA Cardiol 2023;8:640-9.

Invited Commentary: Patel RB. Cardiovascular Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure—Does the Story Begin and End With the Kidney? JAMA Cardiol 2023;8:649-51.

Böhm M, Anker S, Mahfoud F, et al., on behalf of the EMPEROR-Preserved Trial Committees and Investigators. Empagliflozin, Irrespective of Blood Pressure, Improves Outcomes in Heart Failure With Preserved Ejection Fraction: The EMPEROR-Preserved Trial. Eur Heart J 2023;44:396-407.

Butler J, Filippatos G, Siddiqi TJ, et al. Effects of Empagliflozin in Women and Men With Heart Failure and Preserved Ejection Fraction. Circulation 2022;146:1046-55.

Filippatos G, Butler J, Farmakis D, et al., on behalf of the EMPEROR-Preserved Trial Committees and Investigators. Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes. Circulation 2022;146:676-86.

Zannad F, Ferreira JP, Butler J, et al. Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights From the EMPEROR Program. Eur Heart J 2022;43:4991-5002.

Presented by Dr. Faiez Zannad at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 26, 2022.

Böhm M, Butler J, Filippatos G, et al. Empagliflozin Improves Outcomes in Patients With Heart Failure and Preserved Ejection Fraction Irrespective of Age. J Am Coll Cardiol 2022;80:1-18.

Sauer AJ. Empagliflozin and Elderly Patients With Preserved Ejection Fraction Heart Failure: Is Age Just a Number? J Am Coll Cardiol 2022;80:19-21.

Ferreira JP, Zannad F, Butler J, et al. Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled. Eur Heart J 2022;43:2984-93.

Editorial: Verma S, Dhingra NK, Pandey AK, Cosentino F. Emerging role for SGLT2 inhibitors in mitigating the risk of hyperkalemia in heart failure. Eur Heart J 2022;43:2994-6.

Butler J, Filippatos G, Siddiqi TJ, et al. Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial. Circulation 2022;145:184-93.

Presented by Dr. Javed Butler at the American Heart Association Virtual Annual Scientific Sessions (AHA 2021), November 15, 2021.

Presented by Dr. Stefan D. Anker at the American Heart Association Virtual Annual Scientific Sessions (AHA 2021), November 14, 2021.

Anker SD, Filippatos BG, Ferreira JP, et al., on behalf of the EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure With a Preserved Ejection Fraction. N Engl J Med 2021;385:1451-61.

Letter to the Editor: Packer M, Butler J, Zannad F, et al. Empagliflozin and Major Renal Outcomes in Heart Failure. N Engl J Med 2021;385:1531-3.

Editorial: Drazner MH. SGLT2 Inhibition in Heart Failure With a Preserved Ejection Fraction — A Win Against a Formidable Foe. N Engl J Med 2021;385:1522-4.

Presented by Dr. Stefan Anker at the European Society of Cardiology Virtual Congress, August 27, 2021.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: AHA21, AHA Annual Scientific Sessions, ESC21, ESC22, ESC23, ESC Congress, Atrial Fibrillation, Diabetes Mellitus, Type 2, Diuretics, Geriatrics, Glomerular Filtration Rate, Heart Failure, Metabolic Syndrome, Natriuretic Peptide, Brain, Potassium, Prediabetic State, Proteomics, Renal Insufficiency, Secondary Prevention, Stroke Volume, Ventricular Function, Left


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