What EMPOWER Actually Changes in Clinical Practice

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Clinical medical image for trials empower rt: What EMPOWER Actually Changes in Clinical Practice

At a glance

| Parameter | Detail | |-----------|--------| | N | 5,988 | | Intervention | Empagliflozin 10 mg daily | | Comparator | Placebo | | Duration | Median 26.2 months | | Primary endpoint | Composite of CV death or first HF hospitalization | | Key result | HR 0.79 (95% CI 0.69, 0.90); p < 0.001 | | Population | HFpEF, LVEF >40%, NYHA II, IV, elevated NT-proBNP |

The HFpEF Problem Before EMPEROR-Preserved

For decades, HFpEF resisted pharmacotherapy. Trials of ACE inhibitors (CHARM-Preserved), ARBs (I-PRESERVE), and mineralocorticoid receptor antagonists (TOPCAT) either failed their primary endpoints or produced geographically inconsistent results. Clinicians managed volume with diuretics and treated comorbidities. No drug had a Class I recommendation specifically for HFpEF outcomes.

EMPEROR-Preserved, published in the New England Journal of Medicine in August 2021, broke that pattern.

Methodology Worth Noting

The trial enrolled patients with LVEF >40%, which is broader than the traditional HFpEF cutoff of ≥50%. This was deliberate. The protocol included patients in the 41 to 49% "mildly reduced" range (HFmrEF), creating a continuum design that allowed prespecified subgroup analysis by EF category.

The HealthRX Practice-Translation Framework for EMPEROR-Preserved

We evaluate trial-to-practice translation across four dimensions:

  1. Guideline velocity, how quickly societies incorporated the data
  2. Label alignment, whether regulatory approval matches the trial population
  3. Population generalizability, how trial demographics compare to real-world HFpEF
  4. Prescribing friction, barriers between evidence and prescription

Key enrollment criteria that matter for generalizability:

  • NT-proBNP thresholds were stratified: ≥300 pg/mL (sinus rhythm) or ≥900 pg/mL (atrial fibrillation)
  • eGFR ≥20 mL/min/1.73 m² was permitted, capturing moderate-to-severe CKD
  • Patients with type 2 diabetes comprised 49% of the cohort
  • Mean age was 72 years; 45% were female

The NT-proBNP stratification deserves attention. Atrial fibrillation inflates natriuretic peptides, so the higher threshold for AF patients prevented enrollment of hemodynamically stable AF patients without true HF. This was methodologically sound but means clinicians cannot extrapolate to patients with low natriuretic peptides regardless of symptoms.

Results Beyond the Headline

The primary composite endpoint showed HR 0.79 (95% CI 0.69, 0.90, p < 0.001). Dissecting the components:

| Component | Empagliflozin | Placebo | HR (95% CI) | |-----------|--------------|---------|-------------| | CV death or HF hospitalization | 13.8% | 17.1% | 0.79 (0.69, 0.90) | | First HF hospitalization | 8.6% | 11.8% | 0.71 (0.60, 0.83) | | CV death alone | 7.3% | 8.2% | 0.91 (0.76, 1.09) | | Total HF hospitalizations |, |, | 0.73 (0.61, 0.88) | | eGFR slope (mL/min/yr) | −1.25 | −2.62 | Difference +1.36 |

The benefit was driven primarily by HF hospitalization reduction rather than CV mortality. This mirrors what DAPA-HF and EMPEROR-Reduced showed in HFrEF: SGLT2 inhibitors consistently reduce congestion events.

The EF Subgroup Story

Prespecified subgroup analysis revealed the benefit was consistent across the EF spectrum enrolled, though the point estimate was numerically stronger in patients with LVEF 41 to 49% (HFmrEF) compared to those with LVEF ≥50%. A pooled analysis of EMPEROR-Preserved and EMPEROR-Reduced later confirmed a continuous relationship between empagliflozin benefit and LVEF without a threshold effect.

Renal Protection as Secondary Benefit

The eGFR slope difference of 1.36 mL/min/1.73 m² per year favoring empagliflozin is clinically meaningful over time. HFpEF patients frequently have concurrent CKD, and preventing renal decline reduces future diuretic resistance and cardiorenal syndrome progression. The FDA label for Jardiance now reflects heart failure benefit across EF ranges.

What Actually Changed in Guidelines

The speed of guideline adoption was remarkable:

AHA/ACC/HFSA 2022 Guidelines, Published in April 2022, these gave SGLT2 inhibitors a Class 2a recommendation for HFpEF (upgraded from no recommendation). The wording: "In patients with HFmrEF or HFpEF, SGLT2 inhibitors can be beneficial in decreasing heart failure hospitalizations and cardiovascular mortality."

ESC 2023 Focused Update, The European Society of Cardiology upgraded SGLT2 inhibitors to Class I (Level A) for all heart failure regardless of ejection fraction, collapsing the distinction between HFrEF and HFpEF treatment algorithms for this drug class.

KDIGO 2024 Guidelines, Incorporated SGLT2 inhibitors for CKD patients with concurrent HFpEF, recognizing the dual cardiorenal benefit.

This represents the fastest evidence-to-guideline cycle in HF therapeutics in the past decade.

Real Prescribing Shifts

Despite guideline enthusiasm, real-world adoption has been uneven. Registry data from 2023 to 2024 suggest SGLT2 inhibitor prescribing in HFpEF reached approximately 25 to 30% of eligible patients, compared to >50% in HFrEF. Three friction points explain the gap:

  1. Diagnostic uncertainty, HFpEF diagnosis requires echocardiography plus elevated natriuretic peptides. Many patients carry a clinical HF diagnosis without confirmatory testing matching trial entry criteria.

  2. Prior authorization burden, Insurance formularies initially covered empagliflozin only for diabetes. Heart failure indications required separate prior authorization, adding administrative steps.

  3. Specialty siloing, Cardiologists adopted faster than primary care physicians, but most HFpEF patients are managed in primary care settings where SGLT2 inhibitors were historically framed as "diabetes drugs."

Limitations the Authors Acknowledged

The EMPEROR-Preserved investigators were transparent about several constraints in the primary publication:

  • No significant reduction in CV death as an individual endpoint (HR 0.91, CI crossed 1.0)
  • Short median follow-up of 26.2 months limits conclusions about long-term mortality benefit
  • Racial diversity was limited: 76% White, 6% Asian, <1% Black participants
  • Patients with LVEF >65% (the most "pure" diastolic HF) had the weakest numerical signal

The Black patient representation is particularly concerning given higher HFpEF prevalence and distinct pathophysiology in Black populations. Extrapolation requires caution.

What This Means for Patients Who Differ from the Trial

Patients without diabetes: The benefit was consistent regardless of diabetes status (interaction p = 0.61), confirming the mechanism is not glucose-related. Clinicians should not withhold empagliflozin from non-diabetic HFpEF patients.

Elderly patients (>75 years): Subgroup analysis showed preserved benefit. Volume depletion and hypotension risks increase with age, but the trial did not show excess harm in older participants.

Patients with very high EF (>65%): The weakest signal zone. These patients may have a phenotype (restrictive cardiomyopathies, infiltrative disease) where SGLT2 inhibitors address symptoms but not underlying pathology.

Patients with obesity-related HFpEF: The STEP-HFpEF trial of semaglutide (2023) later showed GLP-1 agonists improve symptoms in obese HFpEF. Whether combining SGLT2i plus GLP-1 RA produces additive benefit is being studied but not yet proven. The STEP-HFpEF publication suggests complementary mechanisms.

The Completed HF Coverage Argument

EMPEROR-Preserved is best understood as the final piece of a three-trial program:

| Trial | Population | HR for primary endpoint | |-------|-----------|----------------------| | EMPEROR-Reduced | LVEF ≤40% | 0.75 (0.65, 0.86) | | EMPEROR-Preserved | LVEF >40% | 0.79 (0.69, 0.90) | | EMPA-KIDNEY | CKD ± HF | 0.72 (0.64, 0.82) |

Combined with dapagliflozin data from DAPA-HF and DELIVER, the SGLT2 inhibitor class now has consistent evidence across HFrEF, HFmrEF, HFpEF, and CKD with cardiac involvement. No other HF drug class achieves this breadth.

Bottom Line for Prescribers

The practical translation: every patient with a confirmed HFpEF diagnosis (symptoms plus structural/biomarker evidence) and eGFR ≥20 should be considered for empagliflozin 10 mg or dapagliflozin 10 mg unless contraindicated. The "nothing works for HFpEF" era is over. The remaining clinical question is not whether to start an SGLT2 inhibitor, but how to layer it with emerging therapies (GLP-1 agonists for obese HFpEF, finerenone for cardiorenal overlap) as those evidence bases mature.

Frequently asked questions

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References

  1. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461. https://pubmed.ncbi.nlm.nih.gov/34449189/
  2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145(18):e895-e1032. https://pubmed.ncbi.nlm.nih.gov/35363499/
  3. FDA. Jardiance (empagliflozin) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_cps/retrieve-document?docid=84725
  4. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER). N Engl J Med. 2022;387(12):1089-1098. https://pubmed.ncbi.nlm.nih.gov/36027570/
  5. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity (STEP-HFpEF). N Engl J Med. 2023;389(12):1069-1084. https://pubmed.ncbi.nlm.nih.gov/37622681/