EMPEROR-Preserved Trial: A Plain-English Overview of What It Established
At a glance
| Parameter | Detail |
|---|---|
| N | 5,988 patients |
| Intervention | Empagliflozin 10 mg once daily |
| Comparator | Matching placebo |
| Duration | Median 26.2 months |
| Primary endpoint | Composite of cardiovascular death or first hospitalization for heart failure |
| Key result | HR 0.79 (95% CI 0.69, 0.90); p < 0.001 |
| Population | HFpEF (LVEF > 40%), NYHA class II, IV |
The Question Nobody Had Answered
Heart failure with preserved ejection fraction (HFpEF) accounts for roughly half of all heart failure cases. The heart's squeeze function looks normal on echo, but the chambers stiffen and fill poorly, producing the same breathlessness and fluid retention that reduced-EF patients experience. For decades, every drug that worked in HFrEF (ACE inhibitors, ARBs, beta-blockers, mineralocorticoid receptor antagonists) failed to meet its primary endpoint in HFpEF trials. Clinicians had nothing to offer beyond diuretics and blood pressure control.
SGLT2 inhibitors changed the calculus. Empagliflozin and dapagliflozin had already proven effective in HFrEF. The EMPEROR-Preserved investigators asked a direct question: does empagliflozin work when ejection fraction is above 40%?
Who Got Enrolled
Eligibility required adults with chronic heart failure, NYHA functional class II through IV, and a left ventricular ejection fraction greater than 40%. Patients needed elevated NT-proBNP levels (thresholds adjusted for atrial fibrillation status). About half the cohort had diabetes. Mean age was 72 years. Roughly 45% were women, a much higher proportion than typical HFrEF trials.
Exclusion criteria removed patients with recent acute decompensation, eGFR below 20 mL/min/1.73 m², or type 1 diabetes. The trial protocol enrolled participants across 622 sites in 23 countries between March 2017 and April 2020.
What They Received
Randomization assigned 2,997 patients to empagliflozin 10 mg and 2,991 to placebo. Both groups continued their usual background therapy. There was no run-in period and no dose titration. The pill was taken once daily, with or without food. Background medications included diuretics in 86%, RAS inhibitors in 80%, beta-blockers in 86%, and MRAs in 37%.
Measuring Success
The primary composite endpoint was time to first event of either cardiovascular death or hospitalization for heart failure. Key secondary endpoints included total heart failure hospitalizations (first and recurrent) and rate of decline in eGFR over time. A hierarchical testing strategy controlled the type I error rate across these endpoints.
What the Numbers Showed
The primary endpoint occurred in 415 patients (13.8%) in the empagliflozin arm versus 511 (17.1%) in the placebo arm over the median follow-up of 26.2 months. The hazard ratio of 0.79 (95% CI: 0.69, 0.90, p < 0.001) translated to a 21% relative risk reduction.
| Component | Empagliflozin | Placebo | HR (95% CI) |
|---|---|---|---|
| CV death or HF hospitalization | 13.8% | 17.1% | 0.79 (0.69, 0.90) |
| HF hospitalization alone | 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 | Rate ratio 0.73 (0.61, 0.88) | , | , |
| eGFR slope (mL/min/yr) | −1.25 | −2.62 | Difference +1.36 |
The benefit was driven primarily by fewer heart failure hospitalizations. Cardiovascular death alone did not reach statistical significance. The kidney protection signal (slower eGFR decline) was consistent with SGLT2 inhibitor data from dedicated renal trials.
Subgroup Consistency
The treatment effect was consistent across prespecified subgroups: patients with and without diabetes, those above and below the median EF of 54%, and across geographic regions. One widely discussed finding was that the benefit appeared somewhat attenuated in patients with EF above 60%, though the interaction p-value did not reach significance. Later analyses and the parallel DELIVER trial with dapagliflozin confirmed benefit across the full HFpEF spectrum.
Safety Profile
Empagliflozin showed a safety profile consistent with the SGLT2 inhibitor class. Genital infections occurred more frequently (2.2% vs 0.7%). Hypotension rates were similar. Diabetic ketoacidosis was rare. Amputations and Fournier's gangrene were not increased. The FDA label for empagliflozin was subsequently updated to include the HFpEF indication based partly on these data.
What Critics Point Out
Several limitations deserve attention. The trial was event-driven with a relatively short follow-up, limiting power for the mortality component. The EF cutoff of > 40% means this was not a pure HFpEF trial in the traditional sense (EF ≥ 50%); about 33% of patients had EF 41 to 49%, sometimes called HFmrEF. Dropout rates were modest but present. NT-proBNP enrichment may limit generalizability to patients with lower natriuretic peptide levels.
The lack of a clear mortality reduction matters. Patients live longer without being hospitalized, but the trial could not confirm they live longer overall. Some argue the eGFR benefit reflects hemodynamic changes rather than true nephroprotection, though longer-term renal data from EMPA-KIDNEY suggests genuine structural benefit.
Clinical Practice Today
In February 2022, the FDA approved empagliflozin for heart failure regardless of ejection fraction, making it one of the broadest HF indications ever granted. The 2022 AHA/ACC/HFSA guideline update assigned SGLT2 inhibitors a Class 2a recommendation for HFpEF, later strengthened by the DELIVER results with dapagliflozin.
For clinicians, EMPEROR-Preserved established a practical protocol: 10 mg once daily with periodic monitoring of renal function and volume status. No titration required. The drug works on top of existing background therapy. Patients do not need diabetes to qualify.
The Bigger Picture for SGLT2 Inhibitors
Before this trial, SGLT2 inhibitors had proven benefit in type 2 diabetes (EMPA-REG OUTCOME), HFrEF (EMPEROR-Reduced, DAPA-HF), and chronic kidney disease (DAPA-CKD). EMPEROR-Preserved closed the last major gap by extending efficacy to preserved ejection fraction. The combined data across these trials created a class effect argument that ultimately led to near-universal guideline recommendations for SGLT2 inhibitors in any patient with heart failure, irrespective of EF or diabetes status.
Frequently asked questions
What does EMPEROR-Preserved stand for?
The acronym stands for EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction. It was a phase III, randomized, double-blind, placebo-controlled trial sponsored by Boehringer Ingelheim and Eli Lilly.
Did empagliflozin reduce death in HFpEF?
The trial did not show a statistically significant reduction in cardiovascular death alone (HR 0.91, 95% CI 0.76, 1.09). The primary benefit was driven by fewer hospitalizations for heart failure. All-cause mortality was numerically similar between groups.
Do patients need to have diabetes to benefit?
No. Roughly half the trial population did not have diabetes. The treatment effect was consistent regardless of diabetes status, and the FDA approval does not require a diabetes diagnosis.
How does EMPEROR-Preserved compare to DELIVER?
DELIVER tested dapagliflozin in HFpEF (EF > 40%) and reported similar results: a 18% reduction in the same composite endpoint. Together, the two trials confirm an SGLT2 inhibitor class effect in HFpEF. DELIVER enrolled slightly older patients and included those with recently improved EF.
What ejection fraction cutoff was used?
Patients needed an EF above 40%. This means the trial included both true HFpEF (EF ≥ 50%) and what some guidelines call HFmrEF (EF 41 to 49%). About two-thirds had EF at or above 50%.
How quickly did the benefit appear?
Kaplan-Meier curves began separating within the first few months. By 12 months, a clear difference in cumulative events was visible. The mechanism is thought to involve rapid hemodynamic unloading through natriuresis and osmotic diuresis.
What are the main side effects to watch for?
Genital mycotic infections are the most common class-related adverse event (about 2% excess risk). Clinicians should also watch for volume depletion in patients on high-dose diuretics and rare diabetic ketoacidosis in patients with diabetes, particularly during acute illness.
Is empagliflozin FDA-approved for HFpEF specifically?
Yes. In February 2022, the FDA expanded the empagliflozin (Jardiance) indication to include heart failure in adults, without restriction by ejection fraction. The approval cited EMPEROR-Preserved and EMPEROR-Reduced as supporting evidence.
Does empagliflozin protect the kidneys in HFpEF patients?
In EMPEROR-Preserved, empagliflozin slowed the annual decline in eGFR by 1.36 mL/min/1.73 m² compared to placebo. This is consistent with renal protective signals seen across SGLT2 inhibitor trials, though the initial eGFR dip in the first weeks is hemodynamic and reversible.
Can empagliflozin be combined with other heart failure drugs?
Yes. In the trial, empagliflozin was added on top of standard background therapy including diuretics, RAS inhibitors, beta-blockers, and MRAs. There were no concerning drug interactions, and guideline recommendations support combination use.
References
- 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. PubMed
- 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. PubMed
- FDA. Jardiance (empagliflozin) prescribing information. Revised 2022. FDA Label
- 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. PubMed
- The EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. PubMed