Comprehensive Review of the EMPEROR-Preserved Trial: Efficacy and Outcomes of Empagliflozin in Heart Failure with Preserved Ejection Fraction

Highlights

• Empagliflozin significantly reduces cardiovascular death or heart failure hospitalization in HFpEF patients, consistent across ejection fraction ranges, sexes, BMI, blood pressure, and kidney function.
• Empagliflozin improves health-related quality of life and functional status early and sustained over one year.
• The drug lowers serum uric acid levels and decreases clinical events related to hyperuricemia in HFpEF.
• Empagliflozin reduces the risk of lower respiratory tract infections in HFpEF, an important comorbidity affecting prognosis.

Background

Heart failure with preserved ejection fraction (HFpEF) represents approximately half of all heart failure cases, characterized by significant morbidity and mortality without many conclusively beneficial therapies until recently. The EMPEROR-Preserved trial, a large, placebo-controlled, randomized clinical trial, evaluated the efficacy and safety of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with chronic HFpEF (LVEF >40%). Given the high prevalence of comorbidities and heterogeneous patient population in HFpEF, EMPEROR-Preserved also provides insights into subgroup responses and mechanistic effects relevant to clinical practice.

Key Content

1. Trial Population and Baseline Characteristics

The EMPEROR-Preserved cohort included 5988 patients with NYHA class II-IV symptoms and elevated NT-proBNP, median age 72 years, 45% women, and common comorbidities including diabetes (49%) and chronic kidney disease (50%). The mean LVEF was 54%, with 33% having mildly reduced EF (41-50%). Most patients were on guideline-directed medical therapy, including ACE inhibitors/ARBs (80%) and beta-blockers (86%).

2. Primary and Secondary Outcomes

Empagliflozin reduced the composite primary endpoint of cardiovascular death or hospitalization for heart failure significantly versus placebo (hazard ratio [HR] approx. 0.79), with benefits apparent early (within 18 days) and sustained over median 26 months follow-up. Total heart failure hospitalizations were also reduced. Subgroup analyses revealed consistent benefits regardless of LVEF stratum (≥50% or 41-49%), sex, BMI category, blood pressure, presence of chronic kidney disease, and baseline health status measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).

Key Outcome	Empagliflozin Group	Placebo Group	Hazard Ratio (95% CI)	p-value
Primary composite (CV death or HHF)	13.1%	16.8%	0.79 (0.69–0.90)	0.0004
Total HHF	Reduced events	Reference	Varied by subgroup; ~0.7–0.8	<0.05
All-cause mortality	Not significantly different	Reference	NS
KCCQ Clinical Summary Score (improvement at 52 weeks)	+1.50 points	Reference		<0.01
Serum Uric Acid Reduction at 4 weeks	-0.99 mg/dL	Reference		<0.0001
Lower Respiratory Tract Infection Incidence	5.2 events/100 person-years	6.2 events/100 person-years	0.83 (0.71–0.96)	0.014

3. Effects on Quality of Life and Functional Status

Empagliflozin improved patient-reported outcomes using the KCCQ, showing significant and early improvements in Clinical Summary Score, Total Symptom Score, and Overall Summary Score sustained through 1 year. Responder analyses demonstrated increased odds of clinically meaningful improvements and reduced odds of deterioration.

4. Uric Acid, Metabolism, and Related Outcomes

A post hoc analysis identified hyperuricemia as prevalent (~49%) and associated with more advanced disease and worse outcomes. Empagliflozin rapidly and sustainably reduced serum uric acid levels and decreased hyperuricemia-associated clinical events (e.g., gout) by 38%, without baseline uric acid levels modifying treatment benefit. These metabolic effects may contribute to overall efficacy.

5. Kidney Function and Cardiorenal Outcomes

Empagliflozin slowed eGFR decline consistently across kidney function strata, with benefits on heart failure outcomes apparent irrespective of chronic kidney disease status. Although the composite kidney endpoint (sustained eGFR decline, dialysis, transplant) was not significantly reduced overall, the drug slowed progression to macroalbuminuria and reduced acute kidney injury risk. Safety and efficacy were consistent down to an eGFR of 20 ml/min/1.73 m2.

6. Impact of Body Mass Index (BMI)

Analysis showed similar treatment benefits of empagliflozin on cardiovascular and renal outcomes across BMI categories (<25 to ≥40 kg/m2), with no significant interaction by BMI. Weight reductions were modest and varied slightly by BMI group.

7. Influence of Blood Pressure

Baseline systolic blood pressure (low 130 mmHg) did not moderate empagliflozin’s cardiovascular benefit or safety profile, including adverse events such as hypotension or acute renal failure.

8. Sex-Based Analysis

Empagliflozin’s efficacy and safety were consistent in women and men, with no significant sex interaction on cardiovascular outcomes or quality-of-life improvements.

9. Respiratory Infections

Empagliflozin reduced incidence and total events of lower respiratory tract infections (LRTI), a clinically relevant complication in HFpEF associated with increased mortality risk, though no effect was found on COVID-19 incidence.

10. Liver Function Markers

Elevated liver enzymes and abnormal liver function tests were variably associated with prognosis. Empagliflozin increased albumin levels but had no major effect on other liver parameters. Importantly, baseline liver test abnormalities did not alter treatment response.

Expert Commentary

The EMPEROR-Preserved trial and its subsequent analyses robustly support empagliflozin as a major therapeutic advance in HFpEF, a condition historically lacking effective pharmacotherapy. The drug’s consistent benefit across diverse subgroups (sex, BMI, kidney function, blood pressure, HF severity) underscores its broad applicability. Mechanistically, benefits likely stem from multifactorial effects including diuresis, metabolic modulation (notably uric acid lowering), improved renal function trajectory, and systemic effects such as reduced susceptibility to infections.

Strengths of the EMPEROR-Preserved data include its large, international population and comprehensive subgroup analyses, but limitations include modest absolute risk reductions in some secondary outcomes (e.g., renal endpoints) and attenuation of benefit at very high ejection fractions. Also, while quality of life improvements are statistically significant and sustained, their clinical magnitude, though meaningful, is moderate.

Clinical guideline updates increasingly incorporate SGLT2 inhibitors, with EMPEROR-Preserved providing direct evidence to support empagliflozin use in HFpEF. The reduction of heart failure hospitalizations, improvement in patient-reported outcomes, and manageable safety profile support integration into routine management.

Conclusion

Recent evidence from the EMPEROR-Preserved trial affirms empagliflozin as an effective, safe, and versatile therapy for patients with HFpEF across a wide clinical spectrum. It reduces the primary composite endpoint, heart failure hospitalizations, improves quality of life, and favorably modifies metabolic and renal parameters. Future research is warranted to elucidate long-term mortality effects, mechanisms underlying kidney benefits, and strategies to optimize incorporation into multidimensional heart failure management.

References

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