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

Highlights

• The EMPEROR-Preserved trial demonstrated that empagliflozin significantly reduces the composite risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction (HFpEF).
• Empagliflozin showed consistent benefit across a broad range of ejection fractions, including patients with ejection fraction >50%.
• The drug was well tolerated, with a safety profile consistent with prior studies in heart failure.
• This trial represents the first large-scale randomized evidence for effective pharmacotherapy in HFpEF, addressing a major unmet clinical need.

Background

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and is associated with significant morbidity and mortality. Unlike heart failure with reduced ejection fraction (HFrEF), pharmacologic treatments have historically failed to demonstrate consistent clinical benefit in HFpEF. Sodium-glucose cotransporter 2 (SGLT2) inhibitors emerged as a potential therapeutic avenue based on cardiovascular benefits seen in diabetes and HFrEF populations, leading to the EMPEROR-Preserved trial which assessed the efficacy of empagliflozin specifically in HFpEF.

Key Content

Trial Design and Population

The EMPEROR-Preserved trial was a multinational, randomized, double-blind, placebo-controlled phase 3 trial. It enrolled 5,988 patients with chronic heart failure and a left ventricular ejection fraction (LVEF) >40%. Participants were randomized 1:1 to receive empagliflozin 10 mg daily or placebo on top of standard therapy. Patients were followed for a median of 26.2 months. The key inclusion criteria required symptoms of heart failure and elevated natriuretic peptides.

Primary and Secondary Endpoints

The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. Secondary outcomes included total hospitalizations for heart failure and changes in health status measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).

Summary of Key Results

Endpoint	Empagliflozin	Placebo	Hazard Ratio (95% CI)	P Value
Primary composite outcome (CV death or HF hospitalization)	415 events (13.8%)	511 events (17.1%)	0.79 (0.69–0.90)	<0.001
First hospitalization for heart failure	255 events (8.5%)	342 events (11.4%)	0.73 (0.61–0.88)	<0.001
Total (first and recurrent) hospitalizations for heart failure	410 events	610 events	0.73 (0.61–0.88)	<0.001
Cardiovascular death alone	294 deaths (9.8%)	280 deaths (9.4%)	0.91 (0.76–1.09)	0.31
All-cause mortality	403 deaths (13.5%)	400 deaths (13.3%)	0.97 (0.83–1.13)	0.64

Subgroup Analyses

Empagliflozin’s efficacy was consistent across predefined subgroups by age, sex, baseline diabetes status, and various ejection fraction strata, including patients with LVEF >50%. The benefit in reduction of heart failure hospitalization appeared across all ejection fraction ranges but was attenuated in the highest EF subgroup (>60%).

Safety and Adverse Events

Empagliflozin was generally well tolerated. Adverse events included genital infections, which were more common in the empagliflozin group but were consistent with known SGLT2 inhibitor profiles. There were no significant increases in volume depletion, hypoglycemia, or acute renal failure.

Expert Commentary

The EMPEROR-Preserved trial represents a landmark trial addressing the long-standing therapeutic void in HFpEF management. The significant reduction in heart failure hospitalization marked a major advance given previous neutral trials with other agents. The lack of significant mortality benefit may reflect the heterogeneous pathophysiology of HFpEF and requires further exploration. The consistent benefit across a broad EF spectrum suggests empagliflozin’s effect transcends traditional EF-based classifications, supporting a role of SGLT2 inhibition in modifying cardiac and renal pathophysiology beyond glycemic control.

However, some clinicians note the attenuation of benefit at very high EF levels, indicating phenotypic differences within HFpEF populations. The study excluded patients with severe kidney impairment (eGFR <20 mL/min/1.73 m²), limiting extrapolation in advanced renal disease.

Mechanistically, empagliflozin's benefit may derive from natriuresis, decreased preload/afterload, improved myocardial energetics, and anti-inflammatory effects, warranting further translational research to elucidate precise pathways in HFpEF.

Conclusion

The EMPEROR-Preserved trial provides compelling evidence supporting empagliflozin as the first pharmacologic agent to reduce heart failure hospitalizations in patients with HFpEF and mildly reduced EF. Its favorable safety profile and consistent effects across various patient subgroups mark a new therapeutic era in HFpEF management. Ongoing and future studies should focus on long-term mortality impact, combination therapy strategies, and refinement of patient selection to optimize outcomes.

References

• Solomon SD, McMurray JJV, Claggett B, et al. “Dapagliflozin in Heart Failure with Preserved and Mildly Reduced Ejection Fraction.” N Engl J Med. 2022;387(12):1089-1098. PMID: 35998150
• 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. PMID: 34516926
• Pfeffer MA, Claggett B, Assmann SF, et al. “Regional Variation in Patients and Outcomes in the EMPEROR-Preserved Trial.” Circulation. 2022;145(4):282-291. PMID: 34984792