Empagliflozin in Heart Failure with a Preserved Ejection Fraction
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In patients with heart failure and a preserved ejection fraction, empagliflozin significantly reduced the combined risk of cardiovascular death or hospitalization for heart failure compared to placebo, irrespective of diabetes status.
Key Findings
Study Design
Study Limitations
Clinical Significance
EMPEROR-Preserved was the first major randomized controlled trial to unequivocally demonstrate a clinical benefit with any disease-modifying pharmacological therapy in patients with heart failure with preserved ejection fraction (HFpEF). It established SGLT2 inhibitors as foundational, guideline-directed medical therapy across the full spectrum of heart failure ejection fractions.
Historical Context
For decades, treating heart failure with preserved ejection fraction (HFpEF) was considered the 'graveyard of heart failure trials.' While therapies for reduced ejection fraction (HFrEF) rapidly advanced, numerous trials evaluating ACE inhibitors, ARBs (CHARM-Preserved, I-PRESERVE), MRAs (TOPCAT), and ARNIs (PARAGON-HF) failed to definitively reduce the primary composite endpoint of cardiovascular death or heart failure hospitalizations in the HFpEF population. Management was largely restricted to diuretics for symptom control. EMPEROR-Preserved fundamentally disrupted this paradigm in 2021, proving that the SGLT2 inhibitor empagliflozin significantly improved clinical outcomes in HFpEF. This led to the first-ever Class 1 guideline recommendation for a disease-modifying therapy in this previously untreatable condition.
Guided Discussion
High-yield insights from every perspective
What is the proposed mechanism by which SGLT2 inhibitors like empagliflozin provide cardiovascular benefits in patients with heart failure with preserved ejection fraction, even in the absence of diabetes?
Key Response
SGLT2 inhibitors block glucose and sodium reabsorption in the proximal tubule. Benefits in heart failure are independent of glycemic control and likely involve osmotic diuresis, natriuresis reducing preload without sympathetic activation, improved myocardial energetics via a shift to ketone body utilization, and reduction in ventricular wall stress.
A 72-year-old patient with HFpEF (LVEF 55%) and chronic kidney disease (eGFR 35 mL/min/1.73m2) is seen in the clinic for dyspnea. How does the EMPEROR-Preserved data influence your decision to initiate empagliflozin, and what clinical safety parameters should you monitor upon initiation?
Key Response
EMPEROR-Preserved included patients with an eGFR down to 20 mL/min/1.73m2, and results support initiating empagliflozin to reduce the risk of HF hospitalizations in this population. The resident must monitor volume status, explain that a mild initial, reversible dip in eGFR is expected and not a reason to discontinue the drug, and counsel on the risk of genital mycotic infections.
In the EMPEROR-Preserved trial, the primary composite endpoint was driven largely by a reduction in heart failure hospitalizations rather than cardiovascular death. How should this differential impact on the composite endpoint, along with the subgroup analyses based on LVEF, influence our phenotyping of HFpEF?
Key Response
While HF hospitalizations were significantly reduced, CV mortality was not significantly lowered as an independent endpoint. Fellows should recognize that HFpEF is a highly heterogeneous syndrome. Subgroup analyses suggested an attenuation of benefit at the very high end of the LVEF spectrum (e.g., >65%), prompting advanced discussion on overlapping phenotypes, restrictive physiology, and whether HFmrEF (41-49%) drove a disproportionate share of the benefit.
Given that HFpEF has historically been a graveyard for clinical trials, how do we frame the EMPEROR-Preserved results when counseling a patient about absolute versus relative benefits, and how does this inform our approach to polypharmacy and deprescribing?
Key Response
Attendings need to translate trial data into shared decision-making. EMPEROR-Preserved showed a relative risk reduction of 21% but an absolute risk reduction of about 3.3% for the primary composite over 26 months (NNT ~31). Discussion should focus on prioritizing therapies with proven morbidity benefits over historically used symptom-control medications, actively deprescribing non-evidence-based therapies to avoid pill burden.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
The trial utilized a predefined hierarchical testing strategy for its secondary endpoints, sequentially testing total HF hospitalizations and the slope of eGFR decline. What are the methodological advantages and potential statistical pitfalls of this closed testing procedure in a trial with a highly heterogeneous target population like HFpEF?
Key Response
Hierarchical testing strictly controls the family-wise type I error rate, allowing formal hypothesis testing of secondary endpoints only if the primary endpoint is met. However, if an early step in the hierarchy fails to reach significance, subsequent clinically important endpoints cannot be formally claimed as statistically significant, potentially burying important exploratory insights or sub-phenotype benefits in a heterogeneous disease.
As an editor evaluating the EMPEROR-Preserved manuscript during peer review, how would you critically assess the sponsors definition of preserved ejection fraction as >40%, and what methodological demands would you make regarding the inclusion of patients with mildly reduced LVEF (41-49%)?
Key Response
A critical reviewer would flag that including LVEF 41-49% (now categorized as HFmrEF) might inflate the overall trial benefit, as these patients have established, HFrEF-like responses to neurohormonal blockade. The editor would demand robust interaction testing and forest plots to ensure the drugs efficacy holds in the strictly defined HFpEF population (LVEF >50%) and is not solely driven by the lower LVEF strata.
Based on the findings of EMPEROR-Preserved, how should the ACC/AHA Heart Failure guidelines be updated regarding the Class of Recommendation and Level of Evidence for SGLT2 inhibitors in HFpEF, and how does this compare to previous guideline iterations for this disease state?
Key Response
Prior to this trial, HFpEF treatment was largely Class 2a/2b for symptom relief (diuretics) and managing comorbidities, with marginal recommendations for ARNIs or MRAs. EMPEROR-Preserved provides Level of Evidence A for SGLT2 inhibitors, shifting the guidelines to a Class 2a (subsequently Class 1 in updates) recommendation for reducing HF hospitalizations, effectively establishing the first definitively proven, foundational pillar of HFpEF medical therapy.
Clinical Landscape
Noteworthy Related Trials
PARAGON-HF Trial
Tested
Sacubitril-valsartan
Population
Patients with heart failure and LVEF 45% or greater
Comparator
Valsartan
Endpoint
Composite of total hospitalizations for heart failure and cardiovascular death
EMPEROR-Reduced Trial
Tested
Empagliflozin 10 mg daily
Population
Patients with heart failure and LVEF 40% or less
Comparator
Placebo
Endpoint
Composite of cardiovascular death or hospitalization for heart failure
DELIVER Trial
Tested
Dapagliflozin 10 mg daily
Population
Patients with heart failure and LVEF greater than 40%
Comparator
Placebo
Endpoint
Composite of worsening heart failure or cardiovascular death
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