How does empagliflozin (Empagliflozin) improve outcomes in patients with Heart Failure with Preserved Ejection Fraction (HFpEF)?

How Empagliflozin Improves Outcomes in HFpEF

Empagliflozin 10 mg once daily reduces cardiovascular death or heart failure hospitalization by 21% in HFpEF patients (LVEF >40%), with benefits appearing as early as 18 days after initiation and sustained long-term, regardless of diabetes status. 1, 2

Primary Mechanisms of Benefit

Empagliflozin improves HFpEF outcomes through multiple complementary pathways:

Cardiovascular Event Reduction

• Empagliflozin reduces the composite endpoint of cardiovascular death or heart failure hospitalization by 21% (HR 0.79,95% CI 0.69-0.90; P<0.001) in patients with LVEF >40%. 1, 2
• The drug reduces total heart failure hospitalizations requiring intensive care by 29% (HR 0.71,95% CI 0.52-0.96; P=0.028) and hospitalizations requiring vasopressors or inotropes by 27% (HR 0.73,95% CI 0.55-0.97; P=0.033). 2
• Benefits reach statistical significance within 18 days of starting therapy and are maintained throughout long-term treatment. 2

Diuretic and Decongestion Effects

• Empagliflozin inhibits proximal tubular sodium-glucose reabsorption, producing glucosuria and natriuresis that enhances diuretic efficacy. 3
• Patients on empagliflozin require 24% less outpatient diuretic intensification compared to placebo (482 versus 610 patients; HR 0.76,95% CI 0.67-0.86; P<0.0001). 2
• The natriuretic effect triggers tubuloglomerular feedback through increased distal tubule sodium delivery, causing afferent arteriolar vasoconstriction that prevents glomerular hyperfiltration. 3

Metabolic and Myocardial Effects

• Empagliflozin shifts cardiac metabolism toward ketone utilization, which requires less oxygen than glucose or fatty acid metabolism, directly improving myocardial energetics. 3
• The drug reduces cardiac fibrosis and adverse remodeling through mechanisms independent of glucose-lowering effects. 3, 4

Renal Protection

• Empagliflozin significantly slows estimated glomerular filtration rate (eGFR) decline across all stages of renal function, with an average preservation of 1.37 ml/min/1.73 m²/year compared to placebo. 1, 5
• This renoprotective effect is consistent regardless of baseline diabetes status, though more pronounced in patients with diabetes (1.77 versus 0.98 mL/min/1.73m² in patients without diabetes; P=0.01). 4

Functional and Quality of Life Improvements

Symptom Relief and Functional Status

• Patients on empagliflozin are 20-50% more likely to experience improvement in NYHA functional class, with significant effects apparent at 12 weeks and maintained for at least 2 years. 2
• Conversely, patients are 20-40% less likely to experience worsening of NYHA functional class during treatment. 6
• Empagliflozin produces modest but significant improvements in quality of life scores at 52 weeks. 1

Important Caveat on Exercise Capacity

• Despite robust benefits on hard clinical endpoints, empagliflozin showed disappointing results on exercise capacity measures, with only a 4-meter difference in 6-minute walk distance (P=0.37) compared to placebo. 7
• This contrasts with dapagliflozin (the other SGLT2 inhibitor), which showed an 8.2% increase in 6-minute walk distance in the PRESERVED-HF trial. 7

Consistency Across Patient Subgroups

Diabetes Status

• The benefits of empagliflozin are completely independent of diabetes status, with identical hazard ratios for the primary outcome in patients with diabetes (HR 0.79,95% CI 0.67-0.94) and without diabetes (HR 0.78,95% CI 0.64-0.95; P interaction=0.92). 4
• Baseline hemoglobin A1c does not modify treatment effects (P interaction=0.26), and there is no increased risk of hypoglycemic events. 4

Atrial Fibrillation

• Among HFpEF patients, 52% have baseline atrial fibrillation, and empagliflozin reduces cardiovascular death or heart failure hospitalization equally in patients with AF (HR 0.78,95% CI 0.66-0.93) and without AF (HR 0.78,95% CI 0.64-0.95; P interaction=0.96). 5
• The drug also reduces total heart failure hospitalizations (HR 0.73 versus 0.72, P interaction=0.94) and eGFR decline consistently regardless of AF status. 5

Ejection Fraction Spectrum

• Benefits on total heart failure hospitalizations are similar in patients with LVEF 40-49% and 50-59%, but appear attenuated at higher ejection fractions. 2
• The effect is consistent across the entire HFpEF spectrum (LVEF >40%), with no significant interaction by ejection fraction subgroups. 8

Clinical Implementation

Dosing and Initiation

• The standard dose is empagliflozin 10 mg once daily, with no dose adjustment or titration required regardless of blood pressure, heart rate, or potassium levels. 8
• Empagliflozin should be added to existing guideline-directed medical therapy rather than used as monotherapy. 8
• The drug can be initiated during heart failure hospitalization in stabilized patients, as deferring initiation results in many eligible patients never receiving the medication within 1 year. 3

Renal Function Considerations

• Empagliflozin can be initiated in patients with eGFR ≥20 mL/min/1.73 m² and continued even if eGFR falls below this threshold during treatment. 8
• The FDA label restriction for eGFR <45 mL/min/1.73 m² does not apply to heart failure indications. 8
• The drug is contraindicated in patients on dialysis. 8

Monitoring Requirements

• Monitor renal function and electrolytes at 1-2 weeks, then at 4 weeks after initiation. 8
• Assess volume status at each visit due to the diuretic effects of SGLT2 inhibitors. 8
• Monitor for symptomatic hypotension, particularly in elderly patients, those with low systolic blood pressure, or patients on diuretics. 1
• Assess for signs and symptoms of ketoacidosis, particularly during illness or fasting, as euglycemic ketoacidosis can occur. 1

Safety Profile

• Empagliflozin has minimal blood pressure effects and no excess risk of symptomatic hypotension compared to placebo. 3
• There are numerically fewer serious adverse events with empagliflozin than placebo. 3
• Common risks include genital and soft tissue infections and volume depletion, especially when combined with high-dose loop diuretics. 3