Empagliflozin in Congestive Heart Failure
Empagliflozin is a foundational therapy for congestive heart failure that reduces heart failure hospitalizations and cardiovascular death across the entire spectrum of ejection fractions, and should be initiated in all symptomatic heart failure patients with LVEF >40% regardless of diabetes status. 1
Evidence-Based Recommendations by Heart Failure Type
Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF, LVEF 41-49%)
Empagliflozin receives a Class 2a recommendation (can be beneficial) for decreasing heart failure hospitalizations and cardiovascular mortality in patients with HFmrEF. 1
In the EMPEROR-Preserved trial subgroup of 1,983 patients with LVEF 41-49%, empagliflozin reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 21%. 1
This benefit was driven primarily by a 29% reduction in time to heart failure hospitalization, though cardiovascular death reduction was not statistically significant (HR 0.91,95% CI 0.76-1.0). 1
Heart Failure with Preserved Ejection Fraction (HFpEF, LVEF >40%)
The EMPEROR-Preserved trial of 5,988 adults with NYHA class I-IV heart failure and LVEF >40% demonstrated a 21% reduction (HR 0.79,95% CI 0.69-0.90) in the composite of cardiovascular death or heart failure hospitalization over 26.2 months. 1
Empagliflozin's benefits were consistent regardless of diabetes status at baseline (approximately 50% had type 2 diabetes). 1
Important caveat: A subgroup analysis showed attenuated benefit at LVEF >62.5%, suggesting greatest efficacy in the lower range of preserved ejection fraction. 1
Heart Failure with Reduced Ejection Fraction (HFrEF, LVEF ≤40%)
In the EMPEROR-Reduced trial of 3,730 patients, empagliflozin reduced the primary composite endpoint by 25% (HR 0.75,95% CI 0.65-0.86) over 16 months. 2
Empagliflozin reduced total heart failure hospitalizations requiring intensive care by 33% (HR 0.67,95% CI 0.50-0.90) and those requiring vasopressors/inotropes by 36% (HR 0.64,95% CI 0.47-0.87). 2
The benefit reached statistical significance as early as 12 days after randomization in HFrEF patients. 2
Clinical Benefits Beyond Hospitalization
Functional Status and Quality of Life
Patients on empagliflozin were 20-50% more likely to have better NYHA functional class, with significant effects at 12 weeks maintained for at least 2 years in HFpEF. 3
In HFrEF, patients were 20-40% more likely to experience NYHA class improvement and 20-40% less likely to experience worsening, with effects apparent at 28 days. 2
Empagliflozin resulted in modest but significant improvement in quality of life scores at 52 weeks. 1
Outpatient Heart Failure Events
Empagliflozin reduced outpatient intensification of diuretics by 24% in HFpEF (HR 0.76,95% CI 0.67-0.86) and by 33% in HFrEF (HR 0.67,95% CI 0.56-0.78). 3, 2
The drug reduced emergency/urgent heart failure visits requiring intravenous treatment in both HFpEF and HFrEF populations. 3, 2
Renal Protection
Empagliflozin decreased the slope of eGFR decline across all heart failure phenotypes. 1
In EMPA-REG OUTCOME, empagliflozin reduced the risk of a composite renal outcome (chronic dialysis, renal transplantation, or sustained eGFR reduction) by 50% (HR 0.50,95% CI 0.32-0.77). 1
The renal benefits were consistent across age groups and baseline kidney function. 4
Integration with Guideline-Directed Medical Therapy
Foundational Therapy Concept
Empagliflozin should be considered foundational therapy and can be initiated regardless of existing background therapy or target doses achieved. 5
The drug reduced serious heart failure outcomes across all doses and combinations of ACE inhibitors/ARBs/ARNIs, beta-blockers, and mineralocorticoid receptor antagonists. 5
Empagliflozin provided consistent benefit whether patients were on less than 50% or 50% or more of target doses of ACE inhibitors/ARBs (p-interaction = 0.18) or beta-blockers (p-interaction = 0.15). 5
Benefits were maintained in patients on triple therapy (ACE inhibitor/ARB/ARNI + beta-blocker + MRA) versus those not on this combination (p-interaction = 0.77). 5
Practical Dosing
The standard dose is empagliflozin 10 mg once daily, which was used in all major heart failure trials. 1
Empagliflozin should be added to guideline-directed medical therapy rather than used as monotherapy. 6
For patients with eGFR ≥25 mL/min/1.73 m², the recommended dose remains 10 mg once daily. 6
Empagliflozin is contraindicated in patients on dialysis. 6
Efficacy Across Patient Subgroups
Age Considerations
Empagliflozin's efficacy was consistent across age groups: <65 years (HR 0.71), 65-74 years (HR 0.72), and ≥75 years (HR 0.86), with no significant interaction (p-trend = 0.24). 4
Adverse events increased with age in both treatment arms, but empagliflozin did not increase their incidence over placebo within each age group. 4
Etiology of Heart Failure
Empagliflozin reduced cardiovascular death or heart failure hospitalization in both ischemic (HR 0.82,95% CI 0.68-0.99) and nonischemic (HR 0.67,95% CI 0.55-0.82) causes of heart failure, with no significant interaction (p = 0.15). 7
Benefits on heart failure hospitalization, renal outcomes, eGFR slope, and health status were consistent regardless of heart failure etiology. 7
Safety Profile and Monitoring
Common Pitfalls to Avoid
Monitor renal function regularly when initiating empagliflozin, particularly in patients with baseline kidney disease. 8
Assess volume status regularly due to the diuretic effects of SGLT2 inhibitors, which may necessitate adjustment of concurrent diuretic therapy. 8
Educate patients about symptoms of diabetic ketoacidosis, especially those with diabetes, though this risk is primarily relevant in type 1 diabetes. 8
Tolerability
Empagliflozin was well tolerated with rates of hypotension, symptomatic hypotension, and hyperkalemia similar across all subgroups and background therapies. 5
Serious adverse events and adverse events leading to drug discontinuation did not increase with empagliflozin compared to placebo across age groups. 4
Timeline of Clinical Benefit
Benefits emerge rapidly: Statistical significance was reached at 18 days in HFpEF 3 and 12 days in HFrEF 2, making this an appropriate therapy even in recently decompensated patients once stabilized.
The benefits are sustained long-term, with consistent effects maintained throughout the median 26-month follow-up in EMPEROR-Preserved and 16-month follow-up in EMPEROR-Reduced. 3, 2