What is the role of Empagliflozin (Empagliflozin) in the management of patients with heart failure, particularly those with reduced ejection fraction and impaired renal function?

Empagliflozin in Heart Failure Management

Empagliflozin 10 mg once daily should be initiated in all patients with symptomatic heart failure regardless of ejection fraction, diabetes status, or renal function (down to eGFR 25 mL/min/1.73 m²), as it significantly reduces cardiovascular death and heart failure hospitalizations while improving quality of life. 1, 2

Universal Recommendation Across Heart Failure Spectrum

Heart Failure with Reduced Ejection Fraction (HFrEF, LVEF ≤40%)

• Empagliflozin reduces the composite outcome of cardiovascular death or hospitalization for heart failure by 21% (HR 0.79,95% CI 0.69-0.90; P<0.001) in HFrEF patients. 2
• The benefit appears within 12 days of treatment initiation and is sustained long-term. 3
• Empagliflozin reduces total heart failure hospitalizations requiring intensive care by 33% (HR 0.67,95% CI 0.50-0.90) and those requiring vasopressors or inotropes by 36% (HR 0.64,95% CI 0.47-0.87). 3
• The drug reduces outpatient diuretic intensification by 33% (HR 0.67,95% CI 0.56-0.78; P<0.0001), indicating prevention of early decompensation. 3

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF, LVEF 41-49%)

• The 2022 AHA/ACC/HFSA guidelines provide a Class 2a recommendation for SGLT2 inhibitors in HFmrEF to decrease heart failure hospitalizations and cardiovascular mortality. 1
• In the EMPEROR-Preserved subgroup with LVEF 41-49%, empagliflozin reduced the primary composite endpoint without significant interaction by ejection fraction subgroups. 1
• Patients with LVEF on the lower end of the HFmrEF spectrum (closer to 41%) respond similarly to HFrEF patients and should be treated accordingly. 1

Heart Failure with Preserved Ejection Fraction (HFpEF, LVEF >40%)

• Empagliflozin reduces the composite outcome of cardiovascular death or hospitalization for heart failure by 21% in HFpEF (HR 0.79,95% CI 0.69-0.90). 2
• The benefit reached statistical significance at 18 days after randomization and was sustained over a median of 26 months. 4
• Empagliflozin reduced total heart failure hospitalizations requiring intensive care by 29% (HR 0.71,95% CI 0.52-0.96) and those requiring vasopressors by 27% (HR 0.73,95% CI 0.55-0.97). 4
• The benefit on total heart failure hospitalizations was similar in patients with LVEF 40-50% and 50-60%, but attenuated at higher ejection fractions (>62.5%). 1, 4

Independence from Diabetes Status

• The cardiovascular benefits of empagliflozin are completely independent of diabetes status and glucose-lowering effects. 5, 2
• Efficacy is similar in patients with and without diabetes at baseline, representing a direct cardiovascular benefit through mechanisms beyond glycemic control. 1, 2

Use in Renal Impairment

Pharmacokinetics and Dosing

• Empagliflozin exposure increases by 18% in mild renal impairment (eGFR 60-89), 20% in moderate impairment (eGFR 30-59), and 66% in severe impairment (eGFR <30), but no dose adjustment is required. 6
• The fraction of empagliflozin excreted unchanged in urine and urinary glucose excretion decline with decreasing eGFR, but cardiovascular benefits persist. 6

Renal Protection

• Empagliflozin significantly reduces the slope of eGFR decline across all stages of renal function. 1
• The drug reduces the renal composite endpoint (chronic dialysis, renal transplantation, or profound sustained eGFR reduction) consistently across age groups. 7
• Initial small increases in serum creatinine (mean 0.01-0.02 mg/dL at 12-24 weeks) reverse after treatment discontinuation, suggesting acute hemodynamic changes rather than true renal injury. 6

Practical Implementation

Initiation and Dosing

• Start empagliflozin 10 mg once daily without titration; no dose adjustment needed for age, sex, renal function, or background therapy. 2, 6
• Empagliflozin may be administered with or without food, as food decreases AUC by only 16% and Cmax by 37%, which is not clinically relevant. 6

Timing of Initiation

• Initiate empagliflozin during hospitalization for heart failure in stabilized patients rather than deferring to outpatient follow-up, as benefits accrue within days to weeks. 5
• Clinical benefits reach statistical significance at 12 days in HFrEF and 18 days in HFpEF. 3, 4

Combination with Other Heart Failure Therapies

• Continue all existing guideline-directed medical therapy (ACE inhibitors, ARBs, ARNIs, beta-blockers, mineralocorticoid receptor antagonists) as empagliflozin provides additive benefit. 5
• Empagliflozin does not inhibit or induce CYP450 isoforms or major drug transporters, minimizing drug-drug interactions. 6
• No dose adjustment needed when coadministered with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, hydrochlorothiazide, or torsemide. 6

Efficacy Across Patient Subgroups

Age

• Empagliflozin reduces the primary composite endpoint consistently across age groups: HR 0.71 (95% CI 0.57-0.89) for <65 years, 0.72 (0.57-0.93) for 65-74 years, and 0.86 (0.67-1.10) for ≥75 years (p-trend = 0.24). 7
• Effects on first and recurrent heart failure hospitalization (p-trend = 0.30), eGFR decline (p-trend = 0.78), and renal composite (p-trend = 0.94) are consistent across all age groups. 7

Etiology of Heart Failure

• Empagliflozin reduces 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) heart failure without significant interaction (P=0.15). 8
• Benefits on heart failure hospitalization, renal outcomes, eGFR slope, and health status scores are consistent regardless of heart failure etiology. 8

Safety Profile and Monitoring

Common Adverse Events

• Genital mycotic infections occur in 4.1% with empagliflozin 10 mg and 3.7% with 25 mg versus 0.9% with placebo (female: 5.4-6.4% vs 1.5%; male: 1.6-3.1% vs 0.4%). 6
• Urinary tract infections occur in 9.3% with empagliflozin 10 mg and 7.6% with 25 mg versus 7.6% with placebo. 6
• Increased urination (polyuria, pollakiuria, nocturia) occurs in 3.4% with empagliflozin 10 mg and 3.2% with 25 mg versus 1.0% with placebo. 6

Volume Depletion

• Volume depletion events (hypotension, dehydration, orthostatic hypotension, syncope) occur in 0.5% with empagliflozin 10 mg and 0.3% with 25 mg versus 0.3% with placebo. 6
• Monitor for symptomatic hypotension, particularly in elderly patients, those with low baseline blood pressure, those on diuretics, or those with renal impairment. 2

Diabetic Ketoacidosis

• Monitor for signs and symptoms of ketoacidosis, including euglycemic ketoacidosis, especially during illness or fasting. 2
• Risk exists even in non-diabetic patients, requiring vigilance in all heart failure patients. 2

Hypoglycemia

• When used as monotherapy or with metformin, hypoglycemia rates are similar to placebo (0.4-1.8%). 6
• When combined with sulfonylureas, hypoglycemia increases to 11.5-16.1% versus 8.4% with placebo. 6
• When combined with basal insulin, hypoglycemia occurs in 19.5-28.4% versus 20.6% with placebo, with severe hypoglycemia in 0-1.3%. 6

Contraindications and Cautions

• Use with caution when combined with high-dose loop diuretics due to enhanced natriuresis. 5
• Contraindicated in patients with eGFR <25 mL/min/1.73 m² or on dialysis. 5
• Adverse events increase with age in both treatment arms, but empagliflozin does not increase their incidence over placebo within each age group. 7

Quality of Life and Functional Status

• Patients on empagliflozin are 20-50% more likely to experience improvement in NYHA functional class, with effects apparent at 28 days in HFrEF and 12 weeks in HFpEF, maintained during long-term follow-up. 3, 4
• Empagliflozin results in modest but significant improvements in quality of life scores at 52 weeks. 1
• The drug improves symptoms, physical limitations, and overall quality of life across the heart failure spectrum. 5