How does Jardiance (empagliflozin) work in heart failure?

Mechanism of Empagliflozin (Jardiance) in Heart Failure

Empagliflozin works in heart failure primarily by inhibiting SGLT2 in the proximal tubule of the kidney, which promotes decongestion and reduces cardiac stress through multiple mechanisms, regardless of diabetes status. 1

Primary Mechanism of Action

• Empagliflozin inhibits sodium-glucose co-transporter 2 (SGLT2), which is predominantly responsible for reabsorption of glucose from the glomerular filtrate back into circulation 1
• By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose, increases urinary glucose excretion, and promotes osmotic diuresis and natriuresis 1, 2
• This leads to increased urine volume (341 mL increase on day 1 of treatment) which helps reduce congestion in heart failure patients 1

Cardiovascular Benefits Beyond Glucose Control

Decongestion Effects

• Empagliflozin acts on the proximal convoluted tubule, reducing sodium reabsorption and promoting decongestion 2
• The EMPULSE trial showed significant improvements in markers of decongestion in patients hospitalized with acute heart failure 2
• Empagliflozin reduces the need for loop diuretic intensification (30-40% reduction compared to placebo), indicating improved volume status 3

Hemodynamic Effects

• Reduces preload and afterload, which decreases cardiac stress 2
• Decreases arterial pressure and stiffness 2
• Promotes a shift to ketone-based myocardial metabolism, potentially improving cardiac energetics 2

Remodeling Benefits

• Reduces cardiac hypertrophy and fibrosis 2
• Improves left ventricular ejection fraction (LVEF) and reduces left ventricular end-diastolic diameter (LVEDD) 4
• The 25 mg dose may provide greater improvements in cardiac function parameters compared to the 10 mg dose 4

Clinical Evidence in Heart Failure

• Empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure in patients with HFrEF (hazard ratio: 0.75; 95% CI: 0.65-0.86) 2
• Benefits are seen regardless of diabetes status, with similar efficacy in patients with and without diabetes 5
• Effects appear early (within 12-28 days of starting treatment) and are sustained during long-term therapy 3
• Empagliflozin reduces the total number of heart failure hospitalizations requiring intensive care by 33% (HR: 0.67; 95% CI: 0.50-0.90) 3

Unique Advantages in Heart Failure Treatment

• Unlike many other heart failure medications, empagliflozin does not significantly affect heart rate, blood pressure, or potassium levels 2
• No dose titration is required, simplifying treatment initiation 2
• Can be used in patients with moderate kidney dysfunction (eGFR ≥20 mL/min/1.73 m²) 2
• May facilitate the use of other heart failure medications like MRAs by reducing the risk of severe hyperkalemia 2

Renal Effects Relevant to Heart Failure

• Causes a modest early decline in eGFR that stabilizes over time, with long-term kidney protection 6
• Reduces the burden on proximal tubular epithelial cells, potentially decreasing renal cortical hypoxia 2
• The initial eGFR decline is approximately 2 mL/min/1.73 m² at day 15 compared to placebo, but equalizes by day 90 6

Practical Implications

• Empagliflozin 10 mg daily is recommended for heart failure with reduced ejection fraction (HFrEF) 2
• Also beneficial in heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%) 2
• Can be administered with or without food 1
• Should be considered early in treatment algorithms for heart failure due to its mortality and morbidity benefits 2

Caveats and Considerations

• May cause mild and transient drop in eGFR soon after treatment initiation 2
• Glucosuric effects may be attenuated in patients with very low eGFR (<20 mL/min/1.73 m²) 2
• Caution is advised when using in patients with eGFRs below the inclusion criteria from pivotal studies 2
• Urinary glucose excretion increases immediately following dosing and is maintained during treatment 1