What is the role of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors, such as empagliflozin (Empagliflozin) or canagliflozin (Canagliflozin), in the treatment of Heart Failure with preserved Ejection Fraction (HFpEF)?

Role of SGLT2 Inhibitors in Heart Failure with Preserved Ejection Fraction (HFpEF)

SGLT2 inhibitors are strongly recommended as first-line therapy for heart failure across all ejection fraction ranges, including HFpEF, regardless of diabetes status, with empagliflozin and dapagliflozin demonstrating significant reductions in the composite outcome of cardiovascular death or hospitalization for heart failure. 1

Mechanism of Action and Clinical Benefits in HFpEF

SGLT2 inhibitors work through multiple mechanisms that specifically benefit patients with HFpEF:

• Hemodynamic effects: Reduce preload and afterload through osmotic diuresis and natriuresis
• Metabolic improvements: Shift from glucose to ketone metabolism, improving cardiac energetics
• Anti-inflammatory properties: Reduce systemic inflammation common in HFpEF
• Direct cardiac effects: Improve myocardial function and reduce fibrosis

Evidence Supporting SGLT2 Inhibitors in HFpEF

The strongest evidence comes from large randomized controlled trials:

• EMPEROR-Preserved trial: Empagliflozin demonstrated a 21% reduction in the composite outcome of cardiovascular death or hospitalization for heart failure (HR 0.79 [95% CI 0.69–0.90]; P < 0.001) over a median of 26.2 months 1, 2

• DELIVER trial: Dapagliflozin showed an 18% reduction in the composite outcome (HR 0.82 [95% CI 0.73–0.92]; P < 0.001) 1

• The benefit was primarily driven by a reduction in heart failure hospitalizations rather than cardiovascular death 3, 4

• The effects were consistent regardless of diabetes status 2

Clinical Application

For patients with HFpEF (LVEF >40%):

• Recommended dosing:

  • Empagliflozin: 10 mg once daily
  • Dapagliflozin: 10 mg once daily 1

• Renal considerations:

  • For patients with eGFR ≥25 mL/min/1.73 m², standard dosing applies
  • Not recommended for initiation if eGFR <25 mL/min/1.73 m² 1

• Patient selection: Greatest benefit observed in NYHA class II-III patients with frequent symptoms or hospitalizations for heart failure 4

Monitoring and Precautions

• Before initiation: Assess renal function and volume status 1

• Common adverse effects to monitor:

  • Genital mycotic infections
  • Urinary tract infections
  • Volume depletion/hypotension
  • Euglycemic diabetic ketoacidosis (rare but serious) 5, 1

• Perioperative management: Withhold for at least 3 days before major surgery or procedures requiring prolonged fasting 1

Integration with Other HFpEF Therapies

SGLT2 inhibitors should be used as part of comprehensive heart failure management, which may include:

• Diuretics for symptom relief
• Blood pressure control with RAAS antagonists
• Mineralocorticoid receptor antagonists (MRAs)
• Evidence-based beta blockers 1

Important Clinical Considerations

• SGLT2 inhibitors represent a breakthrough in HFpEF management, which historically has had few evidence-based treatments 3, 6

• These medications should be continued indefinitely as part of heart failure management 1

• The benefits appear greatest in patients with LVEF between 41% and 65% 6

• Avoid thiazolidinediones in patients with symptomatic heart failure due to increased risk 5

• While metformin may be used in stable heart failure with adequate renal function, SGLT2 inhibitors have demonstrated superior outcomes specifically for heart failure endpoints 5

• Monitor for atypical presentation of diabetic ketoacidosis, particularly euglycemic ketoacidosis 5