What is the role of SGLT2 (sodium-glucose cotransporter 2) inhibitors in patients with mid-range ejection fraction (EF) heart failure?

SGLT2 Inhibitors in Mid-Range Ejection Fraction Heart Failure

SGLT2 inhibitors are strongly recommended for patients with heart failure with mid-range ejection fraction (HFmrEF, LVEF 41-49%) to reduce hospitalizations for heart failure and cardiovascular mortality, regardless of diabetes status. 1

Definition and Classification

• HFmrEF refers to heart failure with left ventricular ejection fraction between 41-49%, representing a distinct clinical entity between HFrEF (≤40%) and HFpEF (≥50%) 1
• This classification is important as treatment approaches may differ based on ejection fraction categories 1

Evidence Supporting SGLT2 Inhibitors in HFmrEF

Clinical Trial Evidence

• The EMPEROR-Preserved trial demonstrated that empagliflozin significantly reduced the primary composite endpoint of cardiovascular death or hospitalization for heart failure by 21% in patients with LVEF >40% 1, 2
• In a subgroup analysis of 1,983 patients with LVEF 41-49% from EMPEROR-Preserved, empagliflozin reduced the risk of the primary composite endpoint without significant interaction by LVEF subgroups 1
• The benefit of SGLT2 inhibitors appears consistent regardless of diabetes status, making them appropriate for all HFmrEF patients 1
• Patients with LVEF on the lower end of the HFmrEF spectrum (closer to 41%) appear to respond more similarly to HFrEF patients 1

Guideline Recommendations

• The 2022 AHA/ACC/HFSA guideline gives a Class 2a recommendation (Level of Evidence: B-R) for SGLT2 inhibitors in patients with HFmrEF to decrease HF hospitalizations and cardiovascular mortality 1
• The 2024 AHA/ACC performance measures specifically include SGLT2 inhibitor therapy for patients with HF with LVEF >40% (which includes HFmrEF) as a quality measure 1
• Current guidelines suggest SGLT2 inhibitors should be used across the spectrum of heart failure, including HFmrEF, with or without diabetes 3

Specific SGLT2 Inhibitors with Evidence in HFmrEF

• Empagliflozin 10mg daily has been specifically studied in the HFmrEF population through the EMPEROR-Preserved trial 1
• Dapagliflozin 10mg daily has shown benefits in heart failure patients across the ejection fraction spectrum 1, 4
• The benefits seen likely represent a class effect of SGLT2 inhibitors rather than being specific to a particular agent 1, 5

Additional Treatment Considerations for HFmrEF

• Beyond SGLT2 inhibitors, other evidence-based therapies may be considered for HFmrEF patients (Class 2b recommendation), including:
  • Evidence-based beta blockers (those proven effective in HFrEF) 1
  • ARNIs, ACEIs, or ARBs 1
  • Mineralocorticoid receptor antagonists (MRAs) 1
• Diuretics should be used as needed for symptom relief in patients with fluid overload 1

Implementation in Clinical Practice

• SGLT2 inhibitors should be initiated regardless of the need for additional glucose lowering and independent of metformin use 1
• These medications can be initiated during hospitalization or in the outpatient setting 1
• For patients with existing diabetes medications, SGLT2 inhibitors may need to replace some existing medications to minimize hypoglycemia risk 1
• Monitoring renal function is important, though benefits have been observed across a wide range of renal function 3

Potential Mechanisms of Benefit in HFmrEF

• SGLT2 inhibitors provide multiple beneficial effects beyond glycosuria, including:
  • Improved ventricular loading conditions through diuresis and natriuresis 4
  • Enhanced vascular and renal function 4
  • Reduced myocardial passive stiffness (improved diastolic function) 4
  • Anti-inflammatory effects and reduction of fibrosis 4
  • Improvement of myocardial metabolism and mitochondrial function 4

Common Pitfalls and Caveats

• Despite strong evidence and guideline recommendations, SGLT2 inhibitors remain underutilized in heart failure patients 1, 3
• Therapeutic inertia is a significant barrier to implementation in clinical practice 3
• Insurance coverage may be limited for patients without diabetes, despite clear evidence of benefit 6
• Clinicians should be aware of potential adverse effects, including genital mycotic infections, volume depletion, and rare cases of diabetic ketoacidosis 1

SGLT2 inhibitors represent a breakthrough in HFmrEF management, offering significant benefits regardless of diabetes status. Their implementation should be prioritized in eligible patients to improve outcomes in this challenging patient population.