What is the role of SGLT2 (sodium-glucose linked transporter 2) inhibitors in heart failure patients?

Role of SGLT2 Inhibitors in Heart Failure Patients

SGLT2 inhibitors are strongly recommended for all heart failure patients with reduced ejection fraction (HFrEF) to reduce the risk of worsening heart failure, hospitalization, and cardiovascular death, regardless of diabetes status. 1

Benefits in Different Heart Failure Populations

• SGLT2 inhibitors significantly reduce hospitalization for heart failure by 27-39% across multiple large clinical trials, demonstrating a consistent class effect 1
• For patients with heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%), SGLT2 inhibitors reduce:
  • Worsening heart failure events by 30% 2
  • Cardiovascular death by 18% 1
  • Hospitalization for heart failure by 30% 1
• Benefits are consistent regardless of diabetes status, with similar outcomes in patients with and without type 2 diabetes 1, 2
• In heart failure with preserved ejection fraction (HFpEF, LVEF >40%), empagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure by 21% in the EMPEROR-Preserved trial 1, 3

Evidence from Major Clinical Trials

• DAPA-HF trial showed dapagliflozin reduced the primary outcome of worsening heart failure or cardiovascular death by 26% (HR 0.74 [95% CI 0.65-0.85]) in patients with HFrEF, with consistent benefits regardless of diabetes status 1, 4
• EMPEROR-Reduced demonstrated empagliflozin reduced the primary composite outcome of cardiovascular death or hospitalization for worsening heart failure by 25% (HR 0.75 [95% CI 0.65-0.86]) in HFrEF patients 1, 5
• DELIVER trial showed dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 18% in patients with HFpEF 1
• SOLOIST-WHF trial demonstrated benefits even when initiated during or shortly after hospitalization for acute heart failure 1

Mechanisms of Benefit

• SGLT2 inhibitors promote natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced cardiac preload 6
• They reduce blood pressure, arterial stiffness, and afterload, improving subendocardial blood flow 6
• These agents preserve renal function, with slower annual decline in estimated glomerular filtration rate compared to placebo 1, 5
• Benefits appear to be independent of glucose-lowering effects, explaining efficacy in non-diabetic heart failure patients 2, 7

Clinical Implementation

• SGLT2 inhibitors should be initiated in all eligible patients with HFrEF (LVEF ≤40%) with NYHA class II-IV symptoms 1, 2
• For HFpEF (LVEF >40%), SGLT2 inhibitors are recommended for symptomatic patients (NYHA class II-IV) 1
• No dose adjustment or up-titration is required, unlike many other heart failure medications 2
• Benefits occur within weeks of initiation and are maintained regardless of age, sex, or background medical therapy 2

Important Considerations and Precautions

• Main contraindications include:
  • eGFR <20 mL/min/1.73m² 1, 2
  • Type 1 diabetes (due to risk of diabetic ketoacidosis) 1, 8
  • History of serious hypersensitivity to the medication 2
• Monitor for potential side effects:
  • Genital mycotic infections (1.5-1.7%) 2
  • Volume depletion and hypotension (5.7%), especially in patients taking diuretics 2, 8
  • Mild, transient decrease in eGFR that does not indicate kidney injury and should not prompt discontinuation 2

Comparison with Other Heart Failure Medications

• Unlike some other medications (e.g., thiazolidinediones), SGLT2 inhibitors reduce rather than increase heart failure risk 1
• DPP-4 inhibitors have mixed evidence regarding heart failure risk (saxagliptin may increase risk, while sitagliptin, alogliptin, and linagliptin appear neutral) 1
• GLP-1 receptor agonists have not shown increased risk of heart failure hospitalization but do not have the robust heart failure benefits seen with SGLT2 inhibitors 1

SGLT2 inhibitors represent a breakthrough in heart failure management, providing significant benefits across the spectrum of heart failure with a favorable safety profile, and should be incorporated into standard heart failure treatment regimens.