SGLT2 Inhibitors in Cardiac Amyloidosis

SGLT2 Inhibitors in Cardiac Amyloidosis: Emerging Benefits and Tolerability

1. Introduction

Cardiac amyloidosis (CA) is a restrictive cardiomyopathy due to amyloid protein deposition within the heart, resulting in diastolic dysfunction, arrhythmias, and progressive heart failure.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially created to treat type 2 diabetes, have also become a novel therapy in heart failure, including CA. Early experience and studies indicate that SGLT2i are safe in CA, with favorable effects on cardiac function, fluid status, and symptoms.

This article reviews the role, mechanisms, clinical evidence, patient selection, and safety concerns of SGLT2 inhibitors in CA.

2. Mechanism of SGLT2 Inhibitors in Cardiac Amyloidosis

SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) have most of their action in the kidneys to:

• Block glucose reabsorption, inducing glycosuria
• Cause mild natriuresis, alleviating fluid overload
• Reduce preload and afterload, enhancing ventricular filling
  Further cardiac effects pertinent in CA:
• Decrease in interstitial volume, alleviating congestion
• Enhanced myocardial energy metabolism
• Potential decrease in fibrosis and inflammation
  Implications for CA:
• Beneficial in the management of HFpEF and HFrEF phenotypes
• Generally well tolerated even with mild hypotension or renal involvement

3. Clinical Evidence and Emerging Data

3.1 Tolerability

• SGLT2i are generally well tolerated as reported in CA patients
• Low symptomatic hypotension compared to ACEIs, ARBs, or beta-blockers
• Infrequently causes volume depletion or renal impairment when closely monitored

3.2 Efficacy

• Initial trials demonstrate improvements in:
• Exercise capacity
• Diuretic-sparing effects
• Symptom burden (NYHA class)
• Potential benefit in cardiac biomarkers (NT-proBNP, troponin)

3.3 Real-World Experience

• Application in AL and ATTR amyloidosis demonstrates feasibility
• Benefits seem irrespective of diabetic status
• Combination therapy with low-dose diuretics or disease-specific therapy is safe

4. Patient Selection

Ideal subjects for SGLT2i in CA:

• NYHA class II–III heart failure symptoms
• Stable renal function (eGFR > 30 mL/min/1.73 m²)
• HFpEF or HFrEF phenotype
• Not markedly hypotensive at baseline
  Caution:
• Advanced hypotension
• Severe volume depletion
• AKI or eGFR <30 mL/min/1.73 m²

5. Practical Considerations

5.1 Dosing and Initiation

• Initiate at low standard doses (e.g., dapagliflozin 10 mg daily, empagliflozin 10 mg daily)
• Check blood pressure, renal function, and electrolytes within 1–2 weeks

5.2 Combination Therapy

• Compatible with:
• Low-dose diuretics
• Disease-specific therapy (chemotherapy, tafamidis, RNA therapies)
• Other tolerated GDMT medications

5.3 Monitoring

• BP, renal function, and electrolytes
• Volume status to avoid dehydration
• Symptoms: dizziness, fatigue, hypotension

6. Supportive Benefits Beyond Heart Failure

There are additional benefits of SGLT2i for cardiovascular associated patients.

• Mild weight loss through fluid loss
• Glycemic control improved in diabetic patients
• Renal protection potential
• Hospitalization for heart failure reduced in new studies

7. Multidisciplinary Approach

Ideal management of CA patients on SGLT2i includes:

• Cardiology → observe cardiac condition, modify doses
• Nephrology → observe renal function
• Hematology → coordinate with AL amyloidosis treatment
• Nutrition and Palliative Care → manage diet, hydration, and symptoms
  Benefits:
• Ensures safety, efficacy, and improved quality of life
• Early detection of side effects
• Integration with other heart failure treatments

8. Potential Adverse Effects and Safety

• Volume depletion → dizziness, hypotension
• Genitourinary infections → rare, predominantly mild
• Renal function changes → typically mild and reversible
• Electrolyte disturbances → monitor potassium, sodium
  Mitigation:
• Ensure adequate hydration
• Limit excessive loop diuretics
• Regular monitoring of labs

9. Emerging Research Directions

• Large-scale trials in CA populations to validate efficacy and safety
• Mechanistic research on cardiac fibrosis reduction
• Combination therapy with disease-modifying agents
• Digital health solutions for real-time monitoring of BP and fluid status

10. Prognosis and Outcomes

• SGLT2i seem safe and beneficial in CA
• Early initiation potentially decreases heart failure hospitalizations
• Facilitates multidisciplinary care and quality of life
• Can facilitate greater tolerance of other heart failure drugs

11. Case Example (Optional)

A 65-year-old patient with ATTR cardiac amyloidosis:

• NYHA class II symptoms, mild hypotension
• Started on dapagliflozin 10 mg daily
• Weekly BP and renal function monitoring
• Result: Enhanced exercise tolerance, decreased edema, no notable hypotension
• Added to tafamidis therapy and low-dose loop diuretics

12. Conclusion

SGLT2 inhibitors are a hopeful treatment of heart failure in cardiac amyloidosis:

Main Take-Aways:

• Tolerated well by most CA patients
• Benefit in fluid balance, symptom decrease, and potentially cardiac function
• Safe with judicious monitoring and multidisciplinary coordination
• Ability to add to other heart failure and disease-specific therapies