How is Entresto (sacubitril and valsartan) used in patients with diabetes?

Entresto (Sacubitril/Valsartan) in Patients with Diabetes

Entresto (sacubitril/valsartan) is recommended for patients with diabetes and heart failure with reduced ejection fraction (HFrEF) to reduce cardiovascular mortality and hospitalization, with evidence showing it may offer additional benefits for glycemic control and renal protection compared to ACE inhibitors or ARBs alone. 1

Benefits in Diabetic Patients with Heart Failure

• Entresto reduces cardiovascular mortality by 20% compared to enalapril in patients with HFrEF, including those with diabetes 1
• In diabetic patients with HFrEF, Entresto demonstrates:
  • Similar rates of dose uptitration and tolerability as in non-diabetic patients 2
  • Improved glycemic control with reduction in HbA1c, fasting glucose, and insulin levels 3
  • Potential reduction in oral antidiabetic medication and insulin requirements over time 3

Renal Considerations in Diabetes

• Diabetes is associated with faster renal function decline in heart failure patients 4
• Entresto attenuates eGFR decline in patients with HFpEF, with similar benefits in both diabetic and non-diabetic patients 4
• The renal composite outcome (eGFR reduction ≥50%, end-stage renal disease, or death from renal causes) is reduced with Entresto compared to valsartan alone in both diabetic and non-diabetic patients 4

Combination with SGLT2 Inhibitors

• Co-administration of Entresto and empagliflozin appears safe in terms of renal function in patients with HFrEF and diabetes 5
• SGLT2 inhibitors are recommended to lower the risk of heart failure hospitalization in patients with diabetes 6
• The combination may provide complementary cardiorenal protection through different mechanisms 6

Dosing and Monitoring in Diabetes

• Target dose is 97/103 mg twice daily, with careful monitoring for side effects 1
• In patients with diabetes and moderate chronic kidney disease (CKD), initiate RAAS inhibitors (including Entresto) at a low dose and titrate gradually with careful monitoring of renal function and serum potassium 6
• Contraindications include:
  • Hypersensitivity to any component
  • History of angioedema related to previous ACE inhibitor or ARB therapy
  • Concomitant use of ACE inhibitors (do not administer within 36 hours)
  • Concomitant use of aliskiren in patients with diabetes 7

Hyperkalemia Risk Management

• Patients with diabetes and HFrEF have increased risk of hyperkalemia with RAAS inhibitors 6
• Entresto may have slightly lower rates of hyperkalemia than ACE inhibitors, particularly during concomitant treatment with mineralocorticoid receptor antagonists (MRAs) 6
• Monitoring recommendations:
  • Regular assessment of serum potassium levels
  • Educate patients to avoid over-the-counter potassium supplements and potassium-based salt substitutes
  • Limit intake of high-potassium food and beverages
  • Avoid medications that may increase risk for hyperkalemia (such as NSAIDs) 6

Clinical Algorithm for Entresto Use in Diabetic Patients

1. Assess eligibility:

   • Confirm HFrEF diagnosis (LVEF ≤40%)
   • Check for contraindications (severe renal impairment with eGFR <30 mL/min/1.73m², systolic BP <100 mmHg)
   • Ensure no concurrent use of ACE inhibitors or aliskiren

2. Initiation strategy:

   • Start at lower dose (24/26 mg or 49/51 mg twice daily) in patients with diabetes and CKD
   • Ensure 36-hour washout if switching from ACE inhibitor
   • Monitor blood pressure, renal function, and potassium levels closely

3. Uptitration approach:

   • Gradually increase to target dose of 97/103 mg twice daily as tolerated
   • Assess for hypotension, hyperkalemia, and changes in renal function at each dose increase
   • Consider slower uptitration in patients with more advanced CKD

4. Ongoing monitoring:

   • Regular assessment of renal function and electrolytes
   • Monitor glycemic control as Entresto may improve insulin sensitivity 3
   • Evaluate for potential reduction in antidiabetic medication requirements

Potential Pitfalls and Caveats

• Temporary worsening of renal function may occur initially but doesn't necessarily indicate true tubular injury 6
• Hyperkalemia risk is amplified by both diabetes and CKD, requiring vigilant monitoring 6
• Triple combination of ACE inhibitor, ARB, and MRA is discouraged due to excessive hyperkalemia risk 6
• Patients with severe renal dysfunction (eGFR <30 mL/min/1.73m²) were excluded from major trials, so use with caution in this population 6

By following this structured approach, Entresto can be safely and effectively used in patients with diabetes and heart failure, potentially offering benefits beyond standard RAAS inhibition.