What are the considerations for using Metformin (biguanide) and Entresto (sacubitril/valsartan) together in patients with impaired renal function?

Using Metformin and Entresto in Patients with Impaired Renal Function

When using metformin and Entresto (sacubitril/valsartan) in patients with impaired renal function, metformin should be discontinued when eGFR falls below 30 mL/min/1.73 m², while Entresto requires careful monitoring and potential dose adjustment based on renal function. 1, 2

Metformin Use in Renal Impairment

eGFR-Based Recommendations:

• Metformin can be safely used with standard dosing in patients with eGFR ≥45 mL/min/1.73 m² 1, 3
• For eGFR 30-44 mL/min/1.73 m²:
  • Reduce metformin dose to 1000 mg daily 1
  • More frequent monitoring (every 3-6 months) is required 1, 3
  • Do not initiate metformin in patients with this level of renal function 2
• For eGFR <30 mL/min/1.73 m²:
  • Metformin is contraindicated 1, 2
  • Discontinue metformin completely 1, 2

Special Considerations:

• Temporarily discontinue metformin during:
  • Hospitalizations 1
  • Acute illness that may compromise renal function 1
  • Before procedures with iodinated contrast 2
  • Situations with risk of acute kidney injury 2
• Monitor for vitamin B12 deficiency with long-term use (>4 years) 1, 3

Entresto (Sacubitril/Valsartan) in Renal Impairment

Renal Considerations:

• As an inhibitor of the renin-angiotensin-aldosterone system (RAAS), Entresto may decrease renal function in susceptible individuals 4
• Closely monitor serum creatinine in patients on Entresto, especially those with:
  • Severe heart failure 4
  • Bilateral or unilateral renal artery stenosis 4
  • Pre-existing renal impairment 4
• Consider dose reduction or interruption if clinically significant decrease in renal function occurs 4

Monitoring Recommendations:

• Monitor serum potassium periodically as hyperkalemia may occur 4
• Risk of hyperkalemia increases with:
  • Severe renal impairment 4
  • Diabetes 4
  • Hypoaldosteronism 4
  • High potassium diet 4

Combined Use of Metformin and Entresto

Potential Interactions:

• No significant pharmacokinetic interaction has been reported between metformin and Entresto 5
• Both medications have individual considerations in renal impairment that must be addressed separately 1, 4

Management Strategy:

• For patients with eGFR ≥45 mL/min/1.73 m²:
  • Both medications can generally be used with standard dosing 1
  • Monitor renal function every 3-6 months 1, 3
• For patients with eGFR 30-44 mL/min/1.73 m²:
  • Reduce metformin to 1000 mg daily 1
  • Use Entresto with careful monitoring of renal function 4
  • Increase monitoring frequency to every 3 months 1, 3
• For patients with eGFR <30 mL/min/1.73 m²:
  • Discontinue metformin 1, 2
  • Consider alternative glucose-lowering agents such as SGLT2 inhibitors (if eGFR ≥20 mL/min/1.73 m²) or GLP-1 receptor agonists 1
  • Use Entresto with caution and close monitoring 4

Alternative Medications for Diabetes Management in Advanced CKD

• SGLT2 inhibitors are recommended for patients with T2D and CKD with eGFR ≥20 mL/min/1.73 m² 1
• GLP-1 receptor agonists are recommended when metformin and SGLT2i cannot be used 1
• DPP-4 inhibitors (especially linagliptin) have minimal renal elimination and can be used without dose adjustment in renal impairment 1
• Insulin therapy may be necessary but requires careful titration to avoid hypoglycemia in renal impairment 1

Pitfalls and Caveats

• The risk of lactic acidosis with metformin in mild-to-moderate renal impairment is often overestimated 6
• Abrupt discontinuation of either medication may lead to clinical deterioration 4
• Avoid starting both medications simultaneously in patients with unstable renal function 2, 4
• Entresto may cause symptomatic hypotension, particularly in volume-depleted patients 4
• Monitor for signs of angioedema with Entresto, especially in patients with prior history 4
• Temporary interruption of metformin may be needed during periods of dehydration or acute illness 1