Is metformin safe for use in patients with a Creatinine Clearance (CrCl) of 23 ml/min?

Metformin Use in Patients with CrCl of 23 ml/min

Metformin should be discontinued in patients with a creatinine clearance of 23 ml/min due to increased risk of lactic acidosis. 1

Evidence-Based Rationale

The FDA label for metformin clearly states that it is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² 1. With a CrCl of 23 ml/min, this patient falls below this critical threshold, making metformin use unsafe.

Multiple guidelines support this recommendation:

• The FDA drug label explicitly states that metformin is contraindicated in patients with eGFR <30 mL/min/1.73 m² 1
• The Canadian Society of Nephrology commentary on KDIGO guidelines notes that metformin should be discontinued if creatinine exceeds 220 mmol/L (corresponding to GFR of ~23 mL/min/1.73 m²) 2
• The KDOQI Clinical Practice Guideline recommends stopping metformin when GFR is <30 mL/min/1.73 m² 2
• The European Society of Cardiology working group advises avoiding metformin if CrCl <30 mL/min due to risk of lactic acidosis 2

Mechanism of Risk

The primary concern with metformin use in advanced kidney disease is lactic acidosis, which although rare, can be fatal. Metformin is substantially excreted by the kidneys, and impaired renal function leads to:

• Accumulation of metformin in the blood
• Decreased lactate clearance
• Increased risk of lactic acidosis, particularly during acute illness

Safety Data in Advanced CKD

Research examining metformin in severe CKD (CrCl <30 ml/min) raises significant concerns:

• A large retrospective cohort study from Taiwan found that metformin use in patients with serum creatinine >530 μmol/L (approximately stage 5 CKD) was associated with a significantly increased risk of all-cause mortality compared to non-users (adjusted HR 1.35,95% CI 1.20-1.51) 3

Alternative Options

For patients with CrCl <30 ml/min, safer alternative diabetes medications include:

• GLP-1 receptor agonists with proven cardiovascular benefit
• DPP-4 inhibitors (with appropriate dose adjustments)
• Insulin therapy 4

Important Considerations

• If the patient has been on metformin, it should be discontinued immediately
• Monitor for signs of lactic acidosis (malaise, myalgias, abdominal pain, respiratory distress, somnolence)
• If metformin-associated lactic acidosis is suspected, prompt hemodialysis is recommended 1
• Educate patients about the symptoms of lactic acidosis and instruct them to report these symptoms immediately

Common Pitfalls to Avoid

1. Relying solely on serum creatinine: Using eGFR or CrCl provides a more accurate assessment of renal function than serum creatinine alone 5

2. Continuing metformin during acute illness: Metformin should be temporarily discontinued during conditions that may cause dehydration or hypoxemia (surgery, severe illness, etc.) 1

3. Ignoring the risk of lactic acidosis: While some studies suggest the risk is low 6, 7, 8, the potential severity of this complication warrants caution, especially in patients with advanced CKD

In conclusion, with a CrCl of 23 ml/min, metformin is contraindicated and should be discontinued, with alternative diabetes medications considered based on the patient's specific needs and comorbidities.