Does Metformin affect kidney function?

Metformin's Effects on Kidney Function

Metformin is contraindicated in patients with eGFR <30 mL/min/1.73 m² due to increased risk of metformin accumulation and lactic acidosis, while it can be used with caution and dose adjustments in patients with eGFR 30-45 mL/min/1.73 m². 1, 2

Relationship Between Metformin and Kidney Function

Metformin is primarily eliminated by the kidneys, with renal clearance accounting for approximately 510 mL/min in patients with normal kidney function 3. As kidney function declines:

• Metformin clearance decreases proportionally to the reduction in GFR
• When GFR falls to 60 mL/min/1.73 m², metformin clearance decreases by approximately 75% 4
• Despite this reduction, serum metformin concentrations typically remain only about two-fold higher than in patients with normal kidney function 4

FDA and Clinical Guidelines for Metformin Use Based on Kidney Function

The FDA revised its guidance for metformin use in CKD in 2016, with the following recommendations 2:

1. Metformin is contraindicated in patients with eGFR <30 mL/min/1.73 m²
2. eGFR should be monitored while taking metformin
3. Benefits and risks should be reassessed when eGFR falls to <45 mL/min/1.73 m²
4. Metformin should not be initiated for patients with eGFR <45 mL/min/1.73 m²
5. Metformin should be temporarily discontinued before iodinated contrast imaging in patients with eGFR 30-60 mL/min/1.73 m²

Dose Adjustments Based on Kidney Function

For patients with reduced kidney function who can take metformin:

• eGFR 30-44 mL/min/1.73 m²: Reduce dose to 50% (e.g., 250 mg twice daily instead of 500 mg twice daily) 4
• More frequent monitoring (every 3-6 months) is recommended for those with moderate renal impairment 4

Risk of Lactic Acidosis

The primary concern with metformin use in kidney disease is the risk of lactic acidosis:

• Metformin-associated lactic acidosis is characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis, and increased lactate:pyruvate ratio 1
• Despite theoretical concerns, lactic acidosis remains exceedingly rare even in patients with moderate kidney impairment (eGFR 30-60 mL/min/1.73 m²) 4
• The Canadian Society of Nephrology noted that in a Cochrane meta-analysis of 347 studies, there was no case of lactic acidosis in either metformin patient-years or 55,451 non-metformin patient-years 2

Potential Impact of Metformin on Kidney Function Progression

Recent evidence suggests mixed effects of metformin on kidney function:

• A 2018 study found that continuous metformin treatment in patients with type 2 diabetes and moderate CKD was associated with a greater decline in eGFR compared to those who discontinued metformin (-1.32 vs. 0.75 mL/min/1.73 m²/year) 5
• However, a 2024 Cochrane review found that compared to placebo, metformin may result in a slightly smaller decline in kidney function (MD 1.92 mL/min, 95% CI 0.33 to 3.51) 6

Special Considerations and Precautions

1. Temporary discontinuation: Metformin should be stopped during:

   • Acute illness
   • Surgery
   • Situations that may lead to dehydration or acute kidney injury
   • Before iodinated contrast procedures 4, 1

2. Monitoring recommendations:

   • Regular assessment of kidney function
   • Monitor for vitamin B12 deficiency in patients on long-term therapy (>4 years) 4
   • Assess for symptoms of lactic acidosis (malaise, myalgias, abdominal pain, respiratory distress, increased somnolence) 1

Benefits of Metformin in Patients with Kidney Disease

Despite concerns, metformin offers significant benefits that may outweigh risks in appropriate patients:

• Cardiovascular protection and reduced mortality risk even in patients with mild-to-moderate kidney disease
• Weight neutrality or weight loss benefits
• Improvement in components of metabolic syndrome
• Low risk of hypoglycemia compared to other diabetes medications 4, 7

In conclusion, while metformin does affect kidney function and its clearance is reduced as kidney function declines, it can be used safely with appropriate monitoring and dose adjustments in patients with eGFR ≥30 mL/min/1.73 m². The decision to use metformin should balance its benefits against the potential risks, with absolute contraindication only in severe kidney disease.