Why should metformin be stopped in patients with an estimated Glomerular Filtration Rate (eGFR) less than 30?

Metformin Should Be Stopped When eGFR is Less Than 30 mL/min/1.73m² Due to Risk of Lactic Acidosis

Metformin must be discontinued when eGFR falls below 30 mL/min/1.73m² due to increased risk of metformin-associated lactic acidosis (MALA), as the drug accumulates in the body when kidney function is severely impaired. 1

Mechanism of Risk

• Metformin is substantially excreted by the kidneys, and impaired renal function leads to drug accumulation 1
• When eGFR falls below 30 mL/min/1.73m², the clearance of metformin is significantly reduced, increasing plasma concentrations 2
• Metformin decreases liver uptake of lactate, which increases blood lactate levels - this effect becomes dangerous when the drug accumulates 1
• Patients with severe renal impairment show a 1.97-fold increased risk of acidosis (95% CI 1.03-3.77) compared to those with better kidney function 3

Clinical Presentation of Metformin-Associated Lactic Acidosis

• MALA presents with elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis, and increased lactate:pyruvate ratio 1
• Initial symptoms may be subtle and nonspecific: malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence 1
• In severe cases, hypotension and resistant bradyarrhythmias can occur 1
• MALA can be fatal if not promptly recognized and treated 4

Guideline Recommendations

• The FDA explicitly contraindicates metformin in patients with an eGFR less than 30 mL/min/1.73m² 1
• KDIGO guidelines (2020) recommend stopping metformin when eGFR falls below 30 mL/min/1.73m² 2
• The Lancet Diabetes and Endocrinology (2021) states metformin should be discontinued if eGFR is less than 30 mL/min/1.73m² 2
• The American Diabetes Association supports discontinuing metformin when eGFR falls below 30 mL/min/1.73m² 2

Monitoring and Management Recommendations

• For patients with eGFR between 30-44 mL/min/1.73m², metformin dose should be reduced to half the maximum dose (1000 mg daily) 2, 5
• eGFR should be monitored every 3-6 months in patients with reduced kidney function 2
• Temporary discontinuation is also recommended during:
  • Acute illness that may affect kidney function 5, 4
  • Procedures involving iodinated contrast agents 1
  • Conditions with hypoxia, sepsis, or liver failure 2, 1
  • Situations of dehydration or volume depletion 1, 4

Risk Factors That Compound the Danger

• Advanced age (>65 years) increases risk due to greater likelihood of hepatic, renal, or cardiac impairment 1
• Concomitant use of medications that impair renal function or increase metformin accumulation 1
• Hypoxic states such as congestive heart failure, cardiovascular collapse, or sepsis 1
• Excessive alcohol intake potentiates metformin's effect on lactate metabolism 1
• Hepatic impairment impairs lactate clearance, further increasing risk 1

Alternative Medications for Patients with eGFR <30 mL/min/1.73m²

• For patients with severe renal impairment, other antidiabetic medications should be considered 2
• DPP-4 inhibitors (particularly linagliptin) may be used as alternatives in patients with low GFR 2
• Insulin remains an option for glycemic control in patients with severe renal impairment 2

While metformin is highly effective and the first-line medication for type 2 diabetes, the risk of MALA becomes unacceptably high when kidney function is severely impaired. The evidence clearly supports discontinuing metformin when eGFR falls below 30 mL/min/1.73m² to prevent this potentially life-threatening complication.