What is the mechanism by which metformin (biguanide) causes lactic acidosis?

Mechanism of Metformin-Induced Lactic Acidosis

Metformin causes lactic acidosis primarily by inhibiting mitochondrial respiration in the liver, which decreases lactate clearance and increases lactate production, particularly in the setting of impaired renal function that leads to metformin accumulation. 1, 2

Primary Mechanisms

• Metformin inhibits mitochondrial respiration, particularly in the liver, which impairs oxidative phosphorylation and ATP production 2
• This mitochondrial impairment leads to:
  • Acceleration of glycolytic flux to compensate for reduced ATP production 3
  • Increased glucose uptake and subsequent lactate generation 3
  • Decreased lactate clearance by the liver 2
• Metformin is primarily excreted unchanged by the kidneys, so impaired renal function leads to drug accumulation and increased risk of lactic acidosis 1

Risk Factors for Metformin-Associated Lactic Acidosis (MALA)

• Renal impairment: Primary risk factor as metformin is eliminated by the kidneys; eGFR <30 mL/min/1.73m² is a contraindication 4, 1
• Conditions causing anaerobic metabolism:
  • Sepsis or severe infection 4, 5
  • Hypoxia 4
  • Shock or hemodynamic instability 6
• Impaired lactate clearance:
  • Liver failure or significant hepatic impairment 4, 7
  • Alcoholism 1
• Acute kidney injury which can rapidly decrease metformin clearance 6, 5
• Dehydration which can worsen renal function 5
• Concomitant medications that may impair renal function or interfere with acid-base balance 1

Clinical Presentation

• MALA typically presents with:
  • Nonspecific symptoms: malaise, myalgias, abdominal pain, respiratory distress, somnolence 1
  • In severe cases: hypotension and resistant bradyarrhythmias 1
  • Laboratory findings: elevated blood lactate (>5 mmol/L), anion gap acidosis, increased lactate:pyruvate ratio 1, 7
  • Metformin plasma levels generally >5 mcg/mL in cases of true MALA 1

Important Clinical Considerations

• Most cases of MALA occur in patients with at least one predisposing risk factor (97% of cases in one systematic review) 8
• The incidence of lactic acidosis in metformin users is very low (<10 cases per 100,000 patient-years) when appropriate precautions are taken 2
• MALA often occurs during acute illness when AKI develops in patients taking metformin 4
• Mortality from MALA can be significant (approaching 50% in some reports), highlighting the importance of prevention 2

Prevention Strategies

• Temporary discontinuation of metformin during:
  • Acute illness, especially with dehydration or infection 5
  • Procedures using iodinated contrast 1
  • Major surgery (for at least 48 hours) 6
• Appropriate dose adjustment based on renal function:
  • eGFR 30-44 mL/min/1.73m²: Reduce dose to maximum 1000 mg daily 4
  • eGFR <30 mL/min/1.73m²: Contraindicated 4, 1
• Regular monitoring of renal function:
  • At least annually in all patients taking metformin 1
  • Every 3-6 months if eGFR <60 mL/min/1.73m² 4, 6
• Patient education about "sick day rules" - temporarily stopping metformin during acute illness 6, 5

Treatment of MALA

• Immediate discontinuation of metformin 1, 7
• Supportive care in a hospital setting 1
• Prompt hemodialysis to correct acidosis and remove accumulated metformin (metformin is dialyzable) 1, 7
• Treatment of any underlying conditions contributing to lactic acidosis 7

Understanding the mechanism of metformin-induced lactic acidosis is crucial for appropriate prescribing practices and risk mitigation in patients with type 2 diabetes, particularly those with renal impairment or other risk factors for lactic acidosis.