What are the risks and management of lactic acidosis associated with Metformin (biguanide) use?

Metformin-Associated Lactic Acidosis: Risks and Management

Metformin-associated lactic acidosis (MALA) is a rare but potentially life-threatening complication with high mortality rates of 30-50% if not treated promptly. The risk of metformin-associated lactic acidosis increases significantly when eGFR falls below 30 mL/min/1.73 m², during acute kidney injury (AKI), or in situations that may cause hypoperfusion and hypoxemia. 1

Risk Factors for Metformin-Associated Lactic Acidosis

Renal Function

• eGFR < 30 mL/min/1.73 m²: Contraindicated for metformin use 1, 2
• eGFR 30-45 mL/min/1.73 m²: Increased risk; requires dose reduction to 1000 mg daily 2
• eGFR 45-60 mL/min/1.73 m²: Consider dose reduction in high-risk patients 2

Acute Clinical Situations

• Acute kidney injury 2
• Dehydration 2
• Administration of iodinated contrast agents 1
• Severe heart failure (LVEF < 30%) 2
• Serious intercurrent illness 2
• Surgical procedures 2

Medications That Increase Risk

• ACE inhibitors and ARBs 2
• Diuretics 2
• NSAIDs 2
• Medications that impair renal function or hemodynamics 1

Clinical Presentation of Lactic Acidosis

Metformin-associated lactic acidosis typically presents with:

• Subtle onset with nonspecific symptoms 1
• Malaise, myalgias, abdominal pain 1
• Respiratory distress, increased somnolence 1
• Hypotension and resistant bradyarrhythmias in severe cases 1
• Laboratory findings:
  • Elevated blood lactate (>5 mmol/L) 1
  • Anion gap acidosis without ketonuria/ketonemia 1
  • Increased lactate:pyruvate ratio 1
  • Metformin plasma levels generally >5 mcg/mL 1

Management of Metformin-Associated Lactic Acidosis

Immediate Actions

1. Discontinue metformin immediately 1
2. Provide supportive care in hospital setting 1
3. Initiate hemodialysis or continuous renal replacement therapy (CRRT) promptly 1, 3, 4
   • Hemodialysis corrects acidosis and removes accumulated metformin
   • Metformin is dialyzable with clearance up to 170 mL/min under good hemodynamic conditions
   • Prolonged dialysis may be necessary due to metformin's large volume of distribution 5

Special Considerations

• CRRT is particularly effective in hemodynamically unstable patients 4
• Rebound lactic acidosis may occur after initial dialysis due to metformin accumulation in erythrocytes and intestinal cells 5
• Multiple or prolonged dialysis sessions may be required (7-19 hours) 3
• Early and aggressive treatment with hemofiltration can improve outcomes even in severe acidosis 6

Prevention Strategies

1. Dose Adjustment Based on Renal Function:

   • eGFR ≥45 mL/min/1.73 m²: Standard dosing
   • eGFR 30-44 mL/min/1.73 m²: Reduce to 1000 mg daily 2
   • eGFR <30 mL/min/1.73 m²: Discontinue metformin 2, 1

2. Regular Monitoring:

   • Monitor eGFR at least annually in all patients on metformin 2
   • Increase monitoring to every 3-6 months when eGFR <60 mL/min/1.73 m² 2

3. Temporary Discontinuation ("Sick Day Rules"):

   • Stop metformin during:
     • Acute illness with risk of dehydration 2
     • Before and during surgical procedures 2
     • Before and 48 hours after iodinated contrast procedures 1
     • During episodes of vomiting or diarrhea 5

4. Patient Education:

   • Educate patients about symptoms of lactic acidosis 1
   • Instruct patients to discontinue metformin and seek medical care during illness 5
   • Emphasize importance of hydration and temporary medication cessation during illness

Despite concerns about lactic acidosis, evidence suggests the overall risk is low when metformin is appropriately prescribed with attention to renal function and temporary discontinuation during high-risk situations 2. With prompt recognition and appropriate management including dialysis, outcomes can be favorable even in severe cases 3, 6.