What are the potential side effects of metformin (biguanide)?

Metformin Side Effects: Clinical Considerations

Metformin commonly causes gastrointestinal side effects and rarely can lead to serious complications such as lactic acidosis, particularly in patients with renal insufficiency, requiring careful monitoring and appropriate patient selection. 1, 2

Common Side Effects

Gastrointestinal Effects

• Diarrhea: Affects approximately 53% of patients (vs. 12% with placebo) 2
• Nausea/Vomiting: Occurs in about 26% of patients (vs. 8% with placebo) 2
• Flatulence: Reported by 12% of patients (vs. 6% with placebo) 2
• Abdominal discomfort: Affects 6% of patients (vs. 5% with placebo) 2
• Indigestion: Occurs in 7% of patients (vs. 4% with placebo) 2

Other Common Side Effects

• Metallic taste: Approximately 3% of patients experience this when starting metformin 2
• Asthenia (weakness): Reported in 9% of patients (vs. 6% with placebo) 2
• Headache: Occurs in 6% of patients (vs. 5% with placebo) 2

Serious Side Effects

Lactic Acidosis

• Risk factors: 1, 2

  • eGFR <30 mL/min/1.73 m² (contraindicated)
  • Hypoperfusion or hypoxemia
  • Impaired hepatic function
  • Heart failure
  • Alcohol abuse
  • Acute illness with dehydration
  • Use of iodinated contrast agents

• Warning signs: 2

  • Cold extremities
  • Dizziness/lightheadedness
  • Slow/irregular heartbeat
  • Severe weakness/fatigue
  • Breathing difficulties
  • Drowsiness
  • Stomach pain, nausea, vomiting

Vitamin B12 Deficiency

• Long-term metformin use can lead to vitamin B12 deficiency 1, 3
• Regular monitoring of B12 levels is recommended for patients on long-term therapy
• May contribute to or worsen peripheral neuropathy symptoms 3

Management of Side Effects

Gastrointestinal Side Effects

• Gradual dose titration: Start with low doses and gradually increase to minimize GI side effects 1, 3
• Extended-release formulation: May reduce GI side effects compared to immediate-release 4
• Administration with meals: Can help reduce GI intolerance 2
• Dose reduction or discontinuation: Consider if GI side effects persist despite mitigation strategies 1

Prevention of Lactic Acidosis

• Regular monitoring of renal function: Every 3-6 months in at-risk patients 1
• Temporary discontinuation during:
  • Procedures using iodinated contrast
  • Hospitalizations
  • Acute illness that may compromise renal or liver function 1
• Avoid use in patients with:
  • Advanced renal insufficiency (eGFR <30 mL/min/1.73 m²)
  • Severe hepatic impairment
  • Conditions causing tissue hypoxia 1, 2

Special Considerations

Dosing in Renal Impairment

• eGFR ≥30 mL/min/1.73 m²: Safe to use metformin 1
• eGFR 30-45 mL/min/1.73 m²: Use lower doses with careful monitoring 1
• eGFR <30 mL/min/1.73 m²: Contraindicated 1

Alcohol Interaction

• Excessive alcohol intake increases the risk of lactic acidosis 2
• Patients should be advised against binge drinking or regular heavy alcohol consumption

Clinical Pearls and Pitfalls

• Misdiagnosis of GI side effects: Chronic diarrhea from metformin may be misdiagnosed as irritable bowel syndrome 5
• Temporary discontinuation: Always discontinue metformin before procedures with contrast agents to prevent lactic acidosis 1, 2
• Monitoring B12: Long-term metformin users should have vitamin B12 levels checked periodically 1, 3
• Gradual initiation: Starting with low doses and gradually increasing can significantly improve GI tolerability 1, 3
• Extended-release formulation: Consider switching patients with GI intolerance from immediate-release to extended-release metformin before discontinuing the medication altogether 4

By understanding these side effects and implementing appropriate monitoring and management strategies, the risk-benefit profile of metformin can be optimized for patients with type 2 diabetes.