What are the side effects of metformin (biguanide oral hypoglycemic)

Side Effects of Metformin

Metformin commonly causes gastrointestinal side effects including bloating, abdominal discomfort, and diarrhea, which can be mitigated by gradual dose titration and taking with meals; it may also cause vitamin B12 deficiency with long-term use and rarely lactic acidosis in patients with severe renal impairment. 1, 2

Common Side Effects

Gastrointestinal Side Effects

• Diarrhea (occurs in up to 53% of patients) 2
• Nausea and vomiting (occurs in up to 26% of patients) 2
• Abdominal discomfort/bloating 1
• Flatulence (occurs in up to 12% of patients) 2
• Metallic taste (occurs in approximately 3% of patients) 2
• Reduced appetite 1

These gastrointestinal side effects:

• Are typically mild and transient 3
• Often occur during initial therapy and may improve over time 4
• Can be minimized by:
  • Starting with a low dose and gradually increasing 1
  • Taking metformin with meals 3
  • Using extended-release formulations which may reduce GI side effects compared to immediate-release 5

Vitamin B12 Deficiency

• Long-term metformin use is associated with vitamin B12 deficiency 1, 2
• May worsen symptoms of neuropathy 1
• Periodic testing of vitamin B12 levels is recommended for patients on long-term therapy 1

Rare but Serious Side Effects

Lactic Acidosis

• Very rare but potentially fatal complication 1, 2

• Risk factors include:

  • Advanced renal insufficiency (eGFR <30 mL/min/1.73 m²) 1, 2
  • Hypoperfusion or hypoxemia 1
  • Impaired hepatic function 1
  • Heart failure 1
  • Excessive alcohol consumption 2
  • Dehydration 2
  • Acute illness 1, 2

• Warning signs include: 2

  • Unexplained hyperventilation
  • Myalgias
  • Malaise
  • Unusual somnolence
  • Feeling cold (especially in arms and legs)
  • Dizziness or lightheadedness
  • Slow or irregular heartbeat

Special Considerations and Precautions

Temporary Discontinuation

Metformin should be temporarily discontinued: 1

• Before procedures using iodinated contrast
• During hospitalizations
• During acute illness that may compromise renal or liver function

Renal Function Monitoring

• Safe in patients with eGFR ≥30 mL/min/1.73 m² 1
• Lower doses may be used with eGFR 30-45 mL/min/1.73 m² 1
• Monitor eGFR every 3-6 months in those at risk for decline in kidney function 1
• Contraindicated in advanced renal insufficiency 1, 2

Other Precautions

• May cause hypoglycemia when combined with sulfonylureas or insulin 2
• May result in ovulation in some premenopausal anovulatory women, potentially leading to unintended pregnancy 2

Management of Side Effects

• For persistent GI side effects: 1
  • Reduce dose or eliminate metformin
  • Consider extended-release formulations 5
  • Consider probiotics (may reduce risk of diarrhea, bloating, and constipation) 6
• For vitamin B12 deficiency:
  • Monitor levels periodically 1
  • Supplement as needed

Key Advantages of Metformin Despite Side Effects

• Does not cause hypoglycemia when used as monotherapy 1, 3
• Weight neutral or may cause modest weight loss 1, 3
• Beneficial effects on cardiovascular mortality 1
• Beneficial effects on lipid profile 3

By understanding and proactively managing these side effects, patients can often continue to benefit from metformin's effectiveness in controlling blood glucose and its other favorable properties.