What are the common side effects of metformin (biguanide) in patients with type 2 diabetes?

Common Side Effects of Metformin in Type 2 Diabetes

The principal side effects of metformin are gastrointestinal intolerance including bloating, abdominal discomfort, and diarrhea, which can be mitigated by gradual dose titration and using extended-release formulations. 1

Primary Side Effects

Gastrointestinal Effects

• Diarrhea (affects approximately 53% of patients) 2
• Nausea/vomiting (affects approximately 26% of patients) 2
• Abdominal discomfort/bloating 1
• Flatulence (affects approximately 12% of patients) 2
• Indigestion (affects approximately 7% of patients) 2

These GI side effects are typically:

• Most prominent when initiating therapy
• Often transient, improving over time with continued use
• Reduced when taken with meals 2
• Minimized by starting at a low dose (500 mg once or twice daily) and gradually titrating to the effective dose 1
• Less severe with extended-release formulations compared to immediate-release 3

Other Common Side Effects

• Metallic taste (affects approximately 3% of patients) - typically short-lived 2
• Vitamin B12 deficiency with long-term use - may worsen symptoms of neuropathy 1
• Asthenia (weakness) (affects approximately 9% of patients) 2
• Headache (affects approximately 6% of patients) 2

Serious but Rare Side Effects

Lactic Acidosis

• Very rare but serious complication (less than one case per 100,000 treated patients) 4
• Risk factors include:
  • Severe renal impairment (eGFR <30 mL/min/1.73 m²)
  • Acute kidney injury
  • Overdose
  • Excessive alcohol consumption 2
  • Dehydration from illness with fever, vomiting, or diarrhea 2

Monitoring Recommendations

1. Renal Function:

   • Metformin can be safely used with eGFR ≥30 mL/min/1.73 m² 1
   • Monitor eGFR every 3-6 months in those at risk for declining kidney function 5
   • For patients with eGFR 30-45 mL/min/1.73 m², there's increased risk for periodic decreases of eGFR to ≤30 mL/min/1.73 m² 1

2. Vitamin B12 Levels:

   • Periodic testing of vitamin B12 levels is recommended 1
   • Especially important for patients with anemia or peripheral neuropathy 1

3. Hypoglycemia:

   • Metformin rarely causes hypoglycemia when used as monotherapy 2
   • Risk increases when combined with insulin secretagogues or exogenous insulin 2

Mitigation Strategies

1. For GI Side Effects:

   • Start with low dose (500 mg once or twice daily with food) 1
   • Gradually increase dose over 1-2 weeks 5
   • Consider extended-release formulation for better GI tolerability 3
   • Take with meals to reduce GI symptoms 2

2. For Vitamin B12 Deficiency:

   • Monitor B12 levels periodically, especially in patients with anemia or neuropathy 1
   • Supplement B12 if deficiency is detected

3. To Prevent Lactic Acidosis:

   • Temporarily discontinue metformin during acute illness that may compromise renal function 5
   • Avoid excessive alcohol consumption 2
   • Ensure adequate hydration during illness or exercise 2

Special Considerations

• Despite side effects, metformin remains the preferred first-line agent for type 2 diabetes due to its effectiveness, safety profile, and cardiovascular benefits 1
• Unlike sulfonylureas, metformin does not cause weight gain and has a low risk of hypoglycemia when used as monotherapy 6
• Metformin has beneficial effects on lipid profiles, reducing LDL cholesterol and triglycerides 6, 7

By understanding and anticipating these side effects, appropriate monitoring and mitigation strategies can be implemented to maximize the benefits of metformin therapy while minimizing adverse effects.