What are the common side effects of Metformin (biguanide) and how are they managed in patients with type 2 diabetes?

Common Side Effects of Metformin and Their Management in Type 2 Diabetes

Metformin's primary side effects are gastrointestinal intolerance including bloating, abdominal discomfort, and diarrhea, which can be mitigated by gradual dose titration and using extended-release formulations. 1, 2

Main Side Effects

Gastrointestinal Side Effects

• Diarrhea (occurs in approximately 53% of patients vs 12% with placebo) 2
• Nausea/vomiting (occurs in approximately 26% of patients vs 8% with placebo) 2
• Abdominal discomfort and bloating 1
• Flatulence (occurs in approximately 12% of patients vs 6% with placebo) 2
• Indigestion (occurs in approximately 7% of patients vs 4% with placebo) 2

Other Common Side Effects

• Metallic taste (occurs in approximately 3% of patients when starting the medication) 2
• Vitamin B12 deficiency with long-term use 1
• Asthenia (weakness, occurs in approximately 9% of patients vs 6% with placebo) 2
• Headache (occurs in approximately 6% of patients vs 5% with placebo) 2

Management of Side Effects

Gastrointestinal Side Effects

• Start with a low dose and gradually titrate to reduce adverse reactions 1
• Use extended-release formulations which improve GI tolerability 1, 3
• Take medication with meals to help reduce these side effects 2
• Most GI side effects are transient and generally resolve after taking the medicine for a while 2

Vitamin B12 Deficiency

• Periodic testing of vitamin B12 levels is recommended, especially in patients with anemia or peripheral neuropathy 1
• Supplementation may be necessary if deficiency is detected 1

Hypoglycemia Management

• Metformin rarely causes hypoglycemia when used as monotherapy 1, 2
• Hypoglycemia risk increases when combined with insulin or insulin secretagogues 1, 2
• Follow healthcare provider's instructions for treating hypoglycemia if it occurs 2

Special Precautions

Lactic Acidosis

• A rare but serious complication (very rare occurrence) 1, 2
• Higher risk in patients with:
  • Severe kidney problems (eGFR <30 mL/min/1.73 m²) 1
  • Liver problems 2
  • Excessive alcohol consumption 2
  • Dehydration (from fever, vomiting, diarrhea, or excessive sweating) 2
  • Acute conditions like surgery, heart attack, severe infection 2

Renal Function Monitoring

• Safe to use in patients with eGFR ≥30 mL/min/1.73 m² 1
• Increased risk of lactic acidosis when eGFR falls below 30 mL/min/1.73 m² 1
• For patients with eGFR 30-45 mL/min/1.73 m², monitor renal function more closely 1

Algorithmic Approach to Managing Metformin Side Effects

1. For GI side effects (most common):

   • Start with low dose (500 mg once or twice daily with food) 1
   • Gradually increase dose over 2-4 weeks 1
   • If persistent, switch to extended-release formulation 3
   • If still intolerable, consider alternative medication 1

2. For vitamin B12 deficiency:

   • Monitor B12 levels periodically, especially in patients on long-term therapy 1
   • If deficient, supplement with vitamin B12 while continuing metformin 1

3. For patients at risk of lactic acidosis:

   • Temporarily discontinue metformin during acute illness, surgery, or procedures with iodinated contrast 1
   • Advise patients to stop taking metformin and seek medical attention if experiencing symptoms of lactic acidosis (unexplained hyperventilation, myalgia, malaise, unusual somnolence) 2

4. For patients with renal impairment:

   • Regular monitoring of renal function 1
   • Adjust dose or discontinue based on eGFR values 1

Clinical Pearls and Caveats

• Despite concerns, the occurrence of lactic acidosis with metformin is now known to be very rare 1
• Metformin does not cause weight gain, which is an advantage over many other diabetes medications 1, 4
• Patients should be advised to avoid excessive alcohol consumption while taking metformin 2
• Metformin may have cardiovascular benefits beyond glucose control 5, 6
• Metformin is weight-neutral or may cause modest weight loss, making it particularly suitable for overweight patients with type 2 diabetes 6, 4

By following these management strategies, most patients can successfully continue metformin therapy and benefit from its glucose-lowering effects while minimizing side effects.