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

Side Effects of Metformin

Metformin commonly causes gastrointestinal side effects including diarrhea, nausea, vomiting, abdominal discomfort, and metallic taste, while its most serious but rare adverse effect is lactic acidosis, which can occur in patients with renal insufficiency, liver disease, or other conditions that predispose to hypoperfusion or hypoxemia. 1, 2

Common Side Effects

Gastrointestinal Effects

• Diarrhea: Affects approximately 30-53% of patients 2, 3
• Nausea/Vomiting: Occurs in about 11-26% of patients 2, 3
• Abdominal discomfort/bloating: Reported in 6-8% of patients 2
• Flatulence: Affects about 12% of patients 2
• Metallic taste (dysgeusia): Occurs in approximately 3-7% of patients, usually transient 2, 4
• Decreased appetite: Reported in about 11% of patients 3

These gastrointestinal side effects:

• Are typically most pronounced during initiation of therapy
• Often improve with time as the body adjusts to the medication
• Can be minimized by:
  • Starting with a low dose (500mg daily) and gradually increasing by 500mg every 1-2 weeks 5
  • Taking medication with meals 2
  • Using extended-release formulations, which may reduce GI side effects compared to immediate-release 6

Vitamin B12 Deficiency

• Long-term metformin use can lead to vitamin B12 deficiency 1, 2
• Regular monitoring of vitamin B12 levels is recommended, especially in:
  • Patients on long-term therapy
  • Patients with anemia
  • Patients with peripheral neuropathy 5

Serious Side Effects

Lactic Acidosis

• A rare but potentially fatal complication 2
• Risk factors include:
  • Renal insufficiency (eGFR <30 mL/min/1.73m²)
  • Liver disease
  • Heart failure
  • Hypoperfusion states
  • Hypoxemic conditions
  • Excessive alcohol consumption
  • Dehydration 1, 2

Warning signs of lactic acidosis include:

• Feeling very weak or tired
• Unusual muscle pain
• Difficulty breathing
• Unusual sleepiness
• Stomach discomfort with nausea, vomiting, or diarrhea
• Feeling cold (especially in arms and legs)
• Dizziness or lightheadedness
• Slow or irregular heartbeat 2

Hypoglycemia

• Metformin rarely causes hypoglycemia when used as monotherapy 2
• Risk increases when combined with:
  • Sulfonylureas
  • Insulin
  • Alcohol consumption 2

Special Considerations

Renal Function

• Metformin is safe in patients with eGFR ≥30 mL/min/1.73m² 1
• Lower doses should be used in patients with eGFR 30-45 mL/min/1.73m² 1
• Contraindicated in patients with eGFR <30 mL/min/1.73m² 1
• eGFR should be monitored every 3-6 months in at-risk patients 1

Temporary Discontinuation

Metformin should be temporarily discontinued:

• Before procedures using iodinated contrast
• During hospitalizations
• During acute illness that may compromise renal or liver function 1

Reproductive Effects

• May result in ovulation in some premenopausal anovulatory women
• Can increase the risk of unplanned pregnancy 2

Management of Side Effects

1. For GI side effects:

   • Slow dose titration (start low, go slow)
   • Take with meals
   • Consider extended-release formulation
   • If persistent, dose reduction or discontinuation may be necessary 1

2. For vitamin B12 deficiency:

   • Monitor levels periodically
   • Supplement if deficient 1

3. For lactic acidosis:

   • Immediate discontinuation of metformin
   • Prompt medical attention/hospitalization 2

Pitfalls to Avoid

• Ignoring renal function: Always check eGFR before prescribing and periodically during treatment
• Failing to temporarily discontinue before contrast studies or during acute illness
• Overlooking vitamin B12 monitoring in long-term users
• Misdiagnosing chronic diarrhea as irritable bowel syndrome in patients taking metformin 7
• Continuing full doses despite persistent GI side effects instead of dose reduction or switching to extended-release formulation

By understanding and anticipating these side effects, appropriate monitoring and management strategies can be implemented to improve medication adherence and patient outcomes.