What are the potential complications of metformin (biguanide) therapy?

Potential Complications of Metformin Therapy

The most serious potential complication of metformin therapy is lactic acidosis, which is rare but potentially fatal, characterized by elevated blood lactate concentrations, anion gap acidosis, and increased lactate:pyruvate ratio. 1, 2

Gastrointestinal Side Effects

• Diarrhea (occurs in approximately 53% of patients), nausea/vomiting (26%), flatulence (12%), indigestion (7%), and abdominal discomfort (6%) are the most common adverse effects 1
• Gastrointestinal side effects can be minimized by starting with a low dose and gradually increasing (slow titration), taking medication with meals, and considering extended-release formulations 2
• These side effects are typically transient but may lead to discontinuation in approximately 6% of patients 1

Serious Complications

Metformin-Associated Lactic Acidosis (MALA)

• Characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis without ketonuria, and increased lactate:pyruvate ratio 1
• Presents with subtle onset and nonspecific symptoms including malaise, myalgia, abdominal pain, respiratory distress, somnolence, and in severe cases hypotension and bradyarrhythmias 1, 3
• Mortality rate ranges from 30-50% if not promptly treated 4
• Incidence is approximately 2-9 cases per 100,000 patient-years 4, 5

Risk Factors for MALA

• Renal impairment (eGFR <45 mL/min/1.73 m²) 1, 6
• Acute kidney injury 6
• Liver dysfunction 1
• Severe heart failure (left ventricular ejection fraction <30%) 4
• Advanced age (>65 years) 1
• Hypoxemic conditions 1
• Concurrent use of medications that impair renal function 1
• Dehydration 4
• Administration of iodinated contrast agents 4
• Sepsis or severe infection 3, 7

Management of MALA

• Immediate discontinuation of metformin 1
• Prompt hemodialysis to correct acidosis and remove accumulated metformin 1, 6
• Supportive measures in a hospital setting 1

Vitamin B12 Deficiency

• Long-term metformin use can interfere with vitamin B12 absorption 4, 1
• May lead to worsening of peripheral neuropathy symptoms 4
• Periodic testing of vitamin B12 levels is recommended for patients on long-term therapy 4, 2

Hepatic Effects

• Rare cases of cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported 1

Hypoglycemia

• When used as monotherapy, metformin rarely causes hypoglycemia 4
• Risk increases when combined with other glucose-lowering medications, particularly insulin or sulfonylureas 1

Perioperative Considerations

• Metformin should be stopped the night before major surgery 4
• Should not be restarted before 48 hours for major surgery and only after confirming adequate renal function 4
• For minor or ambulatory surgery, metformin can be continued except in cases of severe renal failure 4

Recommendations for Safe Use

• Assess renal function before initiating therapy and at least annually thereafter 1
• Contraindicated in patients with eGFR <30 mL/min/1.73 m² 1
• Use with caution in patients with eGFR between 30-45 mL/min/1.73 m² 1
• Temporarily discontinue during acute illness or procedures with contrast agents 2
• More frequent monitoring of renal function in elderly patients and those at risk for renal impairment 1
• Educate patients about symptoms of lactic acidosis and when to seek medical attention 1

Special Populations

• Elderly patients require more careful monitoring due to age-related decline in renal function 1
• Patients with multiple comorbidities are at higher risk for complications 3, 7

Despite these potential complications, metformin remains the first-line therapy for type 2 diabetes due to its proven efficacy in glycemic control and reduction of mortality and complications when used appropriately 4.