What are the common and serious side effects of metformin in a patient with type 2 diabetes, particularly those with impaired renal function?

Metformin Side Effects

Metformin is generally well-tolerated, but gastrointestinal side effects are common, vitamin B12 deficiency occurs with long-term use, and lactic acidosis—though rare—is a potentially fatal complication that requires strict attention to contraindications, particularly in patients with impaired renal function. 1

Common Side Effects

Gastrointestinal Effects

• Diarrhea is the most common side effect, occurring in 53% of patients in clinical trials, compared to 12% with placebo 1
• Nausea and vomiting affect 26% of patients (versus 8% with placebo) 1
• Flatulence occurs in 12% of patients, abdominal discomfort in 6%, and indigestion in 7% 1
• These gastrointestinal symptoms can be minimized by starting at 500 mg once or twice daily with food and titrating gradually to the maximum effective dose of 2000-2550 mg/day 2
• Extended-release formulations may reduce gastrointestinal side effects compared to immediate-release metformin 3
• Diarrhea leads to discontinuation in approximately 6% of patients 1

Vitamin B12 Deficiency

• Long-term metformin use is definitively associated with biochemical vitamin B12 deficiency 2, 3
• Approximately 7% of patients develop subnormal vitamin B12 levels during treatment 1
• This deficiency can interfere with vitamin B12 absorption and may worsen peripheral neuropathy symptoms 3
• Periodic measurement of vitamin B12 levels should be considered in all metformin-treated patients, especially those with anemia or peripheral neuropathy 2, 3

Other Common Effects

• Asthenia (weakness) occurs in 9% of patients 1
• Headache affects 6% of patients 1
• Additional effects reported in 1-5% include abnormal stools, myalgia, lightheadedness, dyspnea, rash, increased sweating, and taste disturbances 1

Serious Side Effects

Lactic Acidosis

• Lactic acidosis is a rare but potentially fatal complication with mortality rates of 30-50% if not promptly treated 3, 1
• The incidence is approximately 2-9 cases per 100,000 patient-years 3
• Lactic acidosis is characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis, increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL 1
• Symptoms include malaise, myalgias, abdominal pain, respiratory distress, increased somnolence, hypotension, and resistant bradyarrhythmias 1
• Prompt hemodialysis is recommended if lactic acidosis is suspected, as metformin is dialyzable with clearance up to 170 mL/min 1

Hepatotoxicity

• Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported in postmarketing surveillance 1

Hypoglycemia

• When used as monotherapy, metformin rarely causes hypoglycemia 3
• Risk increases when combined with sulfonylureas or insulin 2

Critical Contraindications and Risk Factors

Renal Impairment

• Metformin is contraindicated when eGFR falls below 30 mL/min/1.73 m² 3, 1
• Dose reduction to 1000 mg daily is required when eGFR is 30-44 mL/min/1.73 m² 3
• Initiation is not recommended in patients with eGFR between 30-45 mL/min/1.73 m² 2
• eGFR should be obtained at least annually in all patients, and more frequently in elderly patients or those at risk for renal impairment 2, 1
• The risk of metformin accumulation and lactic acidosis increases with severity of renal impairment because metformin is substantially excreted by the kidney 1

Other Absolute Contraindications

• Severe heart failure (left ventricular ejection fraction <30%) 3
• Hepatic impairment or liver disease 2, 1
• Acute conditions causing tissue hypoxia: cardiovascular collapse, acute myocardial infarction, sepsis 1
• Alcohol abuse (alcohol potentiates metformin's effect on lactate metabolism) 2, 1
• Conditions predisposing to lactic acidosis 2

Temporary Discontinuation Required

• Stop metformin at the time of or prior to iodinated contrast imaging procedures in patients with eGFR 30-60 mL/min/1.73 m², history of hepatic impairment, alcoholism, heart failure, or those receiving intra-arterial contrast 1
• Re-evaluate eGFR 48 hours after imaging and restart only if renal function is stable 1
• Discontinue during acute illness associated with dehydration, hypoxemia, nausea, vomiting, or any condition causing restricted food and fluid intake 2, 1
• Stop metformin the night before major surgery and do not restart before 48 hours, only after confirming adequate renal function 3
• For minor or ambulatory surgery, metformin can be continued except in severe renal failure 3

Special Population Considerations

Elderly Patients (Age ≥65)

• The risk of lactic acidosis increases with age due to greater likelihood of hepatic, renal, or cardiac impairment 1
• Assess renal function more frequently in elderly patients 1
• Dose selection should be cautious, usually starting at the low end of the dosing range 1
• Gastrointestinal side effects and reduced appetite can be particularly problematic in older adults 3

Pediatric Patients

• Safety and effectiveness established in children 10-16 years old 1
• Adverse reaction profile similar to adults 1
• Maximum daily dose of 2000 mg recommended 1
• Not recommended in children under 10 years old 1

Pregnancy and Lactation

• Metformin crosses the placenta partially 1
• Present in human milk at infant doses approximately 0.11-1% of maternal weight-adjusted dosage 1
• May result in ovulation in anovulatory women, increasing risk of unintended pregnancy 1
• No oral agent should be used during pregnancy 2

Clinical Pearls and Management Strategies

• Despite potential complications, metformin remains first-line therapy for type 2 diabetes due to proven efficacy in glycemic control and reduction of mortality and cardiovascular events when used appropriately 2, 3
• The maximum recommended daily dose is 2550 mg, divided into multiple doses with meals 3
• If glycemic control is inadequate at maximum metformin dose, add a second agent rather than exceeding the maximum dose 3
• Patients should be educated to stop metformin and contact their healthcare provider if symptoms of lactic acidosis develop 1
• Consider DPP-4 inhibitors, GLP-1 receptor agonists, or insulin as combination therapy if needed 3