What is the proper way to take metformin (biguanide), considering dosage, administration, and potential interactions, especially for patients with impaired renal function or a history of liver disease?

Proper Administration of Metformin

Start metformin at 500 mg once or twice daily with meals, titrate by 500 mg weekly to a maximum of 2000-2550 mg daily in divided doses, and adjust or discontinue based on kidney function—halving the dose when eGFR falls to 30-44 mL/min/1.73m² and stopping completely when eGFR drops below 30 mL/min/1.73m². 1

Initial Dosing and Titration

Immediate-release formulation:

• Begin with 500 mg twice daily or 850 mg once daily, taken with meals 1
• Increase by 500 mg weekly or 850 mg every 2 weeks based on glycemic control and tolerability 1
• Maximum dose is 2550 mg daily, though doses above 2000 mg are better tolerated when divided three times daily with meals 1

Extended-release formulation:

• Start with 500 mg once daily, preferably with the evening meal or at bedtime 2
• Titrate upward by 500 mg increments every 7 days 3, 4
• Maximum dose varies by kidney function (see below) 4

Kidney Function-Based Dosing Algorithm

eGFR ≥60 mL/min/1.73m²:

• Continue standard dosing up to maximum of 2000-2250 mg daily 4
• Monitor kidney function at least annually 3, 2

eGFR 45-59 mL/min/1.73m²:

• Consider dose reduction in high-risk patients (advanced age, liver disease, heart failure) 3, 4
• Maximum recommended dose: 1700 mg daily 4
• Increase monitoring frequency to every 3-6 months 3, 2

eGFR 30-44 mL/min/1.73m²:

• Reduce dose to half the maximum, typically 500-1000 mg daily 3, 4
• Do NOT initiate metformin in patients with eGFR in this range 1
• Monitor kidney function every 3-6 months 3, 4

eGFR <30 mL/min/1.73m²:

• Metformin is absolutely contraindicated—discontinue immediately 3, 2, 1
• This includes patients on dialysis 3

Critical Contraindications and Precautions

Absolute contraindications beyond renal impairment:

• Clinical or laboratory evidence of hepatic disease (impaired lactate clearance increases lactic acidosis risk) 1
• Acute congestive heart failure, particularly with hypoperfusion 1
• Conditions associated with hypoxemia (cardiovascular collapse, acute MI, sepsis) 1
• Excessive alcohol intake (potentiates lactate metabolism effects) 1

Temporary discontinuation required:

• Stop metformin before iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73m², history of liver disease, alcoholism, heart failure, or when intra-arterial contrast will be used 1
• Re-evaluate eGFR 48 hours after imaging; restart only if renal function is stable 1
• Implement "sick day rules": temporarily discontinue during serious intercurrent illness that increases acute kidney injury risk (surgery with restricted food/fluid intake, severe infections) 2, 4, 1

Long-Term Monitoring Requirements

Vitamin B12 monitoring:

• Monitor for deficiency in patients treated for more than 4 years 3, 2
• Approximately 7% of patients develop subnormal B12 levels, likely due to interference with B12-intrinsic factor complex absorption 1
• Measure hematologic parameters annually and vitamin B12 every 2-3 years 1

Kidney function surveillance:

• At least annually when eGFR ≥60 mL/min/1.73m² 3, 2
• Every 3-6 months when eGFR <60 mL/min/1.73m² 3, 2
• More frequently in elderly patients at higher risk for renal impairment 1

Important Clinical Caveats

Lactic acidosis risk:

• The incidence is extremely low (0.03 cases per 1000 patient-years) with mortality risk of 0.015 per 1000 patient-years 5
• Most cases occur in patients wrongly prescribed the drug, particularly those with contraindications 5, 6
• Direct metformin-related mortality is close to zero when prescribing guidelines are followed 6
• If lactic acidosis is suspected, discontinue metformin immediately and consider prompt hemodialysis (metformin is dialyzable with clearance up to 170 mL/min) 1

Hypoglycemia considerations:

• Metformin alone does not cause serious hypoglycemia 5
• When combined with insulin or sulfonylureas, lower doses of these agents may be required 1

Gastrointestinal side effects:

• Occur in less than 20% of patients, primarily diarrhea 5
• Starting with low doses and slow titration minimizes these effects 3
• Symptoms typically remit with dosage reduction 5

If glycemic targets are not achieved:

• Add a long-acting GLP-1 receptor agonist as the preferred second agent, particularly in patients with reduced kidney function requiring lower metformin doses 3, 4