What is the maximum dosage of metformin (biguanide oral hypoglycemic agent)?

From the Guidelines

The maximum dosage of metformin is 2,550 mg per day for immediate-release formulations and 2,000 mg per day for extended-release formulations.

Key Considerations

• The dosage of metformin should be adjusted based on kidney function, with reduced doses for patients with moderate renal impairment (eGFR 30-45 mL/min) and contraindicated in severe renal impairment (eGFR <30 mL/min) 1.
• Patients should take metformin with meals to minimize gastrointestinal side effects such as nausea, diarrhea, and abdominal discomfort.
• Metformin works by decreasing hepatic glucose production, reducing intestinal glucose absorption, and improving insulin sensitivity in peripheral tissues.
• Most patients achieve optimal glycemic control at 2,000 mg daily, divided into two doses for immediate-release or as a single dose for extended-release.
• Long-term use of metformin may cause vitamin B12 deficiency, and patients should undergo regular monitoring of renal function and vitamin B12 levels during long-term therapy 1.

Dosage Initiation and Titration

• Typically, metformin is started at a lower dose (500-850 mg once or twice daily) and gradually increased over several weeks to minimize gastrointestinal side effects.
• The dose can be advanced to 850 mg or two 500 mg tablets, twice per day, if gastrointestinal side effects have not occurred after 5-7 days 1.

Important Safety Information

• Metformin is contraindicated in patients with renal insufficiency (serum creatinine >132.6 μmol/L [1.5 mg/dL] for men or >123.8 μmol/L [1.4 mg/dL] in women or an estimated glomerular filtration rate [eGFR] < 45 mL/min/(1.73 m2)), liver dysfunction, severe infection, or hypoxia, or in patients undergoing major surgery 1.
• The relationship between metformin and lactic acidosis risk is uncertain, but the occurrence of this complication is now known to be very rare 1.

From the FDA Drug Label

The recommended starting dose of metformin hydrochloride tablets are 500 mg orally twice a day or 850 mg once a day, given with meals. Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2550 mg per day, given in divided doses. The maximum dosage of metformin is 2550 mg per day for adults, given in divided doses 2.

• For pediatric patients 10 years of age and older, the maximum dosage is 2000 mg per day, given in divided doses twice daily.
• It is essential to note that doses above 2000 mg may be better tolerated given 3 times a day with meals.

From the Research

Maximum Dosage of Metformin

The maximum dosage of metformin is not explicitly stated in the provided studies. However, the studies discuss the risks associated with metformin therapy, particularly lactic acidosis, and the importance of adhering to dosing guidelines.

• The study by 3 found that the prescribed metformin dose exceeded published guidelines in 60% of cases in patients with impaired kidney function, with an average excess of 1000 mg/day.
• The study by 4 notes that metformin has been contraindicated in moderate and severe renal impairment since its FDA approval, and that the reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years).
• The study by 5 compared the risk of lactic acidosis hospitalization between patients treated with metformin versus sulfonylureas following development of reduced kidney function, and found that the occurrence of lactic acidosis hospitalization was uncommon and not statistically different between the two groups.
• The study by 6 assessed the relationship of metformin prescription and other factors to the incidence of lactic acidosis, and found that diabetes rather than metformin therapy is the major risk factor for the development of lactic acidosis.
• The study by 7 compared the risk of lactic acidosis and hypoglycemia among patients with type 2 diabetes using oral antidiabetes drugs, and found that lactic acidosis during current use of oral antidiabetes drugs was very rare and was associated with concurrent comorbidity.

Key Findings

• Metformin therapy is associated with a risk of lactic acidosis, particularly in patients with impaired kidney function 3, 4, 5.
• The incidence of lactic acidosis in clinical practice is very low (<10 cases per 100,000 patient-years) 4.
• Diabetes rather than metformin therapy is the major risk factor for the development of lactic acidosis 6.
• Lactic acidosis during current use of oral antidiabetes drugs is very rare and is associated with concurrent comorbidity 7.