What is the recommended dose and frequency of metformin (biguanide) for patients with impaired renal function?

From the Guidelines

Metformin should be initiated at a low dose of 500 mg once or twice daily and gradually titrated upwards based on glycemic response and tolerability, with dose adjustments made according to the patient's estimated glomerular filtration rate (eGFR). For patients with an eGFR of 45-59 mL/min/1.73m², the maximum recommended dose is 2000 mg daily, but a dose reduction should be considered in certain conditions, as suggested by the KDIGO 2022 guideline 1. When eGFR is 30-44 mL/min/1.73m², the maximum dose should be reduced to 1000 mg daily, as recommended by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) consensus report 1. Metformin is contraindicated when eGFR falls below 30 mL/min/1.73m², and renal function should be monitored regularly, at least annually in stable patients and more frequently in those at risk for declining kidney function 1. Some key points to consider when prescribing metformin include:

• Monitoring eGFR in patients treated with metformin and increasing the frequency of monitoring when the eGFR is <60 ml/min per 1.73 m² 1
• Adjusting the dose of metformin when the eGFR is <45 ml/min per 1.73 m², and for some patients when the eGFR is 45–59 ml/min per 1.73 m² 1
• Monitoring patients for vitamin B12 deficiency when they are treated with metformin for more than 4 years 1
• Temporarily discontinuing metformin before procedures using iodinated contrast media and in situations that may compromise renal function, such as dehydration or acute illness. These restrictions exist because metformin is primarily eliminated by the kidneys, and impaired renal function can lead to drug accumulation, increasing the risk of lactic acidosis, a rare but serious side effect 1.

From the FDA Drug Label

2 DOSAGE AND ADMINISTRATION

1. 3 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of metformin hydrochloride tablets and periodically thereafter. Metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2. Initiation of metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/minute/1. 73 m 2is not recommended. In patients taking metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit risk of continuing therapy. Discontinue metformin hydrochloride tablets if the patient's eGFR later falls below 30 mL/minute/1.73 m 2[see Warnings and Precautions ( 5.1)].

The recommended dose and frequency of metformin for patients with impaired renal function is not explicitly stated in terms of a specific dose adjustment. However, the label provides guidance on:

• Contraindication: Metformin is contraindicated in patients with an eGFR below 30 mL/minute/1.73 m^2.
• Initiation: Initiation is not recommended for patients with an eGFR between 30 to 45 mL/minute/1.73 m^2.
• Continuation: For patients whose eGFR later falls below 45 mL/min/1.73 m^2, the benefit-risk of continuing therapy should be assessed.
• Discontinuation: Metformin should be discontinued if the patient's eGFR later falls below 30 mL/minute/1.73 m^2 2. Key points:
• Assess renal function before and during treatment.
• Be cautious when treating patients with impaired renal function.
• Consider the benefit-risk of continuing metformin in patients with declining renal function.

From the Research

Metformin Dose and Frequency for Patients with Impaired Renal Function

• The recommended dose and frequency of metformin for patients with impaired renal function is not explicitly stated in the provided studies, but some studies provide guidance on the safe use of metformin in patients with reduced kidney function 3, 4, 5.
• A study published in 2017 found that blood lactate levels were not elevated in patients with diabetic kidney disease at a daily dose of metformin <1 g 3.
• Another study published in 2021 found that metformin appears to be associated with reduced mortality and no increased risk of acidosis at an eGFR of 45 mL/min/1.73m2 or higher, but may be associated with fewer benefits and possible increases in the risk of acidosis at an eGFR of less than 30 mL/min/1.73m2 4.
• The US Food and Drug Administration guidelines recommend that metformin should not be used at an eGFR less than 30 mL/min/1.73m2 4.
• A study published in 2020 found that the occurrence of lactic acidosis hospitalization was uncommon and not statistically different between patients who continued metformin and those who continued sulfonylureas after developing reduced kidney function 5.
• In terms of dosing frequency, a study published in 2021 found that metformin extended-release (Met XR) 500 mg/day administered once a day, ideally with or after a meal, can provide therapeutic levels of the drug throughout the day with peak plasma levels being obtained between four to eight hours after administration 6.

Key Considerations

• Patients with impaired renal function should be closely monitored for signs of lactic acidosis, such as elevated blood lactate levels and metabolic acidosis 3, 4, 5.
• The dose and frequency of metformin should be adjusted based on the patient's renal function and individual response to the medication 3, 4.
• Metformin should be used with caution in patients with reduced kidney function, and alternative treatments should be considered if the patient's renal function declines 4, 5.