Why does metformin (Metformin) require dose reduction with impaired renal function due to accumulation?

From the Guidelines

Metformin requires dose reduction in patients with decreased kidney function primarily due to the risk of drug accumulation, which can lead to lactic acidosis. Metformin is eliminated almost entirely by the kidneys, with approximately 90% excreted unchanged in urine. When kidney function declines, the drug's clearance decreases proportionally, causing metformin to accumulate in the body. This accumulation increases the risk of lactic acidosis, a rare but potentially fatal complication with a mortality rate of approximately 50% 1. For patients with mild kidney impairment (eGFR 45-59 ml/min), the maximum recommended dose is typically 2000 mg daily. For moderate impairment (eGFR 30-44 ml/min), the maximum dose should be reduced to 1000 mg daily. Metformin is contraindicated in severe kidney impairment (eGFR <30 ml/min) 1. The mechanism behind metformin-associated lactic acidosis involves the drug's inhibition of mitochondrial respiration and gluconeogenesis, which can lead to increased lactate production and decreased lactate clearance, particularly when the drug accumulates due to impaired kidney function. Regular monitoring of kidney function is essential for patients on metformin therapy, especially in those with risk factors for acute kidney injury.

Some key points to consider:

• Metformin may accumulate with reduced kidney function and may increase risk for lactic acidosis, although this risk is very low in absolute terms 1.
• Patients receiving metformin should have their eGFR monitored, and the dose should be reduced when the eGFR is less than 45 mL/min/1.73 m2 (or 45 to 59 mL/min/1.73 m2 in some patients at high risk for acute kidney injury) or withdrawn when the eGFR is less than 30 mL/min/1.73 m2 or kidney failure develops 1.
• Metformin may cause vitamin B12 deficiency; therefore, monitoring of levels is advised with long-term use (>4 years) 1.
• The FDA has revised the label for metformin to reflect eGFR <30 mL/min/1.73 m² 1.
• A recent randomized trial confirmed previous observations that metformin use is associated with vitamin B12 deficiency and worsening of symptoms of neuropathy 1.

In summary, metformin dose reduction is necessary in patients with decreased kidney function to prevent lactic acidosis, and regular monitoring of kidney function is crucial for patients on metformin therapy.

From the FDA Drug Label

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment The risk of metformin accumulation and metformin-associated lactic acidosis increases with the degree of renal impairment. Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2

Metformin dose reduction is necessary with kidney function impairment because metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the severity of renal impairment 2.

• The risk of lactic acidosis increases with the degree of renal impairment.
• Dose reduction is necessary to prevent metformin accumulation and reduce the risk of lactic acidosis in patients with impaired kidney function 2.

From the Research

Metformin and Kidney Function

• Metformin is renally cleared, and impaired kidney function can lead to the accumulation of metformin, increasing the risk of lactic acidosis 3, 4, 5, 6, 7.
• The relationship between metformin clearance and kidney function estimates has been explored using regression analysis, showing a strong relationship between metformin clearance and estimated kidney function 3.
• Studies have found that metformin may be prescribed to patients with mild to moderate chronic kidney disease, with appropriate dosage reductions and careful follow-up of kidney function, without a significant increase in the risk of lactic acidosis 4, 6.

Dose Reduction and Kidney Function

• A maximum daily dose of 2250,1700,1250,1000, and 500 mg in patients with normal kidney function, CKD stage 2, 3a, 3b, and 4, respectively, has been suggested to provide a reasonable probability of achieving efficacy and safety 3.
• The lower dose of 500 mg daily may be required to maintain concentrations below the safety limits for patients with an eGFR of 15-29 mL/min 3.
• Dosage reductions are necessary to prevent the accumulation of metformin and reduce the risk of lactic acidosis in patients with impaired kidney function 4, 5, 6, 7.

Lactic Acidosis Risk

• The overall incidence of lactic acidosis in metformin users varies across studies, but it is generally considered to be low, approximately 3-10 per 100,000 person-years 4, 7.
• Lactic acidosis is often associated with preventable drug accumulation, and patients should be aware of the risks and take steps to prevent it, such as discontinuing metformin for a limited time if necessary 6.
• Continuous renal replacement therapy (CRRT) may be necessary in cases of lactic acidosis complicated by acute kidney injury to eliminate metformin and improve survival 6.