What is the metformin (Glucophage) cutoff for Glomerular Filtration Rate (GFR) in patients with Impaired renal function?

From the Guidelines

Metformin should be discontinued when a patient's glomerular filtration rate (GFR) falls below 30 mL/min/1.73m², as recommended by the most recent guidelines 1. For patients with a GFR between 30-45 mL/min/1.73m², metformin can be used with caution at reduced doses, with regular monitoring of renal function every 3-6 months. When GFR is between 45-60 mL/min/1.73m², metformin can be used with normal dosing but requires monitoring of renal function at least annually. These cutoffs are important because metformin is primarily eliminated by the kidneys, and impaired renal function can lead to drug accumulation and increase the risk of lactic acidosis, a rare but serious side effect. Lactic acidosis risk increases significantly when metformin cannot be adequately cleared from the body due to poor kidney function. Patients should also be educated to temporarily stop metformin during acute illness, particularly those involving dehydration, and before procedures requiring iodinated contrast, as these situations can further compromise renal function. Key considerations for metformin use in patients with impaired renal function include:

• Monitoring eGFR regularly, especially in those with GFR <60 mL/min/1.73m² 1
• Adjusting the dose of metformin based on the level of kidney function, with a suggested reduction in dose when eGFR is <45 mL/min/1.73m² 1
• Being aware of the potential for metformin to cause vitamin B12 deficiency with long-term use 1
• Temporarily discontinuing metformin in situations that may increase the risk of lactic acidosis, such as acute illness or procedures with iodinated contrast 1

From the FDA Drug Label

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 metformin cutoff for GFR is below 30 mL/minute/1.73 m^2, at which point the drug is contraindicated. For patients with an eGFR between 30 to 45 mL/minute/1.73 m^2, initiation of metformin is not recommended. If a patient's eGFR falls below 45 mL/min/1.73 m^2 while taking metformin, the benefit-risk of continuing therapy should be assessed 2.

From the Research

Metformin Cutoff for Glomerular Filtration Rate (GFR)

• The metformin cutoff for GFR is a crucial consideration in patients with impaired renal function, as metformin is contraindicated in patients with significant renal impairment due to the risk of lactic acidosis 3.
• A study published in 2007 proposed pragmatic eGFR limits to guide metformin prescribing in patients with renal impairment, suggesting that CKD stage 4 or greater (eGFR < 30 ml/min/1.73 m2) should be an absolute contraindication to metformin, while CKD stage 3 (eGFR 30-59 ml/min/1.73 m2) should alert clinicians to consider other risk factors before initiating or continuing treatment 3.
• Another study published in 2017 found that lactate levels and blood pH were comparable in patients with diabetic kidney disease receiving metformin and those not receiving metformin, suggesting that metformin may be safe in patients with moderately decreased kidney function (eGFR ≥ 30 ml/min/1.73 m2) 4.
• A 2023 study examined the prescription trend and lactic acidosis in patients prescribed metformin before and after the revision of package insert for allowing metformin administration to patients with moderately decreased kidney function, and found that the daily metformin dose at the first prescription decreased after the revision, and no lactic acidosis was observed in patients with moderately decreased kidney function (eGFR ≥ 30 ml/min/1.73 m2) 5.
• A 2018 study found that metformin continuation in diabetic patients with a GFR of more than 60 ml/min/1.73 m2 undergoing coronary angiography did not enhance the risk of metformin-associated lactic acidosis (MALA) development 6.
• A 2021 systematic review found that metformin appears to be associated with reduced mortality and no increased risk of acidosis at an eGFR of 45 ml/min/1.73 m2 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/1.73 m2 7.

Key Findings

• Metformin should not be used at an eGFR less than 30 ml/min/1.73 m2 due to the increased risk of lactic acidosis 3, 7.
• Metformin may be safe in patients with moderately decreased kidney function (eGFR ≥ 30 ml/min/1.73 m2), but clinicians should consider other risk factors before initiating or continuing treatment 3, 4, 5.
• The daily metformin dose should be decreased in patients with impaired renal function to minimize the risk of lactic acidosis 5.