At what stage of Chronic Kidney Disease (CKD) should metformin be discontinued?

From the Guidelines

Metformin should be discontinued when a patient's estimated glomerular filtration rate (eGFR) falls below 30 mL/min/1.73m², as recommended by the most recent guideline evidence 1. This recommendation is based on the latest guidance from the FDA, which states that metformin is contraindicated in patients with an eGFR <30 mL/min/1.73 m2 1. The reason for this restriction is that metformin is primarily eliminated by the kidneys, and impaired kidney function can lead to drug accumulation, increasing the risk of lactic acidosis, a rare but serious side effect.

For patients with an eGFR between 30-45 mL/min/1.73m², metformin can typically be continued but with a reduced dose and more frequent monitoring of kidney function, as suggested by the KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease 1. The dose of metformin should be adjusted when the eGFR is <45 mL/min/1.73 m2, and for some patients when the eGFR is 45–59 mL/min/1.73 m2, as recommended by the guideline 1.

Some key points to consider when managing patients with CKD and metformin include:

• Monitoring eGFR regularly, at least every 3-6 months, in patients with declining kidney function 1
• Temporarily stopping metformin before procedures involving iodinated contrast media and restarting 48 hours after the procedure if kidney function remains stable 1
• Considering alternative glucose-lowering medications, such as DPP-4 inhibitors, GLP-1 receptor agonists, or insulin, when metformin is discontinued due to CKD 1

Overall, the management of metformin in patients with CKD requires careful consideration of the risks and benefits, as well as regular monitoring of kidney function and adjustment of the dose as needed.

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

Metformin should be discontinued at CKD stage 4 (eGFR below 30 mL/min/1.73 m^2) or when the eGFR falls below this threshold. For patients with an eGFR between 30-45 mL/min/1.73 m^2, the benefit and risk of continuing metformin therapy should be assessed 2, 2.

From the Research

Metformin Discontinuation in Chronic Kidney Disease (CKD)

• The decision to discontinue metformin in patients with CKD is based on the estimated glomerular filtration rate (eGFR) 3, 4, 5.
• Guidelines recommend metformin to be given at reduced dosages for those with an eGFR <60 mL/min/1.73m2 and omitted in those with eGFR<30 mL/min/1.73m2 3.
• However, some studies suggest that metformin may be safely used in patients with mild to moderate renal impairment (eGFR 30-60 mL/min/1.73m2) 4.
• A study found that stopping metformin after reaching stage 4 CKD was associated with reduced survival, suggesting that continued use of metformin may be appropriate when eGFR falls below 30mL/min/1.73m2 6.
• Another study proposed pragmatic eGFR limits to guide metformin prescribing, suggesting that CKD stage 4 or greater should be an absolute contraindication to metformin, while CKD stage 3 should alert clinicians to consider other risk factors before initiating or continuing treatment 5.
• The use of metformin in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) remains a controversial issue, with some studies suggesting an increased risk of lactic acidosis and all-cause mortality 4, 7.

Stages of CKD and Metformin Use

• CKD stage 3: metformin may be used at reduced dosages, but clinicians should consider other risk factors before initiating or continuing treatment 3, 5.
• CKD stage 4: metformin use is controversial, with some studies suggesting an increased risk of lactic acidosis and all-cause mortality, while others suggest that continued use may be appropriate 4, 7, 6.
• CKD stage 5: metformin is generally not recommended due to the high risk of lactic acidosis and all-cause mortality 3, 4.