What is the relationship between Metformin (Metformin hydrochloride) and Chronic Kidney Disease (CKD)?

From the Guidelines

Metformin should be used with caution in patients with chronic kidney disease (CKD), with specific dosing adjustments based on kidney function, as recommended by the 2022 KDIGO clinical practice guideline for diabetes management in CKD 1.

Key Considerations

• For patients with an estimated glomerular filtration rate (eGFR) of 45-59 mL/min/1.73m², the dose of metformin may need to be reduced in certain conditions, while for those with an eGFR of 30-44 mL/min/1.73m², the dose should be halved 1.
• Metformin is contraindicated when eGFR falls below 30 mL/min/1.73m² due to increased risk of lactic acidosis, as stated in the guideline 1.
• Regular monitoring of kidney function is essential, with assessment at least annually or every 3-6 months, and more frequently if kidney function is declining 1.
• Patients on metformin should also be monitored for vitamin B12 deficiency, especially when treated for more than 4 years 1.

Dosing Adjustments

• The initial dose of metformin can be 500 mg or 850 mg once daily for immediate release, and 500 mg daily for extended release, with titration upwards by 500 mg/d or 850 mg/d every 7 days until maximum dose 1.
• The suggested approach to dosing metformin based on kidney function is outlined in the guideline, with specific recommendations for dose adjustment when eGFR is less than 45 ml/min per 1.73 m2 1.

Clinical Context

• The primary concern with metformin in CKD is the risk of lactic acidosis, as the medication is primarily eliminated by the kidneys, and accumulation can occur when kidney function declines 1.
• Despite these precautions, metformin remains a valuable medication for many patients with type 2 diabetes who have mild to moderate kidney impairment, as it effectively lowers blood glucose, may provide cardiovascular benefits, and has a low risk of hypoglycemia compared to many other diabetes medications 1.

From the FDA Drug Label

Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 Initiation of metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1. 73 m 2. Obtain an eGFR at least annually in all patients taking metformin hydrochloride tablets. In patients taking metformin hydrochloride tablets whose eGFR falls below 45 mL/min/1. 73 m 2, assess the benefit and risk of continuing therapy.

Metformin and CKD: Metformin is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m^2) due to the increased risk of lactic acidosis.

• In patients with mild to moderate CKD (eGFR 30-45 mL/min/1.73 m^2), initiation of metformin is not recommended.
• Monitoring of eGFR is recommended at least annually in all patients taking metformin, and more frequently in patients at risk for renal impairment.
• If the eGFR falls below 45 mL/min/1.73 m^2, the benefit and risk of continuing metformin therapy should be assessed 2.

From the Research

Metformin Use in Chronic Kidney Disease (CKD)

• Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus, but its use has been limited in patients with CKD due to concerns of lactic acidosis 3, 4, 5, 6, 7.
• The risk of lactic acidosis associated with metformin use in individuals with impaired kidney function is considered low, with an incidence of approximately 3-10 per 100,000 person-years, which is generally indistinguishable from the background rate in the overall population with diabetes 5, 6.
• Metformin has been shown to have several benefits beyond its hypoglycemic activity, including weight loss, improvement in metabolic syndrome, and cardiovascular protection, which may be beneficial for patients with CKD 3, 4, 6, 7.
• Current guidelines recommend cautious use of metformin in patients with mild to moderate CKD (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73m2), with careful monitoring of kidney function and dosage adjustments as needed 4, 5, 6.
• The use of metformin in patients with severe CKD (eGFR < 30 mL/min/1.73m2) remains a controversial issue, with some studies suggesting that it may be associated with an increased risk of lactic acidosis and all-cause mortality 4, 7.

Lactic Acidosis Risk and Prevention

• Lactic acidosis is a rare complication of metformin use, and it is often associated with preventable drug accumulation due to concomitant diseases or situations that reduce metformin renal clearance 7.
• Patients should be aware of the importance of discontinuing metformin temporarily in situations that may reduce its renal clearance, such as sepsis, fever, diarrhea, or vomiting, to prevent lactic acidosis 7.
• Continuous renal replacement therapy (CRRT) plays a crucial role in the treatment of lactic acidosis complicated by acute kidney injury, by eliminating metformin, correcting acidosis, and maintaining fluid balance 7.

Clinical Considerations

• Metformin is renally cleared, and its clearance is mainly renal, both by glomerular filtration and tubular secretion, with an apparent clearance of 933-1317 ml/min and a half-life of less than 3 hours 7.
• Patients with CKD should be closely monitored for signs of lactic acidosis, and metformin should be discontinued if renal function falls below a certain level or during acute renal deterioration 4, 7.
• The benefits of metformin use in patients with CKD should be carefully weighed against the potential risks, and individualized treatment decisions should be made based on the patient's specific clinical circumstances 3, 4, 5, 6, 7.