What is the creatinine level at which to switch from metformin (biguanide) to an alternative anti-diabetic medication for patients with diabetes mellitus and impaired renal function?

From the Guidelines

Metformin should be discontinued and alternative antidiabetic medications considered when a patient's serum creatinine exceeds 1.5 mg/dL (133 μmol/L) in men or 1.4 mg/dL (124 μmol/L) in women, as recommended by the most recent guidelines 1. The decision to switch from metformin to an alternative anti-diabetic medication is based on the risk of lactic acidosis, a rare but potentially fatal complication, which increases with impaired renal function.

• Key factors to consider when making this decision include:
  • Serum creatinine levels: 1.5 mg/dL (133 μmol/L) in men or 1.4 mg/dL (124 μmol/L) in women 1
  • Estimated glomerular filtration rate (eGFR): less than 30 mL/min/1.73m² 1
  • Risk of lactic acidosis: increased with impaired renal function 1 Alternative medications to consider include:
• DPP-4 inhibitors (sitagliptin, linagliptin)
• GLP-1 receptor agonists (semaglutide, dulaglutide)
• SGLT-2 inhibitors (if eGFR permits)
• Insulin
• Sulfonylureas (with caution due to hypoglycemia risk) Regular monitoring of renal function is essential for all diabetic patients on metformin, with more frequent assessments needed for those with existing kidney disease or risk factors for renal impairment 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.

The creatinine level at which to switch from metformin to an alternative anti-diabetic medication is not directly provided, but the eGFR levels are given.

• An eGFR below 30 mL/min/1.73 m^2 is a contraindication for metformin.
• An eGFR between 30 to 45 mL/min/1.73 m^2 is not recommended for initiation of metformin.
• If the eGFR falls below 45 mL/min/1.73 m^2, the benefit and risk of continuing metformin therapy should be assessed 2, 2. To determine the creatinine level, the eGFR needs to be calculated using the patient's creatinine level. However, the exact creatinine level at which to switch is not provided in the drug label.

From the Research

Creatinine Level for Switching from Metformin

• The decision to switch from metformin to an alternative anti-diabetic medication for patients with diabetes mellitus and impaired renal function is based on the patient's renal function, specifically the estimated glomerular filtration rate (eGFR) rather than serum creatinine levels alone 3.
• Historically, serum creatinine values equal to or above 1.4 and 1.5 mg/dL were considered contraindications for metformin use in women and men, respectively 3.
• However, current guidelines suggest that metformin can be used safely in patients with eGFR as low as 30 mL/min/1.73 m2, and the use of serum creatinine as the sole marker for renal function may lead to unnecessary under-prescription of metformin 3.
• Alternative markers, such as cystatin C, may provide a more accurate assessment of renal function and cardiovascular risk in patients with diabetes 4.
• Other studies have shown that SGLT2 inhibitors and GLP-1 receptor agonists may be effective alternatives to metformin in patients with impaired renal function, with a lower risk of adverse kidney outcomes 5.

Renal Function Assessment

• The assessment of renal function is crucial in determining the safety of metformin use in patients with diabetes mellitus 3, 6.
• The use of eGFR, calculated using formulas such as the MDRD and CKD-EPI, provides a more accurate assessment of renal function than serum creatinine alone 3.
• Other biomarkers, such as urinary NGAL, may also be useful in assessing renal function and predicting the risk of kidney disease progression in patients with diabetes 7.

Alternative Anti-Diabetic Medications

• SGLT2 inhibitors and GLP-1 receptor agonists have been shown to be effective alternatives to metformin in patients with impaired renal function, with a lower risk of adverse kidney outcomes 5.
• The choice of alternative medication should be based on individual patient characteristics, including renal function, cardiovascular risk, and other comorbidities 5, 4.