When to adjust Metformin (metformin) dosing for impaired renal function, specifically decreased Glomerular Filtration Rate (GFR)?

From the Guidelines

Metformin dosing should be adjusted based on a patient's glomerular filtration rate (GFR) to minimize the risk of lactic acidosis, with specific guidelines for dose reduction and monitoring at different GFR levels, as recommended by the most recent KDIGO guideline 1.

Key Recommendations

• For patients with a GFR of 45-59 mL/min/1.73m², consider dose reduction in certain conditions and monitor kidney function more frequently (every 3-6 months) 1.
• When GFR falls to 30-44 mL/min/1.73m², halve the dose and monitor kidney function every 3 months 1.
• Metformin is contraindicated when GFR drops below 30 mL/min/1.73m² due to significantly increased risk of lactic acidosis, and the medication should be discontinued 1.

Monitoring and Dose Adjustment

• Monitor vitamin B12 levels in patients treated with metformin for more than 4 years or at risk of vitamin B12 deficiency 1.
• Monitor kidney function at least annually or at least every 3-6 months, depending on the patient's GFR level 1.
• Adjust the dose of metformin when the eGFR is <45 ml/min per 1.73 m2, and for some patients when the eGFR is 45–59 ml/min per 1.73 m2 1.

Rationale

These recommendations exist because metformin is primarily eliminated by the kidneys, and impaired renal function leads to drug accumulation, increasing the risk of lactic acidosis, a rare but potentially fatal complication 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)]. Assess renal function prior to initiation of metformin hydrochloride tablets and periodically thereafter. Obtain an eGFR at least annually in all patients taking metformin hydrochloride tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

The dosing of Metformin should be adjusted for impaired renal function as follows:

• Contraindicated in patients with an eGFR below 30 mL/min/1.73 m^2.
• Not recommended to initiate in patients with an eGFR between 30 to 45 mL/min/1.73 m^2.
• In patients taking Metformin whose eGFR later falls below 45 mL/min/1.73 m^2, assess the benefit and risk of continuing therapy.
• Discontinue Metformin if the patient's eGFR later falls below 30 mL/min/1.73 m^2.
• Assess renal function at least annually in all patients taking Metformin, and more frequently in patients at risk for renal impairment 2, 2, 2.

From the Research

Metformin Dosing Adjustment for Impaired Renal Function

• The relationship between metformin clearance and kidney function estimates was explored using a regression analysis, showing a strong relationship between metformin clearance and estimated kidney function using the Cockcroft and Gault, MDRD, and CKD-Epi equations 3.
• A study suggested that a maximum daily dose of 2250,1700,1250,1000, and 500 in patients with normal kidney function, CKD stage 2, 3a, 3b, and 4, respectively, will provide a reasonable probability of achieving efficacy and safety 3.
• Another study found that metformin may have an adverse effect on renal function in patients with type 2 diabetes mellitus and moderate chronic kidney disease, with the continuation of metformin being a risk factor for these patients 4.

Estimated GFR Thresholds for Metformin Presing

• A study aimed to establish pragmatic eGFR limits for use in patients being considered for metformin treatment, finding that few patients with a serum creatinine of 130 or 150 micromol/l have an eGFR of < 30 ml/min/1.73 m(2) [chronic kidney disease (CKD) stage 4 or greater] 5.
• The study proposed pragmatic eGFR limits to guide metformin prescribing in patients with renal impairment, 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.
• New guidelines recommend use of metformin down to a GFR of 30 mL/min under the condition that the dose is adjusted, and that metformin must be stopped only when GFR is below 45 mL/min in connection with administration of iodine contrast media 6.

Dosage Adjustment in Patients with Renal Dysfunction

• Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patient's glomerular filtration rate (GFR) estimated by the Cockroft-Gault formula 7.
• A pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients 7.
• Determination of metformin levels in serum is useful to guide therapeutic dose when GFR is low but also to confirm that lactic acidosis is caused by metformin 6.