Why is metformin (biguanide) discontinued in patients with Chronic Kidney Disease (CKD) stage 4?

Metformin Discontinuation in CKD Stage 4

Metformin should be discontinued in patients with CKD stage 4 (eGFR <30 mL/min/1.73 m²) due to increased risk of lactic acidosis from drug accumulation, as the medication is primarily excreted by the kidneys. 1

Rationale for Discontinuation

• Metformin is primarily eliminated by the kidneys, and reduced kidney function leads to drug accumulation, which may increase the risk of lactic acidosis 2
• FDA labeling explicitly contraindicates metformin use in patients with eGFR below 30 mL/min/1.73 m² (CKD stage 4-5) 1
• The 2020 KDIGO guidelines for diabetes management in CKD recommend discontinuing metformin when eGFR falls below 30 mL/min/1.73 m² 2
• Patients with advanced CKD (stage 5) taking metformin have been shown to have a significantly increased risk of all-cause mortality compared to non-users (adjusted hazard ratio 1.35) 3

Pharmacokinetic Considerations

• Metformin clearance decreases proportionally with declining kidney function 2
• When eGFR falls to 60 mL/min/1.73 m², metformin clearance decreases by approximately 75%, leading to higher blood levels 2
• While serum concentrations at moderate CKD are only about two-fold higher than in normal kidney function, the risk increases substantially in severe CKD 2
• In patients with CKD stage 4-5, metformin can accumulate to potentially toxic levels 4

Risk of Lactic Acidosis

• Lactic acidosis is a rare but serious complication of metformin therapy with high mortality 4
• The risk of lactic acidosis increases significantly when eGFR falls below 30 mL/min/1.73 m² 2
• While the absolute risk of lactic acidosis is low in the general population, it increases in advanced CKD due to impaired drug clearance 2, 4
• Most episodes of metformin-associated lactic acidosis occur during acute illness when acute kidney injury further reduces metformin clearance 2

Guideline Recommendations

• The 2022 ADA/KDIGO consensus report states metformin is contraindicated in patients with eGFR <30 mL/min/1.73 m² 2
• The 2020 KDIGO diabetes management guideline recommends discontinuing metformin when eGFR falls below 30 mL/min/1.73 m² 2
• The Canadian Society of Nephrology commentary on KDIGO guidelines concurs with discontinuing metformin in CKD stages 4-5 (eGFR <30 mL/min/1.73 m²) 2
• FDA drug labeling explicitly contraindicates metformin in patients with eGFR below 30 mL/min/1.73 m² 1

Alternative Medications for CKD Stage 4

• SGLT2 inhibitors are recommended for patients with T2D and CKD with eGFR ≥20 mL/min/1.73 m² due to their cardiovascular and kidney benefits 2
• GLP-1 receptor agonists are recommended as an alternative for patients who cannot use metformin and SGLT2 inhibitors 2
• DPP-4 inhibitors can be used in advanced CKD with appropriate dose adjustments 2
• Insulin remains an option for glycemic control in advanced CKD but requires careful dose adjustment to avoid hypoglycemia 2

Common Pitfalls and Caveats

• Some clinicians continue metformin in CKD stage 4 despite recommendations against it, which increases risk of adverse outcomes 5
• Failure to monitor kidney function regularly in patients on metformin can lead to continued use despite progression to CKD stage 4 2
• Patients with CKD stage 3b (eGFR 30-44 mL/min/1.73 m²) should have metformin dose reduced to 1000 mg daily maximum, not discontinued completely 2
• During acute illness, surgery, or procedures with contrast media, metformin should be temporarily discontinued in all CKD patients (even those with milder CKD) due to risk of acute kidney injury 2, 1

While some observational studies suggest metformin may be used cautiously in selected patients with eGFR <30 mL/min/1.73 m² 2, 6, the most recent high-quality guidelines and FDA labeling clearly contraindicate its use in this population due to safety concerns 2, 1.