Does Metformin (biguanide) exacerbate Impaired renal function and increase albuminuria?

Metformin and Kidney Function: Impact on Renal Function and Albuminuria

Metformin should be discontinued in patients with eGFR <30 mL/min/1.73 m² due to increased risk of lactic acidosis, and dose should be reduced to 1000 mg daily when eGFR is 30-44 mL/min/1.73 m² as it may adversely affect kidney function in patients with moderate to severe chronic kidney disease. 1, 2

Effects on Kidney Function

• Metformin is primarily excreted unchanged by the kidneys, and its clearance is directly proportional to glomerular filtration rate (GFR) 1
• In patients with type 2 diabetes and moderate chronic kidney disease (CKD), continuous metformin use has been associated with a decline in eGFR compared to those who discontinued metformin (-1.32 vs. 0.75 mL/min/1.73 m²/year) 3
• Metformin should be temporarily discontinued during serious intercurrent illness that increases the risk of acute kidney injury (AKI), as recommended by the Canadian Society of Nephrology 1
• Patients should follow "sick-day rules" and avoid taking metformin during periods when they may experience AKI, such as during surgery, angiography, or when they are unwell at home 1

Dosing Recommendations Based on Kidney Function

• FDA labeling and clinical guidelines contraindicate metformin in patients with eGFR <30 mL/min/1.73 m² 2, 1
• For patients with eGFR 30-44 mL/min/1.73 m², the dose should be reduced to 1000 mg daily 1, 2
• For patients with eGFR 45-59 mL/min/1.73 m², dose reduction should be considered in those at high risk of lactic acidosis 1
• Regular monitoring of kidney function is essential: at least annually in all patients taking metformin, and every 3-6 months once eGFR falls below 60 mL/min/1.73 m² 1

Risk of Lactic Acidosis

• The primary concern with metformin use in impaired renal function is the risk of lactic acidosis, which can be life-threatening 2, 4
• Metformin-associated lactic acidosis is characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis, and increased lactate:pyruvate ratio 2
• The incidence of lactic acidosis in metformin users is relatively low, ranging from approximately 3 to 10 per 100,000 person-years 5
• Most cases of lactic acidosis occur in the context of other acute illnesses or conditions that disrupt lactate production or clearance, such as cirrhosis, sepsis, or hypoperfusion 4

Evidence on Albuminuria

• Current guidelines and research do not specifically address whether metformin directly increases albuminuria 1
• The 2020 KDIGO guidelines recommend metformin as a first-line therapy for patients with type 2 diabetes and CKD with eGFR ≥30 mL/min/1.73 m², suggesting that concerns about albuminuria are not a major contraindication 1
• For patients with diabetic kidney disease who have albuminuria, SGLT2 inhibitors are now recommended as they have demonstrated benefits in reducing CKD progression 1

Special Considerations

• Metformin should be discontinued before iodinated contrast imaging procedures in patients with eGFR between 30-60 mL/min/1.73 m², history of liver disease, alcoholism, or heart failure 2, 1
• Kidney function should be reassessed 48 hours after contrast procedures before restarting metformin 2
• In patients with stable renal function and low risk for AKI, some experts consider it reasonable to use metformin, with appropriate dose adjustment, even in selected patients with GFR <30 mL/min/1.73 m², though this is not a formal recommendation 1

Clinical Decision Algorithm

1. Assess baseline kidney function with eGFR before initiating metformin 2
2. If eGFR <30 mL/min/1.73 m²: Do not use metformin 2, 1
3. If eGFR 30-44 mL/min/1.73 m²: Reduce metformin dose to 1000 mg daily 1
4. If eGFR 45-59 mL/min/1.73 m²: Consider dose reduction in patients at high risk for lactic acidosis 1
5. Monitor kidney function at least annually in all patients on metformin, and every 3-6 months if eGFR <60 mL/min/1.73 m² 1
6. Educate patients about "sick-day rules" to temporarily discontinue metformin during illness that could cause dehydration or hypoxia 1
7. For patients with diabetic kidney disease who need additional glucose-lowering medications, consider SGLT2 inhibitors which have demonstrated kidney-protective effects 1