Is metformin contraindicated in Chronic Kidney Disease (CKD)?

Metformin Use in Chronic Kidney Disease

Metformin is NOT contraindicated in all CKD, but IS absolutely contraindicated when eGFR falls below 30 mL/min/1.73 m². 1, 2

eGFR-Based Contraindications and Restrictions

The FDA revised metformin guidance in 2016, shifting from serum creatinine to eGFR-based criteria 1:

Absolute Contraindication

• eGFR <30 mL/min/1.73 m²: Metformin is contraindicated 1, 2
• This represents severe renal impairment (approximately CKD stage 4-5) 2

Do Not Initiate

• eGFR <45 mL/min/1.73 m²: Do not start metformin 1
• If a patient is not already on metformin and has eGFR 30-45 mL/min/1.73 m², choose alternative agents 1, 3

Safe to Use with Standard Dosing

• eGFR ≥60 mL/min/1.73 m²: Use standard dosing without restriction 1, 4, 3
• Monitor eGFR at least annually 4

Use with Caution and Dose Reduction

• eGFR 45-59 mL/min/1.73 m²: Metformin can be continued if already prescribed 1

  • Consider dose reduction to 1000 mg daily in patients at high risk for lactic acidosis (those with comorbidities causing hypoperfusion/hypoxemia) 1, 4
  • Monitor eGFR every 3-6 months 1, 4

• eGFR 30-44 mL/min/1.73 m²: Metformin can be continued if already prescribed 1

  • Mandatory dose reduction to 1000 mg daily maximum 1, 4
  • Reassess benefits versus risks of continuing treatment 1
  • Monitor eGFR every 3-6 months 1, 4

Critical Safety Considerations

Temporary Discontinuation Required

Stop metformin before iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73 m² 1. This prevents acute kidney injury from compounding metformin accumulation and lactic acidosis risk.

Lactic Acidosis Risk

The feared complication of lactic acidosis is actually rare, occurring in approximately 6-8 cases per 100,000 patient-years 5, 6. Most cases occur during concurrent acute illness with acute kidney injury, not from chronic stable CKD alone 1, 7. However, the FDA boxed warning remains due to impaired metformin excretion in advanced CKD 1, 2.

Evidence on Outcomes in Advanced CKD

The evidence on metformin safety in advanced CKD is mixed:

• Favorable data: A retrospective study of 10,426 patients with diabetic kidney disease (including CKD 3B) showed metformin use was associated with lower all-cause mortality (aHR 0.65) and ESRD progression (aHR 0.67), with only one case of metformin-associated lactic acidosis 8

• Concerning data: A Taiwanese national cohort study of patients with serum creatinine >530 μmol/L (approximately stage 5 CKD) found metformin use was associated with significantly increased all-cause mortality (aHR 1.35) compared to non-users 9

These conflicting findings reinforce why the FDA contraindication at eGFR <30 mL/min/1.73 m² should be strictly followed 2. The risk-benefit ratio becomes unfavorable in advanced CKD.

Preferred Alternatives in Advanced CKD

When metformin cannot be used or initiated due to low eGFR 1, 3:

• SGLT2 inhibitors are recommended for eGFR ≥20 mL/min/1.73 m² as they slow CKD progression and reduce heart failure risk independent of glucose control 1
• GLP-1 receptor agonists reduce cardiovascular events and may slow CKD progression 1, 3
• These agents should be prioritized over metformin in patients with eGFR 30-45 mL/min/1.73 m² who are not already on metformin 1, 3

Monitoring Algorithm

• eGFR ≥60: Monitor annually 4
• eGFR 45-59: Monitor every 3-6 months 1, 4
• eGFR 30-44: Monitor every 3-6 months 1, 4
• eGFR <30: Discontinue metformin 1, 2

Additionally, monitor vitamin B12 levels in patients on metformin for more than 4 years 4.