What is the management of metformin (biguanide) in patients with type 2 diabetes during an acute illness, particularly with impaired renal function?

Management of Metformin During Acute Illness

Metformin must be temporarily discontinued immediately when patients with type 2 diabetes develop any acute illness that increases the risk of acute kidney injury (AKI), including serious infections, dehydration, vomiting, diarrhea, or conditions causing hypoperfusion or hypoxemia. 1, 2

Critical Action: Immediate Discontinuation

Stop metformin immediately in the following acute illness scenarios:

• Serious infections or sepsis (risk of hypoperfusion and reduced metformin clearance) 1, 2
• Gastrointestinal illness with vomiting or diarrhea (volume depletion leading to prerenal azotemia) 2, 3
• Dehydration from any cause (reduced renal perfusion) 4, 5
• Acute congestive heart failure (particularly with hypoperfusion/hypoxemia) 2
• Cardiovascular collapse, shock, or acute myocardial infarction (hypoxic states) 2
• Conditions causing hypoxemia (impaired tissue oxygenation increases lactate production) 2
• Perioperative period (restricted oral intake, hemodynamic instability) 2, 6

Rationale: Risk of Metformin-Associated Lactic Acidosis (MALA)

The FDA label explicitly warns that metformin should be discontinued when acute illness occurs because most episodes of metformin-associated lactic acidosis develop concurrent with other acute illness, often when AKI contributes to reduced metformin clearance. 1, 2 Metformin is substantially excreted by the kidney (apparent clearance 933-1317 mL/min), and any condition that impairs renal function causes drug accumulation. 4

Key pathophysiology: Metformin decreases hepatic lactate uptake and inhibits mitochondrial oxidative phosphorylation, increasing lactate production. 2, 7 When renal clearance is compromised during acute illness, metformin accumulates (plasma levels >5 mcg/mL), leading to severe lactic acidosis (lactate >5 mmol/L) with high mortality if untreated. 2, 7

Specific "Sick-Day Rules" for Patients

The Canadian Society of Nephrology explicitly recommends temporary discontinuation of metformin in patients with eGFR <60 mL/min/1.73 m² who have serious intercurrent illness that increases AKI risk. 1 However, this principle applies to ALL patients on metformin during acute illness, regardless of baseline renal function, because previously normal kidneys can rapidly deteriorate. 3

Educate patients to stop metformin and seek medical care when they experience:

• Fever or infection requiring antibiotics 4, 5
• Persistent vomiting or diarrhea (>24 hours) 3, 6
• Inability to maintain oral fluid intake 2
• Severe illness requiring hospitalization 4, 5
• Scheduled surgery or procedures 1, 2

Additional Considerations for Patients with Baseline Renal Impairment

For patients with chronic kidney disease (CKD) who develop acute illness:

• eGFR 45-59 mL/min/1.73 m²: Metformin dose reduction should be considered at baseline if comorbidities place them at increased risk of lactic acidosis due to hypoperfusion/hypoxemia; discontinue during any acute illness. 1
• eGFR 30-44 mL/min/1.73 m²: Baseline dose should already be reduced to 1000 mg daily; discontinue immediately during acute illness. 1
• eGFR <30 mL/min/1.73 m²: Metformin is contraindicated and should not be used. 1, 2

Concomitant Medications That Increase Risk

Discontinue or hold the following medications along with metformin during acute illness in patients with eGFR <60 mL/min/1.73 m²:

• ACE inhibitors and ARBs (increase AKI risk) 1, 3
• Diuretics (volume depletion) 1
• NSAIDs (nephrotoxic) 1
• Aldosterone inhibitors and direct renin inhibitors 1

The combination of metformin with renin-angiotensin system blockers is particularly dangerous during acute illness, as demonstrated in case reports where continued use of both medications during gastrointestinal illness led to severe MALA. 3

When to Restart Metformin After Acute Illness

Do not restart metformin until ALL of the following criteria are met:

1. Complete resolution of the acute illness (no fever, infection controlled, adequate oral intake restored) 4, 7, 5
2. Lactic acidosis has resolved (if present, lactate normalized) 7
3. Renal function has returned to baseline or stabilized (recheck eGFR post-recovery) 7
4. eGFR ≥30 mL/min/1.73 m² (contraindicated below this threshold) 1, 2
5. Patient is hemodynamically stable with normal tissue perfusion 2

The optimal timing for metformin restart has not been well-studied, but it is reasonable to wait 48-72 hours after acute illness resolution and confirm stable renal function before reintroduction. 7

Recognition and Treatment of MALA

Suspect MALA in any patient on metformin who presents with:

• High anion gap metabolic acidosis (pH <7.35) 2, 7
• Elevated lactate (>5 mmol/L, often >15 mmol/L) 2, 7, 3, 6
• Nonspecific symptoms: malaise, myalgias, abdominal pain, respiratory distress, somnolence 2
• Hypotension and resistant bradyarrhythmias in severe cases 2

Immediate management:

1. Discontinue metformin immediately 2, 7
2. Initiate hemodialysis or continuous renal replacement therapy (CRRT) for severe cases (metformin is dialyzable with clearance up to 170 mL/min) 2, 4, 6
3. Provide supportive care: fluid resuscitation, vasopressors if needed, treat underlying infection/illness 7, 3, 6
4. Prolonged or repeated dialysis may be necessary because metformin has a large volume of distribution and accumulates in erythrocytes/intestinal cells, causing rebound lactic acidosis after initial dialysis 3

Common Pitfall to Avoid

The most critical error is patients continuing metformin during acute illness because of inadequate counseling. 4, 5 Research demonstrates that awareness of MALA among both patients and clinicians is insufficient, resulting in preventable cases. 5 Temporary discontinuation of metformin does not harm glycemic control and may prevent a potentially fatal complication. 4, 5

Emphasize to patients: It is safer to stop metformin unnecessarily for a few days than to continue it during illness and risk life-threatening lactic acidosis. 4, 5

1, 8, 2, 4, 7, 3, 6, 5