Metformin and Metformin-Associated Lactic Acidosis
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Direct answer
Metformin-associated lactic acidosis is a rare but serious complication in which metformin accumulates, usually with kidney failure, hypoxia or liver disease, and lactate builds up to cause severe acidaemia. Metformin is contraindicated when eGFR is below 30 mL/min per 1.73 m2, and initiation is not recommended between 30 and 45. Management is immediate withdrawal, supportive care and early haemodialysis for severe acidosis.
What you must remember
- Mechanism: metformin inhibits complex I of the mitochondrial respiratory chain and reduces hepatic gluconeogenesis, so lactate production rises while clearance falls.
- Diagnostic picture: lactate typically above 5 mmol/L with a low pH and raised anion gap in a patient taking metformin.
- eGFR thresholds: contraindicated below 30, not started between 30 and 45, and reviewed for benefit and risk in existing users whose eGFR falls below 45.
- Contrast rule: withhold metformin at the time of iodinated contrast in at-risk patients and restart only after renal function is confirmed stable, usually about 48 hours later.
- Surgery and acute illness: withhold metformin on the day of surgery and during hypoxia, sepsis or dehydration, and restart once eating and renal function are stable.
- Liver and alcohol: decompensated liver disease and heavy alcohol intake raise lactate risk, so metformin is avoided in these patients.
- Long-term effect: metformin reduces vitamin B12 absorption, so B12 levels are checked in long-term users with neuropathy or anaemia.
A stepwise approach to suspected MALA
Suspected metformin-associated lactic acidosis is an emergency, and the work-up runs alongside resuscitation. The steps below show how a clinician confirms the picture and rules out commoner causes.
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Recognise the picture. Nausea, vomiting, abdominal pain, deep rapid breathing, hypotension and altered consciousness appear in a patient taking metformin with kidney, liver or cardiorespiratory illness.
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Confirm with gas and lactate. Measure arterial blood gas, serum lactate and electrolytes, and send a metformin level where it is available. A lactate above about 5 mmol/L with a low pH and raised anion gap supports the diagnosis.
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Exclude commoner causes. Shock, sepsis, ischaemia and toxins cause lactic acidosis far more often than metformin, so the primary cause must be treated at the same time.
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Stop metformin and support. Withhold metformin, correct hypovolaemia and hypoxia, and support the circulation in an intensive care setting.
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Use haemodialysis early. Dialysis removes both metformin and lactate and is the most effective step in severe cases, particularly with failing kidney function or refractory acidosis.
Where the exam tries to catch you
Metformin questions usually test the eGFR threshold, the contrast rule or the first step in management.
- Trap: continuing metformin during iodinated contrast in a patient with reduced kidney function. Correct: withhold metformin at the time of contrast in at-risk patients and restart only after renal function is confirmed stable.
- Trap: attributing every lactic acidosis in a patient on metformin to the drug. Correct: shock, sepsis and hypoxia are commoner causes, so the underlying cause must be treated alongside stopping metformin.
- Trap: choosing bicarbonate as the main treatment for severe metformin toxicity. Correct: haemodialysis is the decisive treatment because it clears metformin and lactate, while bicarbonate is only supportive.
Frequently asked questions
At what eGFR should metformin be stopped or not started?
Metformin is contraindicated when eGFR falls below 30 mL/min per 1.73 m2, and initiation is not recommended when eGFR is between 30 and 45. Existing users with eGFR between 30 and 45 need a benefit-risk review and often a dose reduction. These thresholds are standard in product labelling and diabetes guidance.
Why must metformin be withheld around iodinated contrast?
Iodinated contrast can cause acute kidney injury, and reduced clearance then allows metformin to accumulate and raise the risk of lactic acidosis. Metformin is therefore withheld at the time of contrast in at-risk patients and restarted only after renal function is confirmed stable. Renal function is usually rechecked about 48 hours after the study.
How does metformin cause lactic acidosis?
Metformin inhibits complex I of the mitochondrial respiratory chain and reduces hepatic gluconeogenesis, so lactate production rises while its clearance falls. Lactic acidosis is most likely when kidney, liver or tissue perfusion is impaired. This mechanism explains why hypoxia, alcohol and sepsis are important risk factors.
How is metformin-associated lactic acidosis treated?
Treatment begins with stopping metformin, correcting hypovolaemia and hypoxia, and treating any sepsis in an intensive care setting. Haemodialysis is the most effective step in severe cases because it clears both metformin and lactate. Bicarbonate may be considered for severe acidaemia under intensive care protocols.