From the Guidelines
Metformin-associated lactic acidosis presents as a severe metabolic condition characterized by high anion gap acidosis with elevated lactic acid levels, typically above 5 mmol/L, and is more common in patients with risk factors such as kidney impairment, liver disease, heart failure, excessive alcohol intake, or during acute illness with dehydration, as noted in a recent study 1.
Key Characteristics of Metformin-Associated Lactic Acidosis
- High anion gap acidosis with elevated lactic acid levels
- Nonspecific symptoms including nausea, vomiting, abdominal pain, lethargy, and altered mental status
- Severe manifestations such as hypotension, hypothermia, respiratory distress, and cardiac arrhythmias
- Laboratory findings showing a pH below 7.35, decreased bicarbonate levels, elevated lactate, and signs of kidney dysfunction with increased creatinine
Pathophysiology and Risk Factors
The pathophysiology involves metformin's inhibition of mitochondrial respiration and gluconeogenesis, leading to increased lactate production and decreased lactate clearance, particularly when kidney function is compromised, as discussed in 1 and further supported by older studies such as 1 and 1.
Management and Prevention
Prompt recognition is crucial, and treatment requires immediate discontinuation of metformin, supportive care, and often hemodialysis to remove both metformin and excess lactate, as emphasized in more recent guidelines and studies like 1 and 1.
Important Considerations
- Metformin should be avoided in patients at risk for lactic acidosis, such as those with significant renal impairment, liver failure, or during acute illness with dehydration.
- Dose reduction is recommended if the estimated glomerular filtration rate (eGFR) is 30–45 mL/min per 1.73 m², and metformin should be discontinued if the eGFR is less than 30 mL/min per 1.73 m², as suggested by 1.
- Lactate concentrations should be measured in fragile patients, and metformin should be withdrawn if increased lactate concentrations are apparent.
From the FDA Drug Label
There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis Metformin associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL
Metformin lactic acidosis is characterized by:
- Nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence
- Elevated blood lactate concentrations (>5 mmol/L)
- Anion gap acidosis (without evidence of ketonuria or ketonemia)
- Increased lactate: pyruvate ratio
- Metformin plasma levels generally >5 mcg/mL
- Hypotension and resistant bradyarrhythmias may occur with severe acidosis 2
From the Research
Metformin Lactic Acidosis Characteristics
- Metformin-associated lactic acidosis (MALA) is a rare but serious complication of metformin use, associated with high mortality 3.
- MALA can occur when a patient on metformin suffers disruption in renal function, resulting in the accumulation of metformin 4, 3.
- The condition often presents with nausea, vomiting, and fatigue, which can mimic sepsis 3.
- Laboratory findings may include severe lactic acidosis, renal failure, hyperkalemia, and anion gap metabolic acidosis 5, 3, 6.
Risk Factors and Triggers
- Preexisting renal disease or chronic nephropathy increases the risk of MALA 4, 5.
- Concomitant diseases or situations, such as sepsis, fever, diarrhea, vomiting, or heart failure, can reduce metformin renal clearance and contribute to lactic acidosis 4.
- The use of certain medications, like angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), can also increase the risk of MALA 3, 6.
Treatment and Management
- Treatment of MALA is primarily supportive, with a focus on correcting acidosis, electrolyte alterations, and maintaining fluid balance 4, 5.
- Hemodialysis or continuous renal replacement therapy (CRRT) may be necessary to remove metformin and improve outcomes 4, 5, 6, 7.
- Prolonged dialysis may be required in severe cases of MALA to achieve significant improvement 6.
- Identifying metformin levels can help in diagnosis and management, but this is not widely available 6.