The biguanide metformin is a first-line oral antihyperglycemic agent used to treat type 2 diabetes mellitus.
Metformin decreases hepatic gluconeogenesis from lactate and improves peripheral uptake of glucose. It has been postulated that under certain conditions metformin can cause mitochondrial inhibition, resulting in the release of free protons, which leads to increased lactate concentrations (1).
Another biguanide, phenformin, was removed from the US market in 1977 due to association with a life-threatening metabolic acidosis with elevated lactic acid (1). However, this adverse event is 20x less common in metformin.
This process has been termed metformin-associated lactic acidosis (MALA), also referred to as metabolic acidosis with an elevated lactate concentration.
The biochemical and pathophysiologic process involving this condition is complex, but metformin is typically being taken at doses that exceed recommendations when lactic acidosis occurs. Risk factors for MALA include renal dysfunction, cardiorespiratory insufficiency, septicemia, liver disease, a history of MALA, advanced age, alcohol abuse, and radiologic contrast exposure (1). A retrospective study by Dell’Aglio et al. found no deaths occurring in patients who documented the lowest pH above 6.9, peak serum lactate concentration less than 25 mmol/L, or peak metformin level less than 50 mcg/ml (2).
Common symptoms include nausea, vomiting, abdominal pain, malaise, myalgias, and dizziness. Physical exam findings are non-specific, but severe presentations may have blindness, confusion, respiratory insufficiency, hypothermia, or hypotension (1). Labs should be used to rule out alternative causes. Serum metformin concentration can be ordered, but it is not required if there is a high clinical suspicion.
Management includes aggressive supportive care. A definitive airway should be obtained and pressors initiated, if indicated. Sodium bicarbonate drips are controversial in severe metabolic acidosis, but initiation has been proposed when the serum bicarbonate concentration is less than 5 mEq/L (1). Unfortunately, metformin is only moderately dialyzable due to a large volume of distribution. There are case reports of extracorporeal membrane oxygenation (ECMO) bridging patients to recovery after metformin overdose (3). ECMO should be considered if serum lactate level is greater than 20 mmol/L, pH is less than or equal to 7.00, or with failure of standard therapy (4).