Mechanism of Metformin-Associated Lactic Acidosis
Metformin-associated lactic acidosis (MALA) occurs primarily due to metformin's inhibition of mitochondrial function, which impairs lactate clearance and increases lactate production, particularly in patients with compromised renal function. 1, 2
Primary Mechanisms
- Metformin decreases liver uptake of lactate, increasing blood lactate levels which may increase the risk of lactic acidosis, especially in patients with predisposing risk factors 1
- At the cellular level, metformin causes mitochondrial impairment and subsequent adenosine triphosphate (ATP) depletion, accelerating glycolytic flux and increasing glucose uptake 2
- This leads to increased generation of lactate, which effluxes into circulation rather than being oxidized further 2
- The liver appears to be a key organ for both the antidiabetic effect of metformin and the development of lactic acidosis 2
Clinical Presentation and Diagnosis
- MALA typically presents with subtle onset and nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence 1, 3
- More severe cases may present with hypotension and resistant bradyarrhythmias 1
- Laboratory findings include elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis without evidence of ketonuria or ketonemia, and an increased lactate:pyruvate ratio 1
- Metformin plasma levels are generally >5 mcg/mL in cases of MALA 1
Risk Factors
- Renal impairment is the primary risk factor, as metformin is substantially excreted by the kidney 1, 4
- The risk increases with the severity of renal impairment, particularly when eGFR falls below 30 mL/min/1.73 m² 1, 4
- Other risk factors include:
- Advanced age (≥65 years) due to greater likelihood of hepatic, renal, or cardiac impairment 1
- Drug interactions that impair renal function or increase metformin accumulation 1
- Radiologic studies with iodinated contrast agents 1
- Liver disease (impairs lactate clearance) 2
- Conditions with tissue hypoxia (sepsis, shock, heart failure) 5, 6
Incidence and Mortality
- MALA is a rare complication of metformin therapy with an estimated incidence much lower than previously thought 2, 7
- Almost all cases (97%) present with independent risk factors for lactic acidosis, suggesting metformin plays a contributory rather than causative role 7
- Direct metformin-related mortality is close to zero when properly managed, and metformin may even be protective in cases of very severe lactic acidosis unrelated to the drug 2
Management
- Immediate discontinuation of metformin upon suspicion of MALA 1
- Prompt hemodialysis is recommended to correct acidosis and remove accumulated metformin 1, 6
- Hemodialysis serves both symptomatic and etiological treatment by eliminating lactate and metformin 2
- Continuous renal replacement therapy (such as CVVHDF) may be advantageous over conventional intermittent hemodialysis as it corrects acidosis and removes lactate and metformin without risk of hypernatremia or fluid overload 6
Prevention
- Metformin is contraindicated in patients with eGFR less than 30 mL/min/1.73 m² 1, 4
- For patients with eGFR between 30-45 mL/min/1.73 m², careful dose adjustment and monitoring are required 4
- Temporary discontinuation of metformin is recommended during acute illness, dehydration, or before procedures using iodinated contrast 8, 1
- Patient education about symptoms of lactic acidosis and when to discontinue metformin is essential 1
By understanding the mechanism of metformin-associated lactic acidosis, clinicians can better identify at-risk patients, implement appropriate preventive measures, and provide prompt treatment when necessary.