Risk of lactic acidosis with metformin acute or CKD
What is the risk of lactic acidosis with metformin therapy in patients with acute or CKD?
Metformin can be rarely associated with lactic acidosis, with an incidence of 3 to 10 per 100,000 person-years. Metformin binds to complex I of the mitochondrial respiratory chain, inhibiting oxidative phosphorylation and thereby increasing the proportion of uncoupled respirations. This leads to increased glycolysis and glucose uptake and shuts off gluconeogenesis in the liver. Because oxidative phosphorylation is inhibited, pyruvate is shunted to lactate instead of acetyl CoA in order to restore the NAD+ needed for glycolysis. If metformin levels get too high, the lactate can increase to clinically significant levels and cause metformin associated lactic acidosis (MALA). The greatest risk factor for MALA is impaired kidney function. The FDA recently relaxed use in certain patients with diminished kidney function based on its favorable safety profile. The prior contraindication of a serum creatinine ≥1.5mg/dL in males and ≥1.4mg/dL in females was updated to a genderless, GFR-based definition of <30mL/min. The FDA does not recommend starting metformin in patients with an eGFR of 30 to 45 mL/min, but does support continuing metformin if drug was started at an eGFR >45 mL/min and the patient’s kidney function gradually declines to an eGFR 30 to 45 mL/min. However, kidney function should be monitored frequently. MALA is reversible with drug discontinuation and improvement of kidney function, but has been associated with fatalities. In cases of overdose, HD should be considered to remove metformin and correct the underlying acidosis.
