Metformin-associated lactic acidosis

Today we saw a patient in continuity clinic for hospital follow-up who had been hospitalized with severe lactic acidosis (initial pH <6.8, lactate 14.7), shock, and severe acute renal failure. Her medications at the time of admission included metformin. No other cause of the lactic acidosis/shock was found (all cultures negative). She had longstanding DM and HTN, but no history of CKD. She was dialyzed once, and recovered fully.

Metformin-induced metabolic acidosis is a rare but well-characterized complication of metformin therapy, seen in the setting of either acute kidney injury or chronic kidney disease. Metformin is excreted by the kidneys, hence accumulates to toxic levels in the setting of acute or chronic kidney disease, either with chronic use or in acute overdose. Mortality in this condition is high (45%), and lactate levels are not predictive of mortaility. Metformin is thought to induce lactic acidosis via its inhibition of hepatic gluconeogenesis (conversion of lactate and pyruvate to glucose) and via a direct stimulation of lactate production from glucose in the small intestine. Hemodialysis should be considered in the setting of metformin toxicity, especially when renal failure is present.

It should be noted that when used appropriately, large epidemiologic studies have failed to show an increased risk of metabolic acidosis in patients treated with metformin as compared with other diabetic medications, hence it is considered safe.

-SEM 1/11/13
This was a educational case, I found a good review article 

Use of metformin in mild to moderate renal insufficiency.pdf

• Details
• Download
• 135 KB

According to FDA prescribing guidelines Metformin is contraindicated for SCr >/=1.4 (women) and >/=1.5 (men) but with these SCr values there can be great variation in eGFR. Canadian, UK and Australian guidelines includes eGFR in addition or in place of SCr values and probably will be better to follow to prevent the use of metformin in people with low renal functions.
Higher metformin concentrations do not consistently occur in those with more severe degrees of lactic acidosis. Metformin levels are not linked to mortality in those who develop lactic acidosis, perhaps reflecting the primary effect of the underlying cause of the acidosis (e.g., hypoxia, hemodynamic compromise) on outcomes rather than incriminating metformin itself. Even with these limitations I think MALA should be a differential and as Dr. Maynard mentioned IHD/CRRT should be considered, especially in patients with renal failure.
Pradeep 1/12/13