Clinical Pearls & Morning Reports
Untreated metformin-associated lactic acidosis has a 30 to 50% mortality rate. Read the NEJM Case Records of the Massachusetts General Hospital here.
Q: What causes lactic acidosis in cases of metformin toxicity?
A: Metformin can cause lactic acidosis by increasing lactic acid production and decreasing lactic acid clearance. Metformin is eliminated by the kidneys, and when the creatinine clearance falls below 45 ml per minute per 1.73 m2 of body-surface area, the blood metformin level starts to rise. Metformin inhibits the mitochondrial metabolism of pyruvate by blocking the conversion of pyruvate to oxaloacetate. This leads to increased levels of lactic acid. Lactic acid is cleared by the liver through gluconeogenesis, but metformin also inhibits this process, which leads to lactic acidosis.
Q: Is there a known therapeutic range for metformin?
A: Although metformin has been in use for more than half a century, dose–response trials evaluating plasma concentrations of metformin are lacking, and therefore, a therapeutic range has not been determined.
A: Metformin is generally considered safe and effective for the management of type 2 diabetes. Although the use of metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) of less than 30 ml per minute per 1.73 m2 of body-surface area, it is also generally not recommended in patients with an eGFR between 30 and 45 ml per minute per 1.73 m2. In patients currently receiving therapy, the risks and benefits of continuing therapy need to be evaluated if the eGFR drops below 45 ml per minute per 1.73 m2. The cautious continued use of metformin in patients who have been receiving therapy and have an eGFR between 30 and 60 ml per minute per 1.73 m2 or have other risks has been advocated, in part, because the incidence of lactic acidosis in this population is not substantially greater than the incidence among patients with type 2 diabetes who have sufficient renal function. Furthermore, some reports suggest that the mortality associated with lactic acidosis due to metformin use has generally been decreasing over time. However, it is important to reconcile these guidelines with the medical history of the individual patient.
A: Metformin is a small molecule with minimal protein binding and a large volume of distribution and hence can be removed by dialysis. Metformin can be readily removed with just a few hours of hemodialysis. However, it is also apparent that it can be difficult to remove all the metformin with hemodialysis alone, and a reservoir of metformin can appear to be present in red cells, which can result in a large rebound phenomenon after the discontinuation of hemodialysis. Although hemodialysis is the preferred therapy for the elimination of metformin in patients with severe type B lactic acidosis, this treatment may not be possible in patients who have hemodynamic instability. In these situations, one can use other forms of renal replacement therapy that have a lesser hemodynamic effect, such as continuous venovenous hemofiltration or continuous venovenous hemodialysis. Although such methods result in a slower removal of the metformin, they may still be lifesaving.