Metformin-associated lactic acidosis

Metformin is an oral hypoglycemic drug that has long been employed in the treatment of type 2 diabetes; it is particularly widely prescribed for those diabetics who are obese. Very rarely, metformin use results in severe lactic acidosis, most often occurring in patients with reduced renal function. 

Although a very rare adverse effect, metformin-associated lactic acidosis (MALA) is significant because it has a high (30-50 %) mortality rate. Lactic acidosis (unrelated to metformin) is a relatively common occurrence among the critically ill and usually arises as a result of tissue hypoxia consequent on the inadequate perfusion associated with clinical shock. 

The list of severe acute illnesses/conditions that can result in lactic acidosis is long and includes severe sepsis (septic shock), severe trauma (hemorrhagic shock), anaphylactic shock, cardiac arrest and acute liver failure. In all of these cases prognosis is predicted by the severity of the lactic acidosis; the higher the peak serum lactate and the lower the blood pH falls, the greater is the risk of not surviving these acute illnesses. 

Although metformin is a very rare cause of lactic acidosis, it is almost invariably very severe. Curiously, however, as a recently published study has confirmed, the severity of MALA does not seem to predict outcome. 

This study is a retrospective analysis of all patients (n=197) admitted to one German medical intensive care unit during a 5-year period (2004-2008) with lactic acidosis (defined as serum lactate > 5 mmol/L and blood pH < 7.35). Of the 197 patients, 10 had suffered MALA and 187 had suffered lactic acidosis of other origin (LAOO). 

Lactic acidosis was significantly more severe among the MALA group; mean serum lactate for the MALA group was 18.7 ± 5.3 mmol/L compared with 11.2 ± 6.1 mmol/L for the LAOO group, and mean arterial pH was just 6.78 (range 6.5-6.94) for the MALA group; significantly lower than the mean pH for the LAOO group (7.20 [range 6.46-7.35]). 

All (100 %) patients with MALA had an arterial pH < 7.00 but only 31 (16 %) in the LAOO group had a pH below 7.00. None of the 31 LAOO-group patients with pH < 7.00 survived, but 50 % of patients in the MALA group did survive. The study confirms that the prognosis is far better for patients with metformin-associated lactic acidosis than for patients with similarly severe lactic acidosis resulting from other causes. 

When comparing data for the five patients with MALA who survived with that for the five MALA patients who died there was no difference in the severity of the lactic acidosis. For these patients severity of lactic acidosis did not predict outcome. Quite separately the study has demonstrated that MALA is distinguished from LAOO by severity of renal dysfunction. 

Mean serum creatinine for the MALA group was 796 ± 324 mmol/L; this compared with just 307 ± 265 mmol/L for the LAOO group. This finding reflects the well-documented observation that metformin-associated lactic acidosis very rarely occurs in those with normally functioning kidneys.