ROLE OF METFORMIN ACCUMULATION IN METFORMIN-ASSOCIATED LACTIC-ACIDOSIS

OBJECTIVE - To investigate the role of metformin accumulation in the p athophysiology of metformin-associated lactic acidosis. RESEARCH DESIG N AND METHODS - We used high-performance liquid chromatography to meas ure plasma metformin concentrations in 14 patients who experienced lac tic acidosis (pH <7.35 and lactate concentration >5 mmol/l) while rece iving chronic metformin treatment. Their treatment was generally based on alkalinization and dialysis therapy. RESULTS - Clinical shock and/ or evidence of tissue hypoxia was found in all patients with the excep tion of one who had a nonsteroidal anti-inflammatory drug-induced anur ia. Ten patients had significant metformin accumulation (plasma metfor min concentrations 4.1-84.9 mg/l, normal value 0.6 +/- 0.5 mg/l before drug intake), generally because of failure to withdraw metformin desp ite intercurrent pathological conditions affecting its renal eliminati on (serum creatinine concentrations ranging from 269 to 1,091 mu mol/l ). There was no metformin accumulation (plasma metformin 0.03-0.7 mg/l ) in the four other patients, who had less severe renal failure (serum creatinine 140-349 mu mol/l). The severity of the patient's general c ondition did not predict early hospital mortality (death before discha rge from the intensive care unit) even in patients in shock. Whereas i t was high in those without metformin accumulation (only 1 of 4 patien ts recovered), early hospital mortality was low in the 10 patients wit h metformin accumulation and was not related to its extent (3 patients died with end-stage hepatic failure or cardiac failure). Correlation studies showed a positive correlation between serum creatinine and pla sma metformin and between plasma metformin and arterial lactate but, f or the latter correlation, only in patients with metformin accumulatio n. CONCLUSIONS - Metformin-associated lactic acidosis is not necessari ly due to metformin accumulation; true type B (aerobic) lactic acidosi s, i.e., without an apparent associated hypoxic factor, seems exceptio nal. Neither the severity of the clinical picture nor the degree of me tformin accumulation predicted survival, rather, the prognosis was dep endent upon the severity of the associated pathological conditions.