Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm

Although metformin has been used for over 60 years, the balance between the drug's beneficial and adverse effects is still subject to debate. Following an analysis of how cases of so-called "metformin-associated lactic acidosis" (MALA) are reported in the literature, the present article reviews the pitfalls to be avoided when assessing the purported association between metformin and lactic acidosis. By starting from pathophysiological considerations, we propose a new paradigm for lactic acidosis in metformin-treated patients. Metformin therapy does not necessarily induce metformin accumulation, just as metformin accumulation does not necessarily induce hyperlactatemia, and hyperlactatemia does not necessarily induce lactic acidosis. In contrast to the conventional view, MALA probably accounts for a smaller proportion of cases than either metformin-unrelated lactic acidosis or metformin-induced lactic acidosis. Lastly, this review highlights the need for substantial improvements in the reporting of cases of lactic acidosis in metformin-treated patients. Accordingly, we propose a check-list as a guide to clinical practice.