Metformin‐associated lactic acidosis: Moving towards a new paradigm?

The history of metformin-associated lactic acidosis (MALA) is rooted in the earlier experience with phenformin, another biguanide treatment for type 2 diabetes that was removed from the market owing to a clear causal association with cases of lactic acidosis (LA). Although metformin is less problematic in this regard, metformin can and does induce LA, and under the right circumstances it continues to present a potential risk to patients. Recent liberalization of the prescribing guidelines in the USA and European Union specifically regarding use in more advanced stages of chronic kidney disease (CKD) have led to renewed interest in the topic of MALA, and this issue of Diabetes Obesity Metabolism presents two timely articles on the topic, by Lalau et al. and Connelly et al. Lalau et al. outline a new way of thinking regarding the extremely rare, but often serious and potentially fatal, condition of MALA. They present a thoughtful analysis of existing MALA data and propose a more precise framework and nomenclature for categorizing LA with regard to whether metformin is clearly implicated causally, or is more of an “innocent bystander”. Specifically, the authors propose a framework, primarily based on the presence of any other underlying condition that can cause LA, as well as a metformin measurement, within the proposed “umbrella” category of “lactic acidosis in metformin therapy” (LAMT) as follows. (1) Metformin-induced LA (MILA): cases where (i) no known additional conditions that could lead to LA are present and (ii) a high plasma metformin concentration value is available or there is evidence suggestive of metformin accumulation based on the patient's metformin dose, renal function, and time since last dose. (2) Metformin-unrelated LA (MULA): cases with good evidence of an intercurrent acute illness or condition that can lead to LA, together with low actual or assumed metformin concentration(s). (3) MALA: cases with insufficient information to rule out metformin involvement. While a more precise categorization paradigm may provide useful guidance to clinicians when dealing with suspected cases of MALA, the authors suggest that metformin does not play a contributing role in cases in which any other condition could be attributed to the LA event, and conclude that MULA “is probably by far the most common.” The authors do not provide new data to justify such a conclusion, and this conclusion does not incorporate the additive and perhaps synergistic effect metformin concentration has on inducing LA when a secondary event occurs. Contrary to the authors’ assessment, MALA represents the majority of cases as there is often insufficient information in real-world clinical settings to definitively exclude metformin as a contributing cause of LA. The underlying assumption made by Lalau et al. is that a single low measurement of plasma metformin and the presence of any other hypoxic condition is sufficient to rule out metformin relatedness. We do not believe that metformin's involvement in the development of LA can be so easily excluded for two reasons. Firstly, metformin increases the risk of LA. Because of its ability to disrupt lactate metabolism, metformin accumulation can cause LA on its own in extreme cases (eg, renal failure, overdose), and moderate accumulation can increase the likelihood that a secondary hypoxic event would lead to LA even though the severity of such an event may not have been sufficient to lead to LA in the absence of metformin accumulation. Thus, metformin use presents a risk of metformin plasma accumulation, which lowers the threshold for any relevant other intercurrent event to induce LA. As such, a secondary condition/ event is often present in cases of MALA, but that is an insufficient reason to exclude metformin accumulation as a contributing factor. The relationship between degree of metformin accumulation and severity of a secondary hypoxic condition as it relates to LA risk is complex, as exemplified in Figure 1. Secondly, the temporal relationship between metformin accumulation and effects on oxidative metabolism and ensuing acidosis risk are not completely understood. A recent publication by Neal et al. showed that exposure to high concentrations of metformin can have prolonged effects on oxidative metabolism, even after a lengthy washout. Thus, even if metformin concentrations are low at the time of assessment (possibly many hours after LA ensued), a contributing role of metformin cannot be excluded. This is consistent with reports of MALA that are refractory to the commonly employed treatment haemodialysis. Thus, for reasons stated we believe that, in the vast majority of cases, we do not have the ability to exclude the known ability of metformin to increase LA risk. Our concern is that, while attempting to add more precision to the terms used to define LA in the presence of metformin use, a binary classification system that would discount the contribution of metformin based on a cross-sectional assessment of the patient would be inappropriate from a pharmacovigilance perspective as it will probably lead to underreporting of metformin's association with LA. We refer the reader to a recent report by Boucaud-Maitre et al. not discussed by Lalau et al, which provides a Received: 24 April 2017 Revised: 26 April 2017 Accepted: 27 April 2017