Original Contribution
Can acute overdose of metformin lead to lactic acidosis?

https://doi.org/10.1016/j.ajem.2009.04.012Get rights and content

Abstract

Introduction

Metformin-associated lactic acidosis (MALA) is well described in patients taking therapeutic metformin who develop renal failure or other serious comorbid conditions. Metformin-associated lactic acidosis from acute overdose has also been described in case series but is debated by some clinicians, arguing that metformin overdose does not cause lactic acidosis. Our aim was to perform a multicenter poison control database review to determine if MALA can occur in mono-overdose patients with no comorbid conditions.

Methods

This was a retrospective chart review of the Illinois and Washington Poison Centers between the 2001-2006 and 1999-2006 periods, respectively. Metformin overdoses that were referred to health care facilities were categorized into mono-overdose with or with out MALA and polypharmacy overdose with or without MALA.

Results

The overall prevalence of MALA was 14 (3.5%) of 398 cases referred to a health care facility. Metformin-associated lactic acidosis occurred in 9.1% of mono-overdose and in 0.7% of polypharmacy overdose patients referred to health care facilities and was 16% for intentional mono-overdoses. There was one death of 132 mono-overdoses referred to health care facilities.

Conclusions

Apparent metformin mono-overdose is associated with MALA. Dosages that place patients at risk for MALA will require additional study.

Introduction

Metformin is a commonly prescribed oral antihyperglycemic agent. Metformin-associated lactic acidosis (MALA) is a well-described complication in patients taking metformin chronically. Prevalence of MALA has been reported to be approximately 1 to 10 cases per 100 000 patient years [1], [2], [3]. This phenomenon is generally described during therapeutic dosing rather than overdose. Traditional theory suggests MALA occurs in the context of comorbid pathologic conditions such as renal insufficiency that results in drug accumulation and subsequent lactic acidosis [1], [4]. The link between metformin and lactic acidosis has been called into question by some, suggesting that MALA has been observed in the setting of other acute illnesses that are more likely to be the cause of lactic acidosis (eg, acute renal insufficiency, acute cardiovascular events, respiratory failure, hemodynamic instability, or hepatic failure) rather than metformin itself [2], [3], [5], [6]. Some data support this claim by the lack of correlation between metformin levels and the development of MALA [6], [7]. A recent Cochrane review concluded that there is no evidence of an association between metformin and lactic acidosis; however, these data were analyzed from studies using metformin therapeutically and cannot be applied to the overdose population [8].

There are little data regarding MALA in the setting of acute metformin overdose. Based on 2006 US poison control center data, there were 5151 cases of biguanide exposures reported resulting in 18 critical complications and 9 deaths [9]. Several case reports have described severe MALA from acute overdose [10], [11], [12]. Some authors, however, suggest that lactic acidosis in the setting of acute metformin overdose is not observed, and metformin may even be protective against lactic acidosis [3], [7]. Furthermore, Lalau [7] postulates that lactic acidosis in the setting of acute overdose is due to hemodynamic instability rather than a direct effect of metformin. One retrospective poison center review revealed 6 cases of MALA of 62 acute overdoses with 3 deaths; however, the authors did not characterize coingestants, comorbidities, or hemodynamic status of the patients [4].

Our aim was to determine if lactic acidosis can occur in the setting of acute metformin overdose in patients who were reported to 2 regional poison centers. Our study hypothesis is that an acute mono-overdose of metformin in the absence of comorbidities can result in lactic acidosis.

Section snippets

Study design

This was a retrospective chart review using data from 2 regional poison control centers evaluating lactic acidosis from acute metformin overdose. Institutional review board approval was obtained.

Setting and population

The study was conducted using data obtained from electronic medical records of the Illinois and Washington Poison Centers that have a combined call volume of more than 204 000 calls per year. Cases were queried using the keyword “metformin,” “biguanide,” or “glucophage.” Based on the beginning of

Results

There were 1349 reported patients of which 412 were referred to health care facilities. Table 1 shows the patient characteristics of the study sample. Ninety-six mono-overdose and 209 poly-overdose charts were categorized as non-MALA due to missing pH and lactate values. Of the 412 charts abstracted, there were 28 cases of lactic acidosis. Of these, 12 cases of mono-overdose and 2 cases of polypharmacy were identified as MALA (Fig. 1). The overall estimate of prevalence for MALA was 14 (3.5%)

Discussion

Metformin-associated lactic acidosis was observed with mono-overdose in the absence of comorbidities. Prevalence of MALA in polypharmacy overdoses was substantially lower than for mono-overdose. This could be due to a true effect but could also be due to our stringent exclusion criteria for coingestants and comorbidities. Most MALA cases were associated with large intentional overdoses.

These data provide some evidence that large single acute ingestions of metformin in the absence of documented

Limitations

These data did not include metformin concentrations that would have been useful to document exposure to metformin. We have relied on historical evidence of metformin overdose alone. Unfortunately, metformin levels are not routinely available or sought after and require sending samples to a reference laboratory. There is one case series of metformin overdose that reported a poor correlation between metformin concentration and severity of lactic acidosis [7]. Interpretation of these data can be

Conclusion

Apparent metformin overdose is associated with MALA. These data cannot provide the true prevalence of this disorder but give an estimate for patients referred to health care facilities from regional poison centers. Although MALA was traditionally described with therapeutic dosing in diabetic patients with other comorbidities, we believe MALA can occur after significant acute ingestion of metformin. Whether MALA is strictly a dose-dependent phenomenon or if there are other host predispositions

Acknowledgment

The opinion and assertions contained herein are the views of the author and are not to be construed as official or as reflecting the views of the United States Department of Defense.

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An abstract of these data was presented at the Government Services Chapter of the American College of Emergency Physicians annual meeting held in San Antonio, Tex, 2009.

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