Metformin is a biguanide that is used as a first-line drug for the treatment of type 2 diabetes mellitus (T2DM). Metformin is a safe and effective antihyperglycemic agent whose main mechanism of action is the reduction of hepatic gluconeogenesis and promotion of anaerobic glycolysis, during which lactate is generated.1–5 This drug also reduces intestinal glucose absorption and fatty acid oxidation and has demonstrated cardiovascular benefits,4 protecting endothelial function and reducing cardiomyocyte apoptosis during periods of ischemia.4,6

Under normal conditions, treatment with metformin only moderately increases lactate levels,7 but this increase can be substantial with high levels of metformin (either by accumulation or by an overdose), leading to potentially lethal lactic acidosis.6,8 Moreover, although it demonstrates a good safety profile, some of the side effects of metformin include gastrointestinal problems, headache or taste disorders. However, its most serious adverse effect, type B lactic acidosis, has been associated with mortality rates ranging from 30 to 50%. Although some studies have reported that elevated levels of lactic acid are associated with mortality, there is still little evidence on whether other factors can also influence the severity of metformin intoxication (MI),4,9 since case series published in the literature are not very extensive.

Traditionally, lactic acidosis in people receiving treatment with metformin can be classified into the following three types10: metformin-unrelated lactic acidosis (MULA), metformin-induced lactic acidosis (MILA), and metformin-associated lactic acidosis (MALA). In the first case, as the name suggests, metformin is not the cause of acidosis; instead, another intercurrent pathology, such as sepsis, is solely responsible for the lactic acidosis in the patient. The second type occurs when metformin is the only cause of the lactic acidosis without apparent associated diseases and is usually related to acute poisoning. Finally, MALA is defined by the presence of other associated factors (acute kidney injury [AKI], sepsis, hypoxemia, liver failure, alcoholism, acute myocardial infarction, iodinated contrast media or shock) in addition to the treatment with metformin itself; in these cases, lactic acidosis is a consequence of both conditions.

The objective of this study was to identify possible predictors of severity in patients diagnosed with MI. The main event was defined as the need for extrarenal purification (ERP) and/or death of the patient. The need for ERP was established according to the criteria of the Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup guidelines.11

During the study period, 72 patients who were diagnosed with MI were identified, 50 of whom (69.4%) presented with the main event, which was defined as the need for ERP and/or death (39 patients required ERP and 21 patients died). The mean age was 74.8 ± 10.9 years, and 56.9% of the participants were women.

The majority of MIs were classified as MALA (67 patients, 93%); 51 patients had AKI (48 of prerenal etiology with a history of emetic syndrome and/or diarrheal syndrome in the days prior to MI, one of an obstructive etiology, 1 due to contrast agent administration in a patient with CKD grade 3B and one due to taking nonsteroidal anti-inflammatory drugs (NSAIDs) in a patient with CKD grade 3A), eight patients had an infectious process without hemodynamic repercussions, four had a septic process, three had decompensation of their cardiac insufficiency and one had upper gastrointestinal bleeding. In addition, five patients were diagnosed with MILA-type MIs that were caused by a voluntary metformin overdose with autolytic ideation.

Table 1 shows the baseline characteristics of the patients according to whether they did (Group I) or did not present the main event (Group II). We found that patients in Group II were more likely to have CKD grade 3A and to have overdosed with autolytic intention. At the level of pharmacological treatment, no differences were detected in the numbers of drugs taken by the patients [55 patients (76.4%) took angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists (ARBs), 15 (20.8%) took NSAIDs and five (2.5%) took aldosterone antagonists; the differences for the individual drugs were also not significant]. Fifty patients (69.4%) were taking diuretics, with a higher proportion in Group I. Likewise, 69.4% of the patients received metformin at a dose that was adjusted for their renal function, and 30.6% of the patients received metformin at a higher dose, as recommended on the basis of their baseline eGFR; neither of these proportions differed between the groups.

The analytical data of the patients with MI are shown in Table 2. The patients in Group I had higher plasma creatinine and lactic acid levels and anion gaps and lower pH and bicarbonate levels at the time of diagnosis. Metformin levels were determined in 52 patients (72.2%) (39 in Group I [78%] and 13 in group II [59.1%]), and generally, the levels were higher in the patients in Group I.

In terms of therapeutic management, serum therapy and intravenous bicarbonate were administered to both groups at doses determined according to the protocol and usual clinical practice, but the differences in the percentages of patients treated were not statistically significant (Group I vs. Group II: 85.4% vs. 100% and 81.2% vs. 65.0%, respectively; both p > 0.05).

During follow-up, 39 patients (54.2%) required ERP, of whom 24 (61.5%) received ERP by low-flux hemodialysis and 15 (38.5%) received ERP by continuous veno-venous hemodiafiltration because of hemodynamic instability. The patients who required ERP required greater support with vasoactive drugs (66.7% vs. 12.1%, p < 0.001), were more likely to be admitted to the ICU (71.8% vs. 6.1%, p < 0.001), and had plasma levels of metformin (20.6 [13.6–46.5] vs. 8.5 [4.3–25.6] μg/mL, p = 0.01).

With respect to mortality, 21 patients (29.2%) died after the diagnosis of MI, of whom 10 (25.6%) had undergone ERP and 11 (33.3%) had not; this difference was not significant.

According to the multivariable analysis, the lactic acid concentration at admission was the only predictor of the main event, with an area under the ROC curve of 0.78 and an OR of 10.7 (2.3–50.0) (p = 0.003); the corresponding cutoff point was ≥9.6 mmol/L (Table 3 and Fig. 1).

Figure 1.

ROC curve of lactic acid levels for the main event (need for extrarenal purification and/or death).

In multivariable analysis solely for the need for ERD, the metformin level at admission was identified as a predictive factor, with an area under the ROC curve of 0.75 and an OR of 33.5 [3.7–302.6] (p = 0.002) and a cutoff point of ≥9.4 μg/mL (Table 4 and Fig. 2).

Figure 2.

ROC curve of metformin level for the need for extrarenal purification in patients with metformin intoxication.

Finally, the evolution of renal function was analyzed at 3 months after MI, and no differences were found between the groups. for creatinine concentration, Group I presented an increase of +0.23 ± 0.07 mg/dL with respect to the baseline value, and Group II presented an increase of +0.20 ± 0.08 mg/dL (p = 0.7 between the groups).

Metformin remains the most commonly used drug for the treatment of hyperglycemia in patients with T2DM,12 demonstrating clear benefits even in those with CKD.13 Metformin is effective and safe but also has adverse effects, among which type B lactic acidosis is the most important. Metformin-related hyperlactatemia results from the effects of the drug on glucose metabolism. Under normal conditions, the pyruvate generated by glycolysis is incorporated into the Krebs cycle, where it is converted into CO2 and H2O through an energy generation process. In the presence of metformin, pyruvate is converted into lactic acid through the enzyme lactate dehydrogenase, and although at usual metformin doses, this conversion has no clinical consequences, in the case of a metformin overdose, there is a risk of hyperlactatemia and lactic acidosis.14 Lactic acidosis associated with metformin use is a serious condition and, without treatment, is associated with a mortality rate of 30–50%.10 Therefore, identifying lactic acidosis and understanding factors associated with its occurrence are essential.

This study demonstrated that the levels of lactic acid, bicarbonate and pH at admission, as well as the anion gap and metformin levels, were associated with the need for ERP and/or death in diabetic patients with metformin-associated lactic acidosis. However, only lactate level was identified as an independent factor for the main event.

Several studies support our findings,15 while other studies contradict the associations we observed.16,17 Quesada-Redondo et al. identified advanced age, female sex, and the presence of septic shock and comorbidities as predictive factors for MI-associated mortality.16 Peña Porta et al. reported significant differences between deceased patients with MI and survivors in terms of their creatinine levels and lengths of hospital stay.6 However, unlike in our study, none of these variables maintained their statistical significance in the multivariable analysis.

The importance of hyperlactatemia as a prognostic factor was demonstrated in a study by Boucaud Maitre et al.18 In that study, which included 727 patients with MI, the level of lactic acid was independently associated with mortality, which is consistent with the findings of our study.

Finally, regarding lactate levels, it should be noted that in the EXTRIP guidelines,10 ERP is recommended at a lactate concentration of >20 mmol/L (level of evidence 1D) and suggested at a lactate concentration between 15 and 20 mmol/L (level of evidence 2D). Furthermore, if MI coexists with other conditions (AKI, shock, decreased level of consciousness or liver failure), the guidelines suggest ERP at lower levels of lactate, although a specific concentration is not provided. Our study established a much lower cutoff point of the lactic acid concentration, 9.6 mmol/L as a predictor of the main event; thus, most likely, in patients with MI, ERP was performed at lactate levels below those mentioned in the EXTRIP guidelines.

To confirm metformin contribution to acidemia, its plasma levels must be elevated, and factors such as the dose of metformin taken by the patient, the time elapsed since the last administration, the time of determination of the metformin level, the renal function of the patient and the time of progression must be considered, among other data. Therefore, owing to the difficulty of obtaining metformin levels at the time of care for these patients and given that it is often not possible to obtain all the necessary information, Lalau et al.10 suggested that cases of MALA might be less frequent than initially suspected and that, in the absence of plasma levels, it would be more accurate to define the condition as “lactic acidosis in patients treated with metformin (LATM)”.

In our study, metformin levels were obtained for 52 patients; in the univariable analysis, high metformin levels were related to the need for ERP, and in the subsequent multivariable analysis, these findings were confirmed, with a cutoff metformin level of ≥9.4 μg/mL. This is a novel point, given that other authors, such as Boucaud Maitre et al.,18 who included more than 650 patients with MI, could not demonstrate that metformin was associated with mortality. With respect to metformin levels, it should be emphasized that it took 48–72 h to obtain these levels; thus, the decision to perform ERP was based on the criteria of the EXTRIP guidelines.11 Currently, metformin levels are not included as a criterion for performing ERP, and no previous study has determined a specific level of plasma metformin at which ERP should be indicated. In our study, although we defined a metformin level at which ERP needs to be performed, these levels were assessed 48–72 h after the patient was admitted to the emergency room. It is important to obtain additional scientific evidence by performing studies with a larger number of patients and to develop more rapid methods for obtaining metformin levels so that they can play a more relevant role in the indication for ERD.

Notably, CKD plays a key role in the accumulation of metformin and the development of hyperlactatemia. The importance of renal function is highlighted in the study by Connelly et al.,19 which confirmed the relationship between CKD and lactic acidosis in patients treated with metformin. In addition, this relationship is more pronounced as renal function worsens. In our study, 44.4% of patients had grade 3 CKD, and 30.6% of patients received a higher dose of metformin than recommended for their renal function. Therefore, similar to other studies,20 the results of this study highlight the need to closely monitor renal function in patients with CKD who are treated with metformin as well as the emergence of risk factors that can exacerbate CKD and precipitate MI. This also includes concomitant treatments with different drugs, such as NSAIDs, ACEIs or ARBs, that can affect renal function, as well as the importance of polymedication, as has previously been demonstrated by studies such as that of Boada et al.,21 in which patients diagnosed with MALA received an average of 10 drugs daily, or by our own study, in which the median number of drugs per patient was 9.

The limitations of the present study should be noted. First, this was a retrospective study based on the data collected from medical records. Although it was a simple, fast and cost-effective approach, some records may have been incomplete; nevertheless, we do not consider such incompleteness to have substantially affected the final results of the study. In addition, the retrospective and single-center nature of the study make it difficult to extrapolate the results to populations other than those treated at our hospital.

Finally, it is worth mentioning that to establish the main event criterion, we considered the composite of the need for ERP and/or death, which increased the number of cases in Group I compared with what we would have obtained if the two variables had been analyzed independently.

Future research would benefit from prospective, multicenter studies with larger sample sizes and continuous patient follow-up to increase external validity and facilitate the extrapolation of the findings, thus increasing the quality and scientific relevance of the research.

In conclusion, MI is a serious condition with a high mortality rate. In our study, the only predictive factor for the need for ERP and/or death was the lactic acid concentration, while the metformin level at admission was related to the need for ERP.

This research did not receive specific support from public sector agencies, the commercial sector or nonprofit entities.