# Lactic acidosis with metformin accumulation in the intensive care units of the Nord Pas de Calais region: A known serious adverse event that can be better prevented.

Sophie Gautier, Julie Truong-Minh, Johanna Béné, J. Temime, M. Granier, Benjamin Hennart, Sandrine Bergeron, Emmanuelle Jaillette

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Sophie Gautier, Julie Truong-Minh, Johanna Béné, J. Temime, M. Granier, et al.. Lactic acidosis with metformin accumulation in the intensive care units of the Nord Pas de Calais region: A known serious adverse event that can be better prevented.. Therapie, 2025, Therapie, 10.1016/j.therap.2024.12.009. hal-05043631

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PHARMACOVIGILANCE

# Lactic acidosis with metformin accumulation in the intensive care units of the Nord Pas de Calais region: A known serious adverse event that can be better prevented

Sophie Gautier<sup>a,*</sup>, Julie Truong-Minh<sup>a</sup>, Johana Béné<sup>a</sup>, Johanna Temime<sup>b</sup>, Maxime Granier<sup>c</sup>, Benjamin Hennart<sup>d</sup>, Sandrine Bergeron<sup>a</sup>, Emmanuelle Jaillette<sup>e</sup>

Reçu le 21 octobre 2024 ; accepté le 6 décembre 2024

KEYWORDS

Metformin associated
lactic acidosis ;
Prevention ;
Dehydration ;
Infection

Summary

**Objective.** — Metformin-associated lactic acidosis (MALA) is a rare but serious adverse drug reaction (ADR). The aim of the study was to identify clinical situations associated with the onset of MALA in patients hospitalised in the Nord Pas de Calais regional intensive care units (ICUs), and to assess its preventability.

**Material and methods.** — We included all cases of MALA, identified by metformin accumulation > 2.3 mg/dL and lactate > 2.2 mmol/L, reported by the regional ICU physicians to the Regional Centre of Pharmacovigilance and registered in the French Pharmacovigilance Database between 1 January 2017 and 30 December 2018.

<footnote><sup>a</sup> CHU Lille, University Lille, Pharmacology Department, Regional Centre of Pharmacovigilance, 59000 Lille, France</footnote>

<footnote><sup>b</sup> Department of Anesthesiology and Critical Care Medicine, Lens Hospital, 62300 Lens, France</footnote>

<footnote><sup>c</sup> Department of Critical Care Medicine, Arras Hospital, 62000 Arras, France</footnote>

<footnote><sup>d</sup> CHU Lille, University Lille, Toxicology Unit, Biology and Pathology Centre, 59000 Lille, France</footnote>

<footnote><sup>e</sup> CHU Lille, University Lille, Intensive Médecine Reanimation, 59000 Lille, France</footnote>

<footnote>* Corresponding author. CHU Lille, University Lille, Pharmacology Department, Regional Centre of Pharmacovigilance, place de Verdun, 59000 Lille, France.</footnote>

<footnote>Adresse e-mail : sophie.gautier@chu-lille.fr (S. Gautier).</footnote>

<footnote>https://doi.org/10.1016/j.therap.2024.12.009</footnote>

<footnote>0040-5957/© 2024 The Author(s). Published by Elsevier Masson SAS on behalf of Société française de pharmacologie et de thérapeutique. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</footnote>
*Results.* — One hundred and ninety-eight (198) cases of MALA were included. 38 patients died in direct association with MALA (19.2%). There was a correlation between metformin plasma accumulation and acute renal failure and with the severity of MALA (P < 0.0001). All patients presented an acute intercurrent event favouring MALA, dehydration for 87 (43.9%) patients, severe infection for 65 (32.8%) patients. For 172 patients (86.7%), the prescription was not adapted to the intercurrent medical situation as recommended. Seventy (40.5%) patients consulted their general practitioner for the acute intercurrent event, 1 temporarily stopped metformin and 34.3% had been referred directly to hospital. The remaining 65.7% presented to the hospital around 4 days later due to worsening symptoms. MALA was identified as preventable in 160 patients (80.8%).

*Conclusions.* — MALA in ICUs often follow acute dehydration or infection, and these high-risk situations must be signals to prevent this serious ADR. Specific education programmes for physicians and patients could also reduce this risk.

© 2024 Les Auteurs. Publié par Elsevier Masson SAS au nom de Société française de pharmacologie et de thérapeutique. Cet article est publié en Open Access sous licence CC BY (http://creativecommons.org/licenses/by/4.0/).

## Abbreviations

<table><tr><td>ADR</td><td>adverse drug reaction</td></tr><tr><td>CKD</td><td>chronic kidney disease</td></tr><tr><td>CNIL</td><td>French National IT and Freedom Commission (Commission nationale de l'informatique et des libertés)</td></tr><tr><td>ED</td><td>emergency department</td></tr><tr><td>FPVD</td><td>French Pharmacovigilance Database</td></tr><tr><td>GFR</td><td>glomerular filtration rate</td></tr><tr><td>GP</td><td>general practitioner</td></tr><tr><td>ICU</td><td>intensive care unit</td></tr><tr><td>LA</td><td>lactic acidosis</td></tr><tr><td>MALA</td><td>metformin-associated lactic acidosis</td></tr><tr><td>NSAIDs</td><td>non-steroidal anti-inflammatory drugs</td></tr><tr><td>RCPV</td><td>Regional Centre of Pharmacovigilance</td></tr><tr><td>SPC</td><td>summary of product characteristics</td></tr></table>

## Introduction

In France, more than 3.5 million people are treated for type 2 diabetes [1]. Metformin, the only member of the biguanide family on the French market, is currently the first-line treatment for patients with type 2 diabetes, prescribed alone or in combination and adapted to certain factors, in particular renal insufficiency [2]. A rare but serious and well-described adverse drug reaction (ADR) is metformin-associated lactic acidosis (MALA). In the literature, the incidence of this adverse effect varies from 2 to 60 cases per 100,000 patients, with a high mortality rate of up to 35% [3]. MALA is the result of a multifactorial and complex process, and is often reported in an acute context, in particular dehydration or infection [4–7]. In addition, patients may have comorbidities such as a history of cardiovascular, renal, hepatic or infectious disease, which may also contribute to the development of lactic acidosis. MALA often

presents with non-specific symptoms (general malaise, diarrhoea and vomiting) and may be overlooked, while lack of initial management may lead to admission to an intensive care unit (ICU) [8]. The incidence of MALA in the ICU is rare, about 0.6% to 1% of patients, while lactic acidosis (LA) is a common condition in patients admitted to the ICU [9]. Nevertheless, metformin treatment in ICU patients could significantly complicate patient management by promoting LA [10].

The aim of this study was to identify the acute clinical situations associated with MALA in patients hospitalised in the Nord-Pas de Calais regional ICU, in order to assess its preventability.

## Material and methods

This study was conducted using the French pharmacovigilance database (FPVD). According to French law, every health professionals must report adverse drug reactions (ADRs) to their Regional Centres of Pharmacovigilance (RCPV). After medical and pharmacological analysis and causality assessment score attribution, the reported ADR cases were registered in the FPVD by the French network of regional pharmacovigilance centers [11]. The FPVD is deidentified to protect subject confidentiality and is approved by the French CNIL (National IT and Freedom Commission) as ANSM n° 2014-302.

For this study, we asked for all ICU physicians in the Nord-Pas-de-Calais region to report their suspected cases of MALA. Hospitals from Armentières, Arras, Béthune-Beuvry, Boulogne, Calais, Cambrai, Douai, Dunkerque, Lens, Lille, Maubeuge, Roubaix, Saint Omer, Tourcoing, Valenciennes, and Saint Philibert were solicited. All reported cases were then analyzed and registered in the French Pharmacovigilance Database. We attest that all our data originated from this database.
Cases were included if they met the following criteria: Type 2 diabetic patients treated with metformin alone or in combination; admission to an intensive care unit in the Nord-Pas de Calais region between 1 January 2017 and 30 December 2018; metformin plasma concentration > 2.3 mg/L at admission (upper limit of the therapeutic range defined by the regional toxicology unit); lactatemia > 2.2 mmol/L; unintentional metformin overdose.

For each report, information on the patient (age, sex, medical history), the ADR (type, date and context of onset, duration and course) and the drug exposure (name, dates of intake, doses) is recorded, together with the narrative of the ADR.

A causality assessment is performed for each drug in reports, using the French pharmacovigilance method [11]. This method combine an intrinsic imputability upon a chronological score (temporal link) and semiological score (etiological link), and an extrinsic score, based on previous published similar cases. Only reports with a score of at least ‘‘link possible’’ were analyzed in the present study.

For each case, the avoidability of MALA was assessed using a french scale of adverse drug reactions avoidability [12] based on 2 criteria:

* the inappropriate prescription of the drug, based on the official recommendations stated in the summary of product characteristics (SPC), package leaflets or other validated therapeutic guidelines. For this study, we cannot judge the initial prescription of metformin but only the existence of an adaptation of the prescription (by the physician or the patient) to the clinical situation (dose reduction, discontinuation,..) days or weeks before admission to the ICU. The situations were then defined as follows:

* absolute non adaptation of the prescription: contraindication (must never be violated), warning (situation to be avoided whenever possible, except after a thorough risk-benefit assessment and requiring a close patient monitoring) and dosage (dose/duration) not respected,

* relative non-adaptation of the prescription: precautionary measures (possible use but after implementation of recommendations or preventive measures to limit or avoid the occurrence of adverse effects) not implemented;

* for the absolute non-adaptation situations, it was then assessed: (i) whether the nature of the nonadaptation could be a risk factor for the occurrence of the ADR. If this was not the case, the occurrence of the ADR was considered unavoidable (the ADR would have occurred even if the prescription had complied with the SCPs); (ii) if there were other aetiologies or other risk factors for the ADR, defining a partially or totally avoidable ADR.

Statistical analyses were performed using R® software (version 4.2.1). The significance threshold was set at 5%. Categorical variables were compared using Chi² tests or Fishers exact test when n < 5. Quantitative variables were compared using Student's t-test. Mortality risk factors were analyzed by univariate logistic regression, with significance set at P < 0.05. Spearman correlation was calculated to explore associations between metformin and creatinine, arterial pH, and plasma lactate levels.

# Results

## General characteristics of cases

During the 24-month study period, 198 cases of MALA observed in the regional intensive care units were reported to the pharmacovigilance centre of the Nord-Pas de Calais region. The average age of patients was 70 ± 9 years (median 70 years), and 107 (54%) cases involved women (Table 1). The mean daily dose of metformin was 2.3 (±0.7) g per day. Sixty-two percent of patients were also treated with at least one other antidiabetic agent, such as dipeptidyl peptidase-4 inhibitors, hypoglycaemic sulfonamides, glinides or insulins. Eighty-one (40.9%) patients had at least one chronic medical condition that promoted lactic acidosis (respiratory insufficiency, alcohol intake, renal insufficiency...), and 155 (78.3%) were chronically treated with one or more drugs that could lead to renal dysfunction. Of the 26 patients with chronic renal insufficiency, the dose of metformin was adjusted for renal function in 7 patients, was not adjusted in 12 patients (46%), including 1 patient for whom metformin treatment should have been contraindicated, and was unknown in 7 patients.

The majority of patients were transferred from the emergency department (ED) to the ICU (n = 173, 87.3%). Of these, 70 (40.5%) had consulted their general practitioner prior to admission: 24 (34.3%) had been referred directly to the ED and 46 (65.7%) had been prescribed antibiotics (suspected infectious context) or diuretics (most commonly suspected cardiac decompensation) without stopping metformin and then presented to the ED a few days later. The mean time from onset of symptoms that must be of concern about the risk of metformin toxicity to ED presentation was 5.34 days (SD 4.79), median 4 days.

## Characteristics of lactic acidosis in the intensive care unit

On admission to the ICU, almost 95% of patients with LA had acute renal failure and 70% (of the 148 patients for whom detailed information was available) had impaired consciousness. The median (min-max) plasma metformin concentration was 6 times higher than the upper therapeutic range (14.05 [2.4–110] mg/L, with a mean [SD] of 21.6 [19.7] mg/L) (Table 1). Sampling was performed on the day of admission (70.7% of cases), the following day (24.7%), after 48 hours (2.5%), or later (2.5%). Plasma metformin concentration showed a strong and significant correlation with creatinine excretion (P < 0.0001, R = 0.7) and a moderate correlation with plasma lactate levels (P < 0.0001, R = 0.41) and arterial blood pH (P < 0.0001, R = -0.53).

In addition, the use of haemodialysis becomes much more systematic when metformin accumulates.

In all 198 patients, there was an intercurrent event, whether sudden (hours before admission) or not (days or weeks before admission), which favoured plasmatic metformin overdose and precipitated the onset of lactic acidosis. Analysis of these intercurrent events revealed acute renal failure as the main risk factor, either due to dehydration with digestive loss or reduced fluid intake (n = 87; 43.9%) or due to severe infection (n = 65; 32.8%, including 20 cases
<table><caption>**Table 1** General characteristics of patients and of MALA cases at the entrance in the ICU.</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Patients with MALA in ICU</td><td></td></tr><tr><td>Number of patients</td><td>198</td></tr><tr><td>Age(mean ± SD) (years)</td><td>70(± 9.04)</td></tr><tr><td>Women n (%)</td><td>107(54.0)</td></tr><tr><td>Metformin daily dose (mg/L), mean (± SD)/median (normal &lt; 3 g/d) (n = 154)</td><td>2.30(± 0.7)</td></tr><tr><td>Associated antidiabetic drugs n(%)</td><td>2.55</td></tr><tr><td>Body mass index n (%) (missing data n = 123)</td><td></td></tr><tr><td>BMI ≥ 30</td><td>58(49.5)</td></tr><tr><td>25 &lt; BMI &lt; 30</td><td>17(14.5)</td></tr><tr><td>Chronic renal dysfunction n (%)</td><td>26(13.2)</td></tr><tr><td>Mean estimated glomerular filtration rate mL/min/1.73 m² (± SD)</td><td>47.32 (± 9.98)</td></tr><tr><td>Medical history which could promote lactic acidosis; n (%)<sup>a</sup></td><td>81(40.9)</td></tr><tr><td>Respiratory (chronic insufficiency or chronic obstructive pulmonary disease)</td><td>21/81 (25.9)</td></tr><tr><td>Cardiac (chronic insufficiency or coronary artery disease)</td><td>36/81 (44.4)</td></tr><tr><td>Alcohol poisoning</td><td>21/81 (25.9)</td></tr><tr><td>Denutrition</td><td>2/81 (2.5)</td></tr><tr><td>Anemia</td><td>5/81 (6.2)</td></tr><tr><td>Chronic drugs which could promote renal dysfunction; n (%)<sup>b</sup></td><td>155(78.3)</td></tr><tr><td>Diuretics</td><td>128/155 (82.6)</td></tr><tr><td>Converting enzyme inhibitors/angiotensin receptor blockers</td><td>107/155 (69.0)</td></tr><tr><td>Data in ICU entrance</td><td></td></tr><tr><td>Metformin plasmatic concentration (mg/L), mean (± D)/median (normal &lt; 2.30 mg/L) (n = 198)</td><td>21.59<br>(± 19.71)</td></tr><tr><td>Lactate level (mmol/L), mean (± SD) (normal 0.5–2.2 mmol/L) (n = 196)</td><td>14.05<br>9.81 (± 5.93)</td></tr><tr><td>Arterial pH, mean (± SD) (normal 7.35–7.45) (n = 187)</td><td>7.11(± 0.21)</td></tr><tr><td>Arterial bicarbonates (mmol/L), mean (± SD)<br>(normal 23–27 mmol/L) (n = 179)</td><td>10.65 (± 6.53)</td></tr><tr><td>Acute renal dysfunction n (%) (n = 198)</td><td>187(94.4)</td></tr><tr><td>Mean estimated glomerular filtration rate mL/min/1.73 m² (± SD)/median (n = 182)</td><td>14.63<br>(± 11.75)</td></tr><tr><td>Glasgow score, mean (± SD) (n = 148)</td><td>10<br>11(± 5)</td></tr><tr><td>Score 3–4, n (%)</td><td>30 (20.3)</td></tr><tr><td>Score 5–7, n (%)</td><td>8 (5.4)</td></tr><tr><td>Score 8–10, n (%)</td><td>7 (4.7)</td></tr><tr><td>Score 11–14, n (%)</td><td>103 (69.6)</td></tr><tr><td>LA management</td><td></td></tr><tr><td>Hemodialysis n (%)</td><td>152 (76.8)</td></tr><tr><td>Vasoactive drug prescription n (%)</td><td>129 (65.2)</td></tr><tr><td>Fluid management n (%)</td><td>160 (80.8)</td></tr><tr><td>Invasive mechanical ventilation n (%)</td><td>88 (44.4)</td></tr><tr><td>ICU length of stay(days)mean(± SD)</td><td>7.3(6.2)</td></tr><tr><td>Mortality due to MALA n (%)</td><td>38(19.2)</td></tr></tbody><tfoot><tr><td colspan="2">BMI: body mass index; ICU: intensive care unit; LA: lactic acidosis; MALA: metformin-induced lactic acidosis.</td></tr><tr><td colspan="2"><sup>a</sup> Patients could have more than one medical history promoting lactic acidosis.</td></tr><tr><td colspan="2"><sup>b</sup> Patients could have more than one drug promoting renal dysfunction.</td></tr></tfoot></table>

also presenting dehydration) (Fig. 1). Shocks due to cardio-respiratory decompensation or haemorrhages accounted for 11.1% of cases. Other major factors were surgery (n = 5) and acute medication (non-steroidal anti-inflammatory drugs [NSAIDs] or iodinated contrast media) or alcohol consumption (n = 8). The risk of death varied according to the main factor leading to LA, being higher in the presence of shock or infection (Fig. 1).

Analysis of the clinical intercurrent events promoting LA according to metformin plasmatic accumulation showed that for concentrations below 10 mg/L, other associated factors could be the main cause of lactic acidosis, mostly infections or severe acute medical conditions like shock. For higher plasmatic metformin concentrations (and especially up to 20 mg/L), dehydration, systematically associated with acute and severe renal failure, became the main inter-
<table><caption>**Table 2** Characteristics of patients and intercurrent events promoting MALA according to metformin plasmatic accumulation.</caption><thead><tr><th rowspan="2"></th><th colspan="5">Metformin plasmatic concentration (mg/L)</th></tr><tr><th>2,4 to &lt; 5</th><th>5 to &lt; 10</th><th>10 to &lt; 20</th><th>20 to &lt; 40</th><th>&gt; 40</th></tr></thead><tbody><tr><td>n (%)</td><td>38 (19.2)</td><td>45 (22.7)</td><td>36 (18.2)</td><td>41 (20.7)</td><td>38 (19.2)</td></tr><tr><td>Metformin dosage &lt; 24 h at ICU entry, n (%)</td><td>34 (89.4)</td><td>43 (95.5)</td><td>35 (97.2)</td><td>39 (95.1)</td><td>38 (100)</td></tr><tr><td colspan="6">Context (main clinical situation at the time of MALA)</td></tr><tr><td>Infection, n (%)</td><td>20 (52,6)</td><td>14 (31,1)</td><td>11 (30,5)</td><td>10 (24,3)</td><td>10 (26,3)</td></tr><tr><td>With associated chronic conditions promoting lactic acidosis</td><td>6</td><td>5</td><td>3</td><td>1</td><td>2</td></tr><tr><td>Dehydration</td><td>6</td><td>3</td><td>4</td><td>9</td><td>5</td></tr><tr><td>Deshydration (digestive loss, reduced hydric intake) n (%)</td><td>4 (10,6)</td><td>17 (37,7)</td><td>16 (44,5)</td><td>27 (61.1)</td><td>23 (60.6)</td></tr><tr><td>With associated chronic conditions promoting lactic acidosis</td><td>0</td><td>4</td><td>4</td><td>8</td><td>3</td></tr><tr><td>Acute severe medical condition (cardiorespiratory decompensation, cardiac arrest, stroke, hemorragic shock...) n (%)</td><td>13 (34.2)</td><td>10 (22.2)</td><td>5 (13.9)</td><td>1 (2.4)</td><td>4 (10.5)</td></tr><tr><td>With associated chronic conditions promoting lactic acidosis</td><td>4</td><td>1</td><td>1</td><td>1</td><td>1</td></tr><tr><td>Surgery n (%)</td><td>0</td><td>2 (4.5)</td><td>0</td><td>2 (4.8)</td><td>1 (2.6)</td></tr><tr><td>Acute intoxication (alcool, opioids) n (%)</td><td>0</td><td>2 (4.5)</td><td>1 (2.8)</td><td>0</td><td>0</td></tr><tr><td>Drugs induced renal dysfunction (NSAIDS, contrast iodinated media) n (%)</td><td>1 (2.6)</td><td>0</td><td>3 (8.3)</td><td>1 (2.4)</td><td>0</td></tr><tr><td>Patients with more than one situation, n (%)</td><td>15 (39.4)</td><td>12 (26.6)</td><td>9 (25)</td><td>19 (46.3)</td><td>11 (28.9)</td></tr><tr><td colspan="6">MALA severity</td></tr><tr><td>Metformine plasmatic concentration (mean (± SD); median)</td><td>3.52 (± 0.86)<br>3.49</td><td>7</td><td>14.75 (± 2.88)<br>14.3</td><td>30.38 (± 6.42)<br>31.6</td><td>54.24<br>(± 18.87)<br>51.4</td></tr><tr><td>Estimated glomerular filtration rate (MDRD; mL/min. mean (±SD); median)</td><td>34.71<br>(± 23.48)<br>29</td><td>24.59<br>(± 14.68)<br>21</td><td>13.70 (± 9.24)<br>11.5</td><td>7.7 (± 5.04)<br>6</td><td>6.32 (± 2.86)<br>6</td></tr><tr><td>Lactate level (mmol/L, mean (± SD); median)</td><td>7.36 (± 5.43)<br>5</td><td>8.43 (± 5.91)<br>8.3</td><td>8.33 (± 4.92)<br>7.2</td><td>11.45 (± 5.13)<br>11.8</td><td>13.67 (± 6.04)<br>13.3</td></tr><tr><td>Arterial pH (mean (± SD); median)</td><td>7.23 (± 0.17)<br>7.28</td><td>7.19 (± 0.16)<br>7.23</td><td>7.16 (± 0.18)<br>7.2</td><td>7.03 (± 0.21)<br>7.08</td><td>6.92 (± 0.17)<br>6.9</td></tr><tr><td>Bicarbonates (mmol/L, mean (± SD); median)</td><td>15.67 (± 5.81)<br>17</td><td>12.33 (± 6.54)<br>13</td><td>11.18 (± 4.21)<br>11</td><td>8.35 (± 6.2)<br>6.85</td><td>5.57 (± 4.35)<br>5</td></tr><tr><td>Glasgow score &lt; 10, n (%)</td><td>10 (26.3)</td><td>4 (8.8)</td><td>6 (16.6)</td><td>8 (19.5)</td><td>13 (34.2)</td></tr><tr><td colspan="6">Care and evolution</td></tr><tr><td>Dialysis, n (%)</td><td>12 (31.5)</td><td>34 (75.5)</td><td>30 (83.3)</td><td>39 (95.1)</td><td>37 (97.3)</td></tr><tr><td>Vasoactive support</td><td>22 (57.8)</td><td>28 (62.2)</td><td>23 (63.8)</td><td>28 (68.3)</td><td>28 (73.7)</td></tr><tr><td>Ventilatory support</td><td>17 (44.7)</td><td>17 (37.7)</td><td>12 (33.3)</td><td>16 (39.0)</td><td>26 (68.4)</td></tr><tr><td>Death, n (%)</td><td>12 (31.5)</td><td>15 (33.3)</td><td>10 (27.7)</td><td>10 (24.4)</td><td>10 (26.3)</td></tr></tbody></table>

ICU: intensive care unit; MALA: metformin-induced lactic acidosis; MDRD: modification of diet in renal disease; NSAIDs: non-steroidal anti-inflammatory drugs.
<figure><img src="image_4.png" /><figcaption>**Figure 1.** Main identified intercurrent events and/or risk factors leading to MALA for patients in ICU in the North of France during the study period. ICU: intensive care unit; MALA: metformin-associated lactic acidosis.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 2.** Main clinical intercurrent event promoting MALA according to metformin plasmatic accumulation in parallel to impact on lactates and GFR. GFR: glomerular filtration rate; MALA: metformin-associated lactic acidosis.</figcaption></figure>

current event (Table 2, Fig. 2). Furthermore, with regard to the seasons in which MALA occurred, dehydration was more frequent in spring and summer, whereas infection was the most frequent intercurrent event in spring and autumn (Fig. 3).

## Mortality

Fifty-seven patients died during hospitalisation (28.8%). Of these, 38 deaths were considered by ICU physicians to be directly related to MALA (19.2% of all reported cases). The
<figure><img src="image_6.png" /><figcaption>**Figure 3.** Frequency occurrence of MALA in regard to the seasons. MALA: metformin-associated lactic acidosis.</figcaption></figure>

other 19 deaths were attributed to other causes (pulmonary embolism, myocardial infarction, septic shock, etc.). The population of patients whose death was directly related to MALA was compared with the population of patients who did not die from this complication or who died from other causes. These patients were older (P = 0.031), mostly treated with antidiabetic monotherapy (P = 0.005), and had more severe LA (P < 0.001) and chronic respiratory insufficiency (P = 0.004). Dehydration as the main acute intercurrent event was on the borderline of statistical significance. In line with the greater severity of LA, management was significantly more invasive (P < 0.001) and hospital stay was shorter in the group of patients who died from MALA, with patients dying rapidly (P < 0.05).

## Preventability of MALA

For 172 patients (86,7%), the prescription of metformin was not adapted to the chronic medical situation or the acute intercurrent event observed days or weeks before MALA, in accordance with the SPC (Table 3).

Therefore, according to the avoidability scale, preventability of the MALA was ascertained for 160 patients (80.8%) in whom metformin contributed partially (n = 75) or completely (n = 85) to lactic acidosis, depending on whether it was the only risk factor of lactic acidosis (mainly after deshydration due to digestive loss) or there were several risk factors (for example, deshydration and infection or infection and chronic respiratory insufficiency...). In 12 patients, the lactic acidosis was unavoidable in a context of acute and unexpected events directly or indirectly promoting lactic acidosis (peritonitis, fall, stroke...). In these cases, the contribution of metformin overdose and the link with non-compliance with the SPC in the development of lactic acidosis could not be evaluated.

## Discussion

The aim of this study was not to blame metformin, a drug with clear benefits in type 2 diabetes and in the prevention

of adverse cardiovascular events, but rather to raise awareness among healthcare professionals and patients on the precautions that absolutely need to be taken when prescribing, dispensing and monitoring this treatment. Over a 24-month period, 198 cases of metformin overdose associated with lactic acidosis were reported to the Nord Pas de Calais RPVC by regional ICUs and almost 20% of these patients died directly from MALA. In 80% of all cases, the occurrence and/or severity of MALA could have been limited or even prevented.

Our study confirms the seriousness of this rare but well known risk of severe lactic acidosis in metformin overdose, with characteristics in terms of mortality and conditions of occurrence that are very similar to those already published in the literature [13–17]. MALA occurs as a consequence of an abrupt increase in the plasmatic concentration of metformin, often following a rapid decline in renal function [3,4,18]. Two situations are described: (i) one in which metformin accumulation is significant (> 10 mg/L), associated with an acute situation of severe renal failure, often induced by dehydration. In this context, the role of metformin in LA seems to be predominant. It is interesting to note that, in our study, this situation is more frequent during the hot periods of the year; (ii) the other, in which metformin accumulation is moderate (around 5 mg/L) but associated with a severe pathological situation (sepsis, shock...), which probably largely explains the lactic acidosis [19]. Renal dysfunction is also present, but more moderate and less systematic. In this situation, the role of metformin on LA seems to be additive. In our study, infection/sepsis is described more often in spring and autumn. The question of seasonality has already been raised for MALA, with conflicting results [20,21]. According to our data, this point deserves attention, at least for the summer period, when there is a higher risk of dehydration. Besides, the recommendations for managing treatment in heatwave situations clearly identify metformin as a drug at risk in this context [22].

In our study, 30% of metformin samples were not collected on the day of hospital admission. In these cases, it means that the contribution of metformin to lactic acidosis was not evoked, certainly in situations where another, more
<table><caption>**Table 3** Type of non-adaptation of metformin prescription according to the summary of product characteristics (SPC) and analysis of adverse drug reaction (ADR) avoidability.</caption><tbody><tr><td>Patients with absolute non-adaptation of metformin prescription, n (%)</td><td>172</td></tr><tr><td>Type of non conformity<sup>a</sup></td><td></td></tr><tr><td>Contra-indication</td><td></td></tr><tr><td>Acute conditions likely to impair renal function</td><td></td></tr><tr><td>Dehydration</td><td>114 (66.3)</td></tr><tr><td>Chronic conditions likely to induce tissue hypoxia</td><td>26 (15.1)</td></tr><tr><td>Respiratory insufficiency</td><td>21</td></tr><tr><td>Anemia</td><td>5</td></tr><tr><td>Chronic alcoholic intoxication</td><td>21 (12.2)</td></tr><tr><td>Dose not adapted</td><td></td></tr><tr><td>Chronic renal insufficiency</td><td>12 (6.9)</td></tr><tr><td>Warning</td><td></td></tr><tr><td>Acute infection (of which 20 evolved to sepsis shock)</td><td>65 (37.8)</td></tr><tr><td>Iodinated contrast media, acute use</td><td>5 (2.9)</td></tr><tr><td>Surgical intervention</td><td>5 (2.9)</td></tr><tr><td>Adverse drug reaction avoidability</td><td></td></tr><tr><td>unavoidable ADR</td><td>12 (6.9)</td></tr><tr><td>partly avoidable ADR</td><td>75 (43.6)</td></tr><tr><td>entirely avoidable ADR</td><td>85 (49.5)</td></tr><tr><td>Patients with relative non adaptation of metformin prescription<sup>b</sup>, n (%)</td><td>159</td></tr><tr><td>Precautionary use<sup>c</sup></td><td></td></tr><tr><td>Diuretics, chronic use, n (%)</td><td>128 (80.5)</td></tr><tr><td>ACE/ARB, chronic use, n (%)</td><td>107 (62.2)</td></tr><tr><td>NSAIDs, acute use, n (%)</td><td>13 (8.1)</td></tr></tbody></table>

ACE: angiotensin-converting enzyme inhibitor; ADR: adverse drug reaction; ARB: angiotensin II receptor blocker; NSAIDs: non-steroidal anti-inflammatory drugs; SPC: summary of product characteristics.

noisy, acute pathological context of LA was observed (sepsis, shock, etc.). This delayed measurement of plasma metformin may have missed the diagnosis of MALA, especially when the measured plasma concentration is above 5 mg/L [6,23]. However, it has been shown that taking into account others parameters, as lactate, creatinine and metformine use at hospital admission, allows early detection of a role of metformine in lactic acidosis, with a sensitivity and specificity of 85% and 99%, respectively [13]. Therefore, when a patient with LA is admitted to the ICU, it seems important to systematically consider the possibility of metformin treatment, in order to improve LA management and reduce morbidity and mortality [9,10,24].

The mortality associated with MALA is high and does not necessarily correlate with the initial severity or extent of metformin accumulation [24–27]. MALA mortality has recently been estimated to be about 30% when metformin plasma accumulation is above 5 mg/j versus 11% when metformin plasma accumulation is below 5 mg/j [27]. However, some studies suggest that the prognosis of MALA is better than that of severe lactic acidosis from other causes [15], as seen in our study with acute shock. The question of how to manage these patients is crucial. Rapid supportive treatment and removal of metformin toxic plasmatic levels by haemofiltration is essential to improve patient survival

[28–31]. In our study, once the metformin accumulation exceeds 5 mg/L, the management changes and much more frequently combines haemodialysis with haemodynamic support.

The majority of publications report plasma metformin accumulation with concomitant acute renal impairment and highlight the risk of MALA associated with conditions that affect renal function [3, 18, 24, 32]. As in our study, plasma metformin accumulation is significantly correlated with acute renal impairment and the severity of lactic acidosis [6,7,16,25,27,33,34].

In a cohort of 320,882 diabetic patients recently started on antidiabetic treatment, the risk of LA was significantly associated with exposure to metformin in the previous three months and with renal dysfunction (moderate to severe) [35]. Dehydration due to digestive losses or reduced intake is the main initial cause (between 75% and 80% of cases) [6,7,14,31]. Symptoms usually begin in the few days prior to hospital admission. The potential impact on the kidneys of drugs prescribed concomitantly with metformin should also be emphasised: in our study, 78% of patients were taking one or more potentially nephrotoxic chronic treatments (ACE, ARB and/or diuretics). In addition, 9% of our patients reported acute use of PCI or NSAIDs, which may have favoured acute kidney injury. It is clear that additional medications

<footnote><sup>a</sup> 66 patients presented more than one reason of non conformity from the SPC (54 with 2 reasons, 12 with three reasons).</footnote>

<footnote><sup>b</sup> All patients also presented an absolute non adaptation of metformin prescription.</footnote>

<footnote><sup>c</sup> Patients could have more than one drug promoting renal insufficiency.</footnote>
that affect glomerular filtration rate or renal perfusion pressure increase the propensity to develop AKI and metformin accumulation [5,36]. Therefore, the warnings and precautions for the use of metformin indicate that all these drugs should be used with caution in diabetic patients treated with metformin, in addition to contraindicating its use in the event of severe renal insuffisancy.

In our study, more than 85% of patients with MALA did not had adjustment of their metformin treatment to a chronic or acute pathological situation identified and recognised as a risk factor for metformin accumulation and/or favouring the development of LA. This result is largely found in published cohorts or series of patients with MALA [5-7,10,13,14,18,37].

One study suggested that chronic medical conditions had little effect on the incidence of MALA [16]. Only hepatocellular dysfunction would be a chronic condition significantly associated with MALA [17,18,25]. Some studies also showed a modest or no significant effect of chronic kidney disease (CKD) on MALA [33,38]. On the other hand, a highly significant association between acute intercurrent events and the occurrence of MALA was shown [16,39]. The frequent occurrence of digestive loss (drug-induced, infection or other causes) in patients taking metformin who develop MALA suggests that these symptoms are red flags for possible MALA [6]. These intercurrent events led 40% of patients to consult their general practitioner (GP), without metformin being stopped or reduced in all except one patient, despite this adaption could have limited the severity or prevented the risk of MALA [5,14,18,23,36]. A study carried out in the Nord-Pas de Calais region showed that GPs were well aware of the risk of MALA [40]. Nevertheless, our study in the same region showed that, the two-thirds consulting patients were initially treated at home, without stopping metformin, 4 or 5 days before hospital admission.

Patients and physicians should therefore be aware that MALA, although rare, results from a combination of chronic or sudden risk factors and drug interactions. The recent communiqué from the French Medicines Agency makes this clear, in line with European or US recommendations on metformin [41]. In addition, informing patients about the intercurrent disease that may contribute to the risk of LA on metformin must be part of the consultation at the start of treatment as well as during follow-up [39]. In this respect, an extensive educational campaign carried out by internal medicine and metabolism specialists led to a reduction in the number of patients hospitalised with MALA in the following year [31]. In the event of an acute illness, a medical consultation should be recommended to at least establish monitoring and possibly discuss the temporary discontinuation of metformin as well as a review of other treatments affecting renal function [6,23,42]. In a French teaching hospital which had set up a programme for the early detection of MALA in all metformin-treated patients presenting to the hospital emergency department, a reduction in mortality and faster patient management following the implementation of the early detection of lactate, pH and metformin was observed, demonstrating that it is possible to prevent the risk of MALA [43].

One of the limitations of this study is the under-reporting of MALA in ICUs to the regional pharmacovigilance centre (despite of a specific request to our regional units), which

could introduce a bias in patient selection. The retrospective collection of MALA cases could also introduce potential uncertainties due to missing data. However, almost all ICUs participated in this study and tried to be exhaustive, in a region representing 6% of the French population and particularly affected by type 2 diabetes. In addition, the expertise of the clinicians in the ICUs, combined with the expertise of the regional pharmacovigilance centre, ensures the accuracy of the diagnoses (all of which correspond to the definition of MALA provided by [19]) and the integration of important data on the patients' clinical history and conditions, and allows a proper analysis of the clinical situations of MALA and the potential axis of its prevention.

## Conclusion

This study confirms that MALA should be systematically considered and treatment with metformin queried in patients with LA admitted in ICUs. In about 80% of cases, these severe lactic acidoses are potentially preventable. The risk situations and symptoms of overdose, which are often non-specific, are either unknown or underestimated by patients (and healthcare professionals). Early diagnosis of MALA is crucial for patient outcome, as is recognition of risk factors predisposing to or precipitating the risk of LA when initiating and monitoring metformin therapy. General advice should be given regarding dose reduction or transient withdrawal of metformin during acute intercurrent illness (infection, digestive loss...) or during the summer in case of heatwave. Dissemination of information about preventing the risk of MALA remains essential, particularly to physicians, community pharmacists and, most importantly, to patients, in order to limit this largely avoidable risk.

## Author contributions

JT, EJ, JB, SB, BH and SG were involved in the conception and the design of the study. JT and SG conduct the study and the analysis and interpretation of the results. JT and SG wrote the first draft of the manuscript, and all authors edited, reviewed, and approved the final version of the manuscript. SG is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. JT and MG were the major contributors in terms of cases reported to the RCPV. All authors read and approved the final manuscript.

## Acknowledgments

The authors thank all the physicians in ICU of the North Pas de Calais region concurring to the declaration of the MALA cases to the RCPV: Isabelle Alves, Justine Lemtiri (ICU of Valenciennes hospital); Pierre-Yves Delannoy (ICU of Tourcoing hospital); Mohamed Bouguettaya (ICU of Maubeuge hospital); Vincent Pages (ICU of St Philibert hospital, Lille); Patrick Herbecq, Clément Vanbaelighem (ICU of Roubaix hospital); Emmanuelle Jaillette (ICU of Lille hospital); Johanna Temime (ICU of Lens hospital); Caroline Blazejewski (ICU
of Dunkerque hospital); Anne Guaguere (ICU of Douai hospital); Jean Nicolas Chatelet (Hospital pharmacy of Saint Omer); Mostapha Hajjar (ICU of Cambrai hospital); Francois Xavier Ferrand (ICU of Calais hospital); Guillaume Brunin, Sylvain Lecaillet (ICU of Boulogne hospital); Dominique Malacrino (ICU of Béthune hospital); Maxime Granier (ICU of Arras).

Disclosure of interest

The authors declare that they have no competing interest.

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