Severe metformin intoxication without development of lactic acidosis: clinical case

Introduction

Metformin is the most widely used oral antidiabetic drug for the treatment of type 2 diabetes mellitus, belonging to the biguanide pharmacological group [1-4]. Buformin and phenformin, which belong to the same family, have been associated with an increased risk of lactic acidosis. Phenformin was withdrawn from the market in the late 1970s, and buformin, being less commonly administered, was banned a little later for the same reason. Compared to metformin, phenformin has a higher affinity for mitochondrial complex I, and a plasma half-life of 9-12 h, is mainly metabolized in the liver, and has a renal clearance rate of only 35%. Therefore, the main effect of phenformin is the inhibition of peripheral oxidative metabolism, which is subsequently associated with increased lactate levels and the occurrence of lactic acidosis, which explains the reason for the withdrawal of phenformin from the market. Regarding buformin, there are few data available on its pharmacokinetics and pharmacodynamics [5, 6].

Metformin acts as a hypoglycemic agent by reducing hepatic glucose production, through the inhibition of glycogenolysis and gluconeogenesis; by increasing glucose absorption at the muscle level; by decreasing the level of glucose absorption at the gastrointestinal tract level, and by increasing insulin sensitivity [5, 6]. It has a large volume of distribution of 1-5 L/kg and accumulates intracellularly, predominantly in intestinal cells and erythrocytes [7]. Once in the cell, metformin increases anaerobic glycolysis, which is also one of its main adverse effects. However, under physiological conditions, the lactate produced when metformin is administered at a dose adjusted to eGFR (estimated glomerular filtration rate) is eliminated without accumulating significantly [7].

Metformin is administered orally; the therapeutic dose varies between 500 mg and 2000 mg per day, with a maximum dose of 2500-3000 mg. It has a bioavailability of approximately 50-60%, circulates in plasma unbound to proteins, and is eliminated unmetabolized by the kidneys in a proportion of 90%. When the concentration of metformin in plasma is > 5 mg/l, its elimination may be prolonged [8].

Most cases of metformin-associated poisoning have had independent risk factors for lactic acidosis, supporting the hypothesis that the drug has a contributory role in the development of this complication. Thus, the risk of developing lactic acidosis when taking metformin is increased by several factors such as age > 65 years; concomitant diseases that have the ability to induce hypoxemia (chronic renal failure, congestive heart failure, cardiogenic shock, acute respiratory distress, sepsis, advanced liver disease, history of lactic acidosis); excessive alcohol consumption; and administration of iodinated contrast media. The toxic dose of metformin is 5 g in adults and 100 mg/kg in children [9]. Lactic acidosis occurs when the concentration of metformin in the blood exceeds the therapeutic level (0.5-2 mg/l) and reaches a toxic level (> 5.0 mg/l), mainly when the glomerular filtration rate decreases [3, 4]. To prevent complications induced by metformin in patients with chronic kidney disease (CKD), it is essential to adjust the dose to 1 g/day when eGFR is between 30 and 44 ml/min/1.73 m² and to discontinue the drug when eGFR values are < 30 ml/min/1.73 m² [10].

Next, we will present a clinical case of metformin poisoning, in which the patient did not develop lactic acidosis despite numerous risk factors.

Case presentation

A 46-year-old man was urgently admitted to the Holy Trinity Municipal Clinical Hospital. The patient had been discharged 3 days earlier from another municipal medical unit, with an improving general condition and stable hemodynamics. The hypoglycemic treatment recommended to the patient upon discharge was long-acting insulin. At the prehospital stage, with the aim of self-harm, he ingested 50 metformin tablets, each tablet having a dose of 500 mg (total dose 25 g), as a result; as a result, symptoms such as repeated vomiting, dizziness, drowsiness, andlethargy appeared. The patient requested Emergency Medical Assistance approximately 12 hours after ingesting the tablets. At the Emergency Department stage, the condition was assessed as extremely serious, with sopor; therefore, the patient was admitted to the Intensive Care Unit. The patient’s personal pathological history included: type 2 diabetes mellitus for 8 years; toxic liver cirrhosis, slowly progressive evolution, compensated Child-Pugh A, recently diagnosed; arterial hypertension; CKD  stage G3aA2 KDIGO. Objective data upon admission were: passive position, icteric skin and sclerae, diminished skin turgor, without edema, afebrile, vesicular breath sounds present bilaterally, absent rales, SpO₂ (oxygen saturation in the blood) - 95% on room air, respiratory rate 24 breaths per minute, rhythmic heart sounds, diminished first sound at the apex, BP (blood pressure) - 150/90 mmHg, HR (heart rate) - 114 beats/min. On palpation, the abdomen was tender in the epigastrium, and the lower edge of the liver exceeded the costal margin by 3 cm. The stool was semi-formed, with steatorrhea; diuresis was monitored by Foley catheter, with a urine output of 150 ml/24 h, on the first day of hospitalization. During the neurological examination, meningeal signs were negative, the pupils were of equal size, and the pupillary light reflex was preserved. The verbal response was inappropriate (3 points), the motor response – the patient localized the pain (5 points), and the ocular response was eyes opening to verbal stimuli (3 points), therefore, the Glasgow Coma Scale at admission was assessed with a total score of 11 points.

Paraclinical investigations upon admission detected the presence of metabolic acidosis: pH  - 7.24, BE (base excess) - 3.5 mmol/l, HCO₃^- - (bicarbonate) - 21.2 mmol/l, lactate - 2.70 mmol/l, AnGap (anion gap) - 19.2 mmol/l, osmolality - 308.5 mOsm/kg. Biochemical data showed renal dysfunction with azotemia: creatinine - 5.3 mg/dl, urea - 100.9 mg/dl; moderate cytolytic syndrome - ALT (alanine aminotransferase) 75 U/l, AST (aspartate aminotransferase) 83 U/l; cholestatic syndrome – total bilirubin 34 µmol/l, direct bilirubin -22.4 µmol/l, alkaline phosphatase – 112 U/l, GGT (gamma-glutamyltransferase) – 457.8 U/l; severe hypoglycemia – 1.7 mmol/l; inflammatory syndrome – leukocytes – 13 × 10³/Ul, neutrophils – 81.2%, ESR (erythrocyte sedimentation rate) – 24 mm/h; hepatocellular insufficiency: albumin 32 g/l, total protein 49 g/l; coagulation disorders: prothrombin index 65%, APTT (activated partial thromboplastin time) – 23 s, D-dimers 1.61 µg/ml; and pancreatic dysfunction – amylase 231 U/l, lipase 93 U/l. Urinalysis: cloudy urine, leukocytes covering the field of view, and bacteria 3+. Abdominal ultrasonography showed findings consistent with liver cirrhosis with portal hypertension, minimal ascites, diffuse changes in the pancreatic parenchyma, and bilateral post-inflammatory sequelae in the kidneys.

Twenty-four hours after admission, the patient’s general condition was assessed as extremely serious and unstable; the patient was conscious, with a Glasgow Coma Scale score of 14 points. Vital parameters: BP - 180/90 mmHg, HR 95 beats/min, respiratory rate - 21 breaths per minute, andSpO₂ 96%. The acid-base balance and metabolic parameters were: pH - 7.18, lactate - 3.46 mmol/L, HCO₃^- - 16.7 mmol/l, AnGap - 20.1 mmol/l, glucose - 23.3 mmol/l, and osmolality 325.55 mOsm/kg. Progressive azotemia was recorded, with rising urea and creatinine values; the patient was therefore transferred to the Nephrology and Hemodialysis Department in order to initiate renal replacement therapy, namely hemodialysis. The results of serial laboratory investigations are presented in Table 1.

During the hospitalization, 14 hemodialysis sessions were performed, with a gradual decrease in urea and creatinine. The values of the laboratory investigations, after the initiation of hemodialysis, and before discharge are presented in Table 2.

After 15 days of treatment at the Holy Trinity Municipal Clinical Hospital, the patient was discharged, with hemodynamic stability and significant improvement in clinical and laboratory parameters (considerable decrease in serum creatinine and urea).

During the hospitalization, the patient received a series of psychological counseling sessions aimed at raising the patient’s awareness, addressing emotional and behavioral problems and improving self-esteem.

Discussion

Metformin may be safe when administered in therapeutic doses adjusted to the glomerular filtration rate, so not all cases of lactic acidosis can be attributed to this drug. Lalau and colleagues proposed a new diagnostic approach to specify the contribution of metformin to the elevation of lactate. Depending on the plasma concentration of metformin and the patient’s comorbidities, we can distinguish: MULA (lactic acidosis not correlated with metformin), MILA (lactic acidosis induced by metformin), LAMT (lactic acidosis during metformin therapy), and MALA (lactic acidosis associated with metformin and the presence of systemic comorbidities). The acronym MULA is used when metformin is not detected in the blood or is present at a normal or low concentration. In this situation, the factor that triggers lactic acidosis is a systemic pathology. MILA is caused only by metformin, the blood concentrations are elevated due to intoxication with this drug and/or acute kidney injury. LAMT includes cases in which metformin concentration has not been assessed [7, 8]. The determination of metformin concentration is not well defined in clinical practice. Several studies conducted in recent years have not been able to indicate a specific value of metformin in the blood. At the same time, the threshold value of the metformin concentration in serum for identifying cases of metformin intoxication remains unspecified. In the study conducted by Lalau and colleagues, the values of metformin, more precisely its plasma concentrations and erythrocyte levels, were 2.7 and 2.0 mg/l, respectively [7]. According to the data of a cohort study, the plasma concentration of metformin was not positively correlated with the level of lactate. Instead, the main determinant of the negative prognosis in the patients in the analyzed study was the decline in renal function (acute kidney injury) [7]. Patients with type 2 diabetes and moderate to severe chronic kidney disease (GFR 30 to 60 mL/min/1.73 m²) may have plasma metformin concentrations 2-4 times higher than those in healthy subjects [8].

Metformin-associated lactic acidosis (MALA) is a rare event, with an incidence of approximately 19 cases per 100,000 patient-year [11]. The exact incidence of MALA is unknown, as available estimates are based on spontaneous case reports [8]. MALA is defined by a blood lactate level greater than 5 mmol/l, decreased pH (<7.35) and bicarbonate levels, with increased anion gap. The most common risk factors predisposing to MALA are renal failure, chronic respiratory failure, pre-existing heart disease, liver failure, sepsis, advanced age, and alcohol consumption [2, 5].

Lactate is an intermediate metabolite, produced by the reduction of pyruvate by lactate dehydrogenase under anaerobic conditions, and is produced at a rate of approximately 1 mmol/kg/h in skeletal muscle, circulating erythrocytes, intestine, liver, and brain [5]. The liver, kidneys, myocardium, and skeletal muscle are the main sites of lactate metabolism. At the hepatic and renal levels, lactate clearance is 60% and 30%, respectively. Lactate can be oxidized to carbon dioxide and water by mitochondria for energy generation (Krebs cycle), or it can be converted to glucose in the liver and kidneys (Cori cycle). Lactic acidosis can occur in the case of excessive lactate production and/or defective metabolism [7, 8]. The hepatic clearance of lactate is approximately 320 mmol/h, which significantly exceeds the rate of its synthesis. Increased peripheral lactate production alone rarely causes lactic acidosis, but increased lactate synthesis in the case of impaired hepatic metabolism (e.g. cirrhosis, sepsis, hypoperfusion) can contribute to its accumulation and, subsequently, the development of severe lactic acidosis [8]. There are two types of lactic acidosis: type A (in case of hypoxia) and type B with three subtypes, namely B1 (caused by bronchial asthma and diabetes), B2 (induced by metformin or adrenaline intoxication), and type B3 (hereditary). MALA has been attributed to type B [5, 12].

Ethanol is a potential trigger for lactic acidosis. It is metabolized in the liver by the enzyme alcohol dehydrogenase, oxidized to acetaldehyde, and then to acetic acid by aldehyde dehydrogenase. These reactions result in excess NADH (the reduced form of nicotinamide adenine dinucleotide). Delayed NADH reoxidation increases the NADH/NAD⁺ ratio, favoring the metabolism of pyruvate to lactate. Lactate clearance depends on its conversion to pyruvate and on the subsequent oxidation of pyruvate to acetyl-CoA by the thiamine-dependent enzyme pyruvate dehydrogenase, as well as on gluconeogenesis in the liver and kidneys. Both ethanol metabolism and low thiamine levels promote lactate formation with the potential to trigger alcohol-associated lactic acidosis (AALA) in subjects who abuse alcohol acutely or chronically [13].

A multicenter study, based on the analysis of 242 cases of metformin toxicity at therapeutic doses, reported that the most common adverse event was MALA, present in 224 patients (92.6%). Most patients presented with neurological and gastrointestinal symptoms, and a small number of patients presented with severe metabolic acidosis and hyperlactatemia. The lowest pH reported was 6.28, in a postoperative patient with underlying chronic kidney disease who received long-term metformin therapy [14].

Signs and symptoms associated with metformin intoxication are nonspecific and can be divided by system. Gastrointestinal symptoms (nausea, vomiting, metallic taste, abdominal pain, and watery diarrhea) can be misinterpreted as mesenteric ischemia. Cardiovascular involvement in MALA can be identified by the presence of hypotension and rhythm disturbances (bradycardia, multifocal ventricular extrasystoles, ventricular fibrillation), which can result in cardiac arrest. From a neurological point of view, the patient may present with mydriasis, absence of corneal reflexes, confusion, agitation, seizures, lethargy, drowsiness, sopor, and coma [7, 11]. Severe respiratory dysfunction with hypercapnia and hypoxemia, progressing to the need for mechanical ventilation, has also been described [11]. Other complications of metformin intoxication include: hypoglycemia, encephalopathy, acute liver failure, pancreatitis, lactic acidosis, acute kidney injury [14]. In our case, gastrointestinal symptoms and altered neurological status were observed, without the association of lactic acidosis, despite the fact that the patient suffered from chronic kidney disease and liver cirrhosis of toxic etiology. Over the course of the admission, the lactate level never exceeded 5 mmol/l, although rising urea, creatinine, metabolic acidosis and persistent uremic syndrome required the initiation of renal replacement therapy

As a small non-protein-bound molecule with a molecular weight of 165 Da, metformin is readily dialyzable. After gastrointestinal absorption, it is rapidly distributed into the intracellular compartment, with a large volume of distribution of 63–276 L (1–5 L/kg). Lalau and colleagues previously demonstrated a biphasic model of metformin elimination. This model suggests that a short hemodialysis session is not sufficient to eliminate metformin due to the rebound phenomenon [15]. An increase in serum metformin concentration is expected after the end of a hemodialysis session due to its redistribution [2, 9, 15]. According to the EXTRIP (Extracorporeal Treatments in Poisoning Workgroup) recommendations, intermittent hemodialysis is preferable to prolonged hemodialysis. The EXTRIP guidelines recommend the initiation of hemodialysis at pH ≤ 7, lactate > 20 mmol/l, or when conservative treatment measures are ineffective. Hemodialysis is also suggested when lactate is 15-20 mmol/l, pH is 7-7.1 or in the presence of comorbid conditions such as shock, impaired renal or hepatic function and altered neurological status. The criteria for stopping renal replacement therapy are pH > 7.35 and lactate < 3 mmol/l [16].

In our case, the patient developed severe hypoglycemia after ingesting metformin tablets. The mechanism of hypoglycemia was attributed to alcohol ingestion and preexisting liver cirrhosis. Given that the liver is the main glycogen storage site (60%) in the body, liver cirrhosis results in decreased glycogen synthesis and storage. Alcohol also contributes to the onset of hypoglycemia by inhibiting hepatic gluconeogenesis, but not glycogenolysis. In addition, alcohol alters the counterregulatory hormonal response, delaying the secretion of glucagon, cortisol, and catecholamines in response low blood glucose [6].

The distinctive feature of this case is the absence of lactic acidosis. Despite the severe clinical course with altered neurological status, hypoglycemia and pre-existing comorbidities (chronic kidney disease, KDIGO stage G3aA2, complicated by acute kidney injury,, liver cirrhosis of toxic etiology), , the patient survived.

Conclusions

Metformin is the most widely used oral antidiabetic agent, but when it is administered to patients with multiple comorbidities and those with risk factors associated with diabetes mellitus, lactic acidosis may develop. Although metformin is recognized as being highly safe, it is important to administer the drug with caution to patients with pre-existing kidney disease, chronic liver failure, and pathologies associated with chronic hypoxemia. Metformin intoxication can induce lactic acidosis with an increased risk of serious, potentially fatal adverse events. Lactic acidosis can manifest with nonspecific signs and symptoms, which can be misinterpreted. Thus, it is essential to establish the diagnosis of MALA as early as possible, with prompt initiation of renal replacement therapy and serial monitoring of biochemical parameters.

Competing interests

None declared.

Authors’ contributions

EB evaluated the patient, collected clinical and paraclinical data, participated in the selection of bibliographic sources and drafted the manuscript. TD evaluated the patient, analyzed the bibliographic sources and drafted the manuscript. OG, FS, DS systematized the literature data, drafted the clinical case and discussions on it. All the authors reviewed the work critically and approved the final version of the manuscript.

Patient consent

Obtained.

Acknowledgements and funding

No external funding.

Provenance and peer review

Not commissioned, externally peer reviewed.

Authors’ ORCID IDs

Elena Bivol – https://orcid.org/0009-0004-4040-7048

Tatiana Dumitras – https://orcid.org/0000-0001-5538-189X

Olesea Gușanu – https://orcid.org/0009-0002-4976-6579

Felicia Sîrbu – https://orcid.org/0009-0008-4820-5116

Daniela Stîngaci – https://orcid.org/0009-0005-0787-2201

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