Continuing Education Activity

Metformin is an antidiabetic drug that is widely used and generally well tolerated. Metformin toxicity is rare with therapeutic dosing but can be severe in overdose and may include metformin-associated lactic acidosis (MALA). Patients and clinicians need to be aware of its toxicity and factors that increase the probability of developing MALA. This activity reviews the evaluation and management of MALA and highlights the role of an interprofessional team in caring for patients with this condition.

Objectives:

• Summarize the pathophysiology leading to toxicity with metformin-associated lactic acidosis.
• Review risk factors for developing metformin-associated lactic acidosis.
• Explain the evaluation process for metformin-associated lactic acidosis.
• Outline the importance of a multispecialty approach to managing and preventing metformin-associated lactic acidosis

Introduction

Metformin is a biguanide compound used as first-line therapy for the treatment of diabetes mellitus and prevention of diabetic-related microvascular and macrovascular complications.[1] It is also used to treat several other conditions, including polycystic ovary syndrome (PCOS), hyper-insular obesity, and weight gain from antipsychotic therapy. It is a derivative of Galega officinalis, also known as French lilac or goat’s rue. It was used as an herbal remedy in Medieval Europe and found in the 1920s to contain guanidine, an anti-hyperglycemic compound.[2] Phenformin, metformin’s predecessor, was the first oral biguanide that was withdrawn from the market for a high incidence of fatal lactic acidosis.

Metformin exerts several physiologic actions directed at overall blood glucose reduction through insulin sensitization, antagonization of gluconeogenesis, and increasing intracellular glucose uptake. It has several notable side effects, including gastrointestinal symptoms (nausea, vomiting, and diarrhea), increased lactate production, reduced lactate clearance, and the potential to induce acidosis.

Metformin-associated lactic acidosis (MALA) is a rare complication of altered lactate and hydrogen metabolism defined as pH < 7.35 and lactate > 5.0 mmol/L in the setting of metformin use or overdose.[3] Depending on the setting, it carries a mortality rate of up to 50%, which is correlated with worsening of acidosis and hyperlactatemia.[4]

Etiology

Supratherapeutic metformin levels contribute to hyperlactatemia and separately a metabolic acidosis through impairment of oxidative phosphorylation.[5] There are two subsets of metformin toxicity, chronic or incidental MALA and intentional or acute metformin-induced lactic acidosis (MILA). These definitions are often blurred. In the incidental variant of MALA, a predisposing pathophysiological condition leads to supra-therapeutic accumulation of metformin in the bloodstream and subsequent hyperlactatemia and metabolic acidosis.[6] This typically occurs in the setting of acute or chronic medical comorbidities, including renal injury, hepatic or heart failure, shock, critical illness, or in the presence of other coingestants. In MILA, acute metformin overdose and supratherapeutic drug levels primarily drive the sequelae of hyperlactatemia and metabolic acidosis.[6]

Epidemiology

Determining the true incidence of MALA is challenging since it represents a spectrum of illnesses ranging from coincidental metformin use in critically ill patients to acute metformin overdose in the absence of other causal pathology. Additionally, data show a poor correlation between metformin levels, pH, and lactate levels leading to speculation regarding causality and diagnostic accuracy of attributing hyperlactatemia and metabolic acidosis to metformin overdose.[7][8] Given the temporal course of many MALA presentations, metformin concentrations may not be drawn until after corrective interventions have improved acid-base and lactate indices leading to poor correlation.[9] Previous studies estimate the incidence of MALA at 1 to 9 cases per 100,000 people.[3] In the case of isolated metformin overdose, there was a 9% incidence of MALA and a 0.7% incidence in the setting of a poly-substance overdose.[10]

Pathophysiology

Metformin overdose induces two distinct metabolic derangements – hyperlactatemia and metabolic acidosis – primarily through inhibition of aerobic respiration.

Hyperlactatemia results from several processes. Supratherapeutic metformin levels cause inhibition of complex 1 in the mitochondrial respiratory chain leading to impaired oxidative phosphorylation.[5] Metformin also causes inhibition of pyruvate carboxylase leading to reduced metabolism of pyruvate and increased conversion to lactate.[11] With impaired oxidative phosphorylation and pyruvate utilization, ATP generation is decreased. This leads to increased AMP levels, which inhibit fructose-1-6-bisphosphatase, a rate-limiting enzyme in gluconeogenesis.[12] Impaired gluconeogenesis leads to reduced hepatic clearance of lactate. Additionally, metformin inhibits glucose-6-phosphatase, which impairs glycogenolysis.[13] Both reduced gluconeogenesis and glycogenolysis, in addition to reliance on glycolysis and increased glucose utilization, all contribute to hypoglycemia, which can occasionally be seen in some MALA cases.[14]

Another consequence of inhibition of complex 1 in the mitochondrial respiratory chain is the reduced ability of mitochondria to recycle and intracellularly buffer hydrogen ions produced by ATP hydrolysis. These hydrogen ions are normally used in oxidative phosphorylation to create the energy gradient driving ATP production, but this process is disabled in metformin toxicity. The hydrogen ions accumulate and overcome endogenous buffering systems to produce metabolic acidosis.[11] This is distinct from hyperlactatemia, which represents a marker for anaerobic respiration rather than the direct cause of metabolic acidosis.

The resultant metabolic acidosis can be severe and lead to a shock state with depressed hemodynamics. The acidotic state can lead to impaired myocardial contractility, decreased function of catecholamines, and subsequent multiorgan dysfunction [15]. As the acidosis progresses and shock ensues, type A lactate production can worsen the acidosis. Renal and hepatic failure can exacerbate the pathophysiology of MALA through reduced metformin and lactate clearance, respectively.

Toxicokinetics

Metformin is available in immediate and extended-release tablet and liquid formulations. It is primarily absorbed in the small intestine with about 40 to 60% bioavailability.[16] Intestinal absorption and renal excretion are mediated by Organic Cation Transporter (OCTs) and Multidrug and Toxin Extrusion Transporter (MATE).[17] Metformin levels peak between 4 to 8 hours of absorption and have an elimination half-life of 18 hours.[11]

Approximately 90% of the absorbed metformin is excreted unchanged, renally suggesting little to no drug metabolism. Since most of the drug is renally excreted, acute or chronic renal failure can contribute to accumulation and toxicity. Metformin exhibits two-compartment behavior and a high volume of distribution, with most of the drug residing in tissue, primarily erythrocytes, intestinal tissue, skeletal muscle, and hepatocytes.[8] This multi-compartmental distribution has implications for the observational period for patients at risk of MALA. In terms of time to development of MALA, one study of 40 acute MALA cases noted that 18 developed MALA within 6 hours (45%), 9 within 12 hours (23%), and 3 over 12 hours (7.5%) and 10 with unknown timing.[18]

History and Physical

If the clinical status permits history taking, it is important to determine the amount of metformin ingested, and the time it was ingested. In addition, determine any coingestants that may have been taken. A comprehensive medication history should be performed to identify any other anti-hyperglycemic medications. Certain formulations of metformin are combined with other anti-hyperglycemic agents; most concerning are sulfonylureas. Intentional overdose of these medications can present with both MALA and hypoglycemia. Psychiatric history and intent of the ingestion should also be pursued to determine the need for psychiatric consultation and intervention after medical stabilization and clearance.

Patients often present with vague signs and symptoms. They may initially complain of gastrointestinal side effects such as nausea, vomiting, abdominal pain, and/or diarrhea, which are commonly seen with metformin use and toxicity. The patient may also complain of dyspnea, dizziness, lightheadedness, fatigue, or general malaise in the setting of acidosis.[19] More severe cases may present with altered mental status (AMS) or coma.

Physical exam should begin with overall visual assessment and evaluation of airway, breathing, and circulation (ABCs). Signs of MALA are non-specific but can be similar to acidemia from other conditions, which may include tachypnea, hyperpnea, and tachycardia.[20] Severe acidemia may impair myocardial contractility and catecholamine binding, resulting in shock and hypothermia.

Evaluation

Patients presenting with MALA may be critically ill and unable to provide history, so broad laboratory testing is reasonable. MALA is also a diagnosis of exclusion, so other etiologies of elevated lactate levels and metabolic acidosis should be ruled out first. Initial testing should include a point of care blood glucose, blood gas analysis to assess the acid-base status, basic metabolic profile to assess the patient for electrolyte abnormalities, bicarbonate level, renal function, and lactate level.

A metformin level can be obtained if there is a concern for metformin toxicity based on history and labs. Metformin levels are usually a send-out to a reference lab. As such, they are not immediately useful in determining the etiology of the patient’s presentation, and the levels do not always correlate with the severity of MALA. Nevertheless, a level may be obtained to inform downstream patient care and determine the etiology of an acute presentation of lactic acidosis.

Additional lab investigations include complete blood count to assess for SIRS criteria and other causes of shock such as hemorrhage, hepatic panel, and coagulation studies to evaluate liver dysfunction or injury, blood cultures, urinalysis, and urine culture. Computed tomography of the abdomen may aid in differentiating MALA from other etiologies such as ischemic gut. Specific drug concentrations should be obtained of acetaminophen, salicylate, ethanol, and in the right clinical setting, ethylene glycol and methanol.

An electrocardiogram should be performed to evaluate cardiac rhythm and conduction delays from potential electrolyte abnormalities or coingestants. Troponin should also be obtained to assess for cardiac injury. Continuous cardiac monitoring should be initiated. Computed tomography of the head may also be indicated in the undifferentiated patient with altered mental status.

Treatment / Management

There is no antidote for MALA. The mainstay of therapy is supportive care aiming to restore physiologic acid-base status, treat concomitant disease, and, when indicated, enhance elimination metformin. All patients should be observed for a minimum of 12 hours for symptoms and lab findings consistent with the development of MALA in an acute overdose.[18] Decontamination with activated charcoal (AC) can be used if patients present early after ingestion. Delayed AC may be reasonable for extended-release formulations due to prolonged absorption time. Activated charcoal may be used if there are no contraindications such as bowel obstruction, perforation, hypotension, or decreased gut motility. Relative contraindications include altered mental status and the inability to protect their airway.

Initial resuscitation is focused on airway, breathing, and circulation. Patients may present with central nervous depression and require intubation for airway protection. Bedside glucose should be measured and corrected for all altered patients. Care must be taken when considering intubation of the acidotic patient as physiological compensatory mechanisms may be blunted by mechanical ventilation with typical lung-protective ventilation settings (i.e., lower tidal volumes and typical respiratory rates of 10 to 16). If intubation is indicated, a higher respiratory rate and/or tidal volume should be selected to target high minute ventilation to approximate the patient’s compensatory efforts in the setting of acidosis. If patients are intubated, the ventilator setting should be adjusted to compensate for underlying acidosis with frequent monitoring of arterial blood gases.  

Treatment of severe acidosis can include a sodium bicarbonate infusion. Evidence-based indications are lacking, but some have advocated starting a bicarbonate infusion for a pH < 7.20 in the setting of underlying cardiovascular disease and/or hemodynamic compromise.[11] The bicarbonate infusion should be used to maintain a pH > 7.20. It should be noted that sodium bicarbonate works on an extracellular basis while the issue in MALA encompasses an intracellular acidosis that is impairing normal respiration and glucose utilization. In one review of metformin toxicity, there was no mortality benefit to bicarbonate administration.[21] Another review suggested improved survival with higher doses of bicarbonate as a bridge therapy to hemodialysis.[22] Sodium bicarbonate can also cause excess sodium, hyperchloremia, increased carbon dioxide production, and reflex vasodilation after bolus injection.[23] Hypotension and shock should be approached traditionally with intravenous crystalloids and vasopressors if needed. In the setting of refractory shock, methylene blue may be attempted adjunctively. It functions as a nitric oxide synthase inhibitor and an alternative electron carrier bypassing complex 1 in the mitochondrial electron transport chain and may facilitate oxidative phosphorylation.[24]

Enhanced clearance and correction of acid-base status can be achieved with hemodialysis or continuous renal replacement therapy in hemodynamically unstable patients. The extracorporeal treatments in the poisoning workgroup (EXTRIP) recommend initiating hemodialysis in the setting of pH <= 7.0, lactate > 20 mmol/L, and/or comorbid conditions including shock, acute or chronic renal or hepatic failure, and altered mental status.[6] Metformin exhibits mixed characteristics regarding dialyzability. It is lipophilic and has a high volume of distribution; however, it also has low protein binding and a prolonged half-life. Intermittent hemodialysis appears to be more effective at clearing metformin and lactate than continuous clearance modalities.[25] Given the large volume of distribution, there may be some utility to prolonged hemodialysis sessions for successful clearance of metformin and lactate. Some case reports required between 21 and 31 hours of continuous treatment for complete clearance in the setting of acute renal failure.[26][27] Hemodialysis can be discontinued after the lactate level is below 3 mmol/L and the pH is 7.35.[6]

Extracorporeal membrane oxygenation (ECMO) may be used for patients unable to tolerate clearance by hemodialysis in the setting of hemodynamic compromise.[28][29] Venoarterial (VA) ECMO may be indicated for appropriate patients in the setting of hemodynamic instability refractory to fluid resuscitation, bicarbonate therapy, and vasopressors. Patients can be started on continuous renal replacement therapy while on the ECMO circuit.

Differential Diagnosis

The differential diagnosis for MALA includes other causes of hyperlactatemia and metabolic acidosis. MALA is a diagnosis of exclusion and investigation, and initial treatment should be aimed at excluding the etiologies mentioned below.

Other toxicological etiologies resulting in hyperlactatemia may include cellular asphyxiants, uncoupling agents, impaired hepatic clearance of lactate, and overdoses resulting in seizures. Examples include cyanide, isoniazid, antiretroviral drugs, linezolid, propylene glycol, rotenone, hydrogen sulfide, nalidixic acid, salicylate, propofol infusion syndrome, antiretroviral medications, ethylene glycol, and massive acetaminophen overdose.[30]

Nontoxicological etiologies include sepsis, shock states, status epilepticus, liver failure, inborn errors of metabolism, mesenteric ischemia, diabetic ketoacidosis, thiamine deficiency, and alcoholic ketoacidosis.[11]

Prognosis

The reported mortality rate is variable and likely reflects selection bias. The highest mortality rate estimates for MALA may be as high as 30 to 50%, but most are lower.[3] Mortality is more likely in patients who present with initial pH < 7.1 and lactate > 25. In one systematic review examining 22 cases of MALA, 83% of patients with pH < 6.9 and/or serum lactate concentration was > 25 died [31]. Other studies have found no clear correlation between metformin concentration, pH, and lactate or major differences between survivors and non-survivors based upon these values.[32][33] The prognosis was strongly correlated with the presence of kidney, heart, and liver failure,  sepsis, and multi-drug intoxication.[32]

Patients presenting with altered mental status, coma, severe acidosis, renal failure, hepatic failure, or those on mechanical ventilation will need admission to a critical care unit. Patients who do not have any evidence of acidosis and remain asymptomatic after an observation period of a minimum of 12 hours may be discharged or medically cleared for psychiatry, depending on intent.

Complications

In the case of severe MALA, persistent renal dysfunction is a potential complication. There have been case reports detailing persistent renal dysfunction after the resolution of acute MALA. In one case, a patient presented with intentional metformin overdose and had mildly elevated creatinine with hyperlactatemia and metabolic acidosis treated with continuous renal replacement therapy (CRRT).[34] The lactate cleared after 24 hours but later developed anuria and worsening renal function requiring subsequent intermittent hemodialysis before renal function recovered.

Deterrence and Patient Education

Patients should be counseled on the risks of metformin overdose and the importance of adhering to the prescribed dose. Caution should be used in chronic renal disease, and appropriate dose decreases made if metformin therapy is continued. Metformin can still be used in patients with chronic kidney disease without dose adjustment if glomerular filtration rate (GFR) is above 30 ml/min/1.73 m^2, but kidney function must be monitored every 3 to 6 months.[35] Patients should avoid ethanol consumption while taking metformin to avoid the development of MALA and hepatotoxicity.

Metformin use should be withdrawn in the setting of hypoxia or hypoperfusion, such as myocardial infarction or shock. It is recommended to withdraw metformin three days after using intravenous iodinated contrast and restart only after kidney function has stabilized. It is also advised to stop metformin two days before general anesthesia.[36] Primary care physicians and endocrinologists should be conscientious when prescribing to account for other medications, medical comorbidities, age, and nutrition status. 

Pearls and Other Issues

• Metformin is a biguanide compound used as an antihyperglycemic in the treatment of diabetes mellitus
• Metformin associated lactic acidosis (MALA) is defined as pH < 7.35 and lactate > 5 mM in the setting of known or suspected metformin use
• There are two subsets of metformin toxicity:
  • Chronic or incidental MALA - a predisposing pathophysiological condition that leads to supra-therapeutic accumulation of metformin
  • Intentional or acute metformin-induced lactic acidosis (MILA) – an acute overdose of metformin
• MALA occurs in about 9% of mono-overdoses of metformin and 0.7% of poly-substance overdoses
• Patients at risk for the development of MALA should be observed for a minimum of 12 hours
• A broad workup to evaluate for other etiologies of metabolic acidosis and shock states should be initiated
• Patients presenting with MALA may exhibit signs of shock requiring aggressive management, including intubation, ventilation, and vasopressor support
• Sodium bicarbonate infusion is recommended for pH < 7.20, especially in the setting of underlying cardiovascular disease or hemodynamic compromise
• Hemodialysis should be initiated for pH < 7.0, lactate > 20, and in patients who do not respond to more conservative therapies
• Hemodialysis exhibits a higher clearance rate of metformin and lactate than CRRT and is preferred with concurrent use of vasopressors
• ECMO, when available, is a potential intervention if hemodynamics doesn’t allow for hemodialysis and if unresponsive to vasopressors
• Methylene blue may be used adjunctively as a possible rescue agent for vasoplegic shock and metabolic bypass

Enhancing Healthcare Team Outcomes

Metformin-associated lactic acidosis is an important topic for practitioners of different specialties, including emergency physicians, internists, critical care physicians, toxicologists, pharmacists, and nephrologists. A multidisciplinary approach is required to stabilize patients during the acute toxicity phase. Patients with concerns for MALA should have the following:

• Obtain and monitor vital signs
• Contact your local Poison Control Center for assistance with management and epidemiology collection.
• Extensive laboratory assessment to search for additional and alternative causes of patient’s presentation.
• Aggressive treatment of severe acidosis with initiation sodium bicarbonate and hemodialysis when indicated.

Patients with symptoms or evidence of MALA should be admitted. If the acidosis is severe, they require bicarbonate or extracorporeal renal clearance or require vasopressor or ventilator support; they should be admitted to the ICU. Patients who remain asymptomatic and do not have evidence of MALA on evaluation during an observational period of at least 12 hours can be safely discharged.