Metformin poisoning

INTRODUCTION — In normal individuals, fasting plasma glucose levels range from about 60 to 100 mg/dL (3.3 to 5.6 mmol/L) [1]. In patients with diabetes mellitus, insulin deficiency or insulin resistance leads to a state of hyperglycemia. Galega officinalis (goat's rue or French lilac) was used to treat diabetes in medieval Europe. The active ingredient, guanidine, was used to synthesize other antidiabetic agents in the 1920s [2], and the biguanide hypoglycemic agents phenformin and metformin became available for clinical use in the 1950s.

Biguanides are antihyperglycemic agents, not hypoglycemic agents; they promote euglycemia but alone are unlikely to cause hypoglycemia. Biguanides are used both as monotherapy and in combination with other oral hypoglycemic agents. They can exacerbate hypoglycemia caused by other types of antidiabetic medicines [3,4].

The major toxicity from acute or chronic biguanide use is lactic acidosis. The high rate of severe lactic acidosis from phenformin led to the withdrawal of this drug from the US market in 1976, although it remains available in several countries. Metformin is the principal biguanide in clinical use.

The management of metformin toxicity is reviewed here. A summary table to facilitate emergent management is provided (table 1). General issues relating to hypoglycemia, the therapeutic use of biguanides, and the general clinical management of drug intoxication are presented separately.

●(See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

●(See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)

●(See "Metformin in the treatment of adults with type 2 diabetes mellitus".)

●(See "General approach to drug poisoning in adults".)

PHARMACOLOGY — Metformin decreases insulin resistance, decreases hepatic glucose output, and enhances peripheral glucose uptake [5]. Proposed mechanisms of action include enhanced suppression of gluconeogenesis by insulin, reduced glucagon-stimulated gluconeogenesis, and increased uptake of glucose by muscle and adipose cells [5]. The net effects of these changes in diabetic patients are to decrease fasting and post-prandial blood glucose by 20 to 40 percent, decrease hemoglobin A1C, decrease body weight slightly, decrease low density lipoprotein (LDL), and increase high density lipoprotein (HDL) [6]. (See "Metformin in the treatment of adults with type 2 diabetes mellitus".)

KINETICS — Metformin absorption occurs primarily in the upper part of the intestine [7]. The drug has negligible plasma protein binding and a volume of distribution ranging from 63 to 276 L (1 to 5 L/kg) [6-8]. The elimination half-life of metformin in patients who take multiple doses and have good renal function is approximately five hours [7]. Metformin is excreted, unmetabolized, via transporters in the proximal tubules of the kidneys, and may accumulate in acute and chronic kidney disease [9].

CLINICAL FEATURES OF TOXICITY

Signs and symptoms — Patients with metformin overdose may complain of nausea and abdominal pain [10-12]. In the setting of chronic metformin use and lactic acidosis accumulation (metformin-associated lactic acidosis [MALA]), the most common complaints are gastrointestinal (including nausea, vomiting, and diarrhea) followed by altered mental status and shortness of breath [13].

Physical examination findings may include tachycardia, hypotension, and tachypnea in patients with severe lactic acidosis. Alterations in mental status may be due to acidosis or hypoglycemia [10-12], although the latter is uncommon without concurrent use of a hypoglycemic agent.

Lactic acidosis

Incidence — MALA may occur following acute overdose [10,11,14-17]. A United Kingdom poison control center study that included 117 patients with isolated metformin overdose found that 28 percent developed a lactic acidosis [18]. MALA may also develop in patients with comorbidities such as kidney or hepatic insufficiency or a precipitating disease (eg, acute infection), leading to acute kidney injury and impaired metformin elimination. Otherwise, MALA is unlikely to occur. A systematic review of 347 trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 47,846 patient-years of metformin use and calculated the upper limit of the incidence of such lactic acidosis to be 4.3 cases per 100,000 patient years [19]. (See "Causes of lactic acidosis", section on 'Diabetes mellitus'.)

Mechanism — The mechanism of MALA is complex. Metformin promotes the conversion of glucose to lactate in the splanchnic bed of the small intestine [20]. Metformin also inhibits mitochondrial respiratory chain complex 1, leading to decreased hepatic gluconeogenesis from lactate, pyruvate, and alanine [13]. This results in additional lactate and substrate for lactate production [21].

Risk factors — Because reports of dosages in overdose are often unreliable, it is unclear what minimum dose of metformin leads to toxicity. The clinician should have a high index of suspicion for toxicity in children who ingest more than one or two tablets, anyone who presents with intentional overdose, and patients with comorbidities such as acute or chronic kidney disease, liver disease, or heart failure.

Clinically significant lactic acid accumulation almost always occurs in the presence of comorbid conditions, such as the following:

●Impaired kidney function (precise thresholds vary; details are provided separately) [22] (see "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'))

●Concurrent liver disease

●Active alcohol use

●Unstable or acute heart failure

●History of lactic acidosis during metformin therapy

●Decreased tissue perfusion or hemodynamic instability

●Hypoxic states or serious acute illness

Outcomes — Mortality is high in patients with MALA. A metanalysis (44 studies, 170 cases) found a mortality of 36 percent [23]. Similarly high mortality has been reported in multiple case series [13,24-26].  

In patients with MALA from a precipitating disease, neither arterial lactate levels nor plasma metformin concentrations predict mortality. Death more closely correlates with underlying acute or comorbid conditions. In a case series of 66 patients with MALA, the absolute metformin and lactate concentrations were not different in survivors and non-survivors [13]. Multiple organ dysfunction, such as liver dysfunction as demonstrated by an elevated prothrombin time, has been found to predict mortality in patients with MALA [25].

In patients with MALA from confirmed acute metformin overdose, a systematic review found that lower serum pH and higher serum lactate concentrations correlated with increased mortality [27]. All 16 survivors had a serum pH above 6.9 and a serum lactate below 25 mmol/L, while 5 of the 6 patients with a pH less than 6.9 or a lactate greater than 25 mmol/L died. The United Kingdom poison center study found that the degree of toxicity correlated with the serum lactate concentration and inversely correlated with the arterial pH. These laboratory values did not correlate with each other, and either could be an independent marker of poisoning severity [18].

Hypoglycemia — Metformin can contribute to hypoglycemia when in combination with other hypoglycemic drugs but is alone unlikely to cause hypoglycemia [3,4].

EVALUATION

History — In the setting of acute overdose, clinicians should seek information about dose and co-ingestants, although such information is frequently unreliable. Whether the patient has an acute overdose or chronic toxicity, clinicians should also ask whether other antidiabetic agents are used.

Studies to obtain — Routine evaluation of any acutely poisoned patient should include the following:

●Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status; this is particularly important in patients in whom metformin toxicity is suspected, and in diabetics generally

●Acetaminophen and salicylate levels, to rule out these common co-ingestions

●Electrocardiogram, to rule out conduction system poisoning by co-ingestants that affect the QRS or QTc intervals

●Pregnancy test in women of childbearing age

Specific laboratory testing in cases of known or suspected metformin toxicity should include the following:

●Arterial or venous blood gas, for accurate determination of the patient's acid-base status

●Basic chemistries, to determine the bicarbonate concentration and to assess kidney function

●Serum lactate level, to confirm that any metabolic acidosis is in fact a lactic acidosis

Role of metformin concentration — Obtaining a serum metformin concentration is unhelpful in most cases because few hospitals perform the test and thus timely results are rarely available, and because the serum concentration often does not correlate with the severity of the poisoning or patient outcome [13,24,27,28]. An undetectable concentration excludes metformin as the cause of lactic acidosis in most cases. Nevertheless, it is important to consider other causes of lactic acidosis (eg, sepsis, bowel ischemia) in patients who take metformin.

DIAGNOSIS — Metformin overdose is diagnosed by history of intentional metformin ingestion. Metformin-associated lactic acidosis (MALA) is diagnosed with an elevated serum lactate concentration in conjunction with taking metformin.

The priority in diagnosis is identifying the presence of lactic acidosis and any precipitating illnesses. Distinguishing whether metformin is causing or contributing to the acidosis and clinical picture does not alter management. Therefore, while some authors use the term "metformin-induced" lactic acidosis (rather than "metformin-associated") to distinguish the condition where metformin is clearly responsible, making this distinction may require obtaining a metformin concentration, which is not readily available [26].

An extremely elevated lactate concentrations suggests that metformin is contributing to the clinical presentation. For example, a retrospective study of emergency department patients with suspected sepsis-induced lactic acidosis found that patients with MALA had much higher lactate concentrations (14.7 versus 5.9 mmol/L) [29]. The combined parameters of lactate >8.4 mmol/L, creatinine >2.9 mg/dL, and history of metformin use had a specificity of 99 percent for MALA in patients with suspected sepsis-induced lactic acidosis.

MANAGEMENT OF OVERDOSE OR TOXICITY — The following treatment recommendations are based upon our clinical experience and the limited available evidence. A summary table to facilitate emergent management is provided (table 1).

Airway, breathing, circulation — Patients with acute or chronic metformin toxicity rarely require endotracheal intubation. It is important to note that hyperpnea and tachypnea may reflect compensation for a metabolic acidosis and may not represent impending respiratory failure. If intubation is required, the clinician should pay special attention to ventilator management. Minute ventilation sufficient to compensate for any underlying acidosis should be maintained and arterial blood gas results checked frequently until the patient is stabilized. (See "Simple and mixed acid-base disorders".)

Hypotension should initially be treated with intravenous fluids, followed by vasopressors if needed. Persistent hypotension suggests profound toxicity, and in such cases hemodialysis treatment is often necessary. (See 'Extracorporeal removal' below.)

Gastrointestinal decontamination — Gastrointestinal (GI) decontamination with activated charcoal (AC) is suggested in patients with acute metformin ingestion, unless specific contraindications (such as bowel obstruction or GI perforation) exist. Patients with toxicity from chronic use are unlikely to benefit from GI decontamination. The clinician must assess aspiration risk, including mental status and ability to protect the airway, in all patients before any attempts to administer AC. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

Hypoglycemia — If hypoglycemia is present, it should be treated with 0.5 to 1 g/kg IV dextrose, followed by a meal if food is not contraindicated. Metformin alone should not cause hypoglycemia and other causes should be sought. The acute management of hypoglycemia in children is discussed separately. (See "Approach to hypoglycemia in infants and children".)

Lactic acidosis

Sodium bicarbonate — The use of sodium bicarbonate in metformin-associated lactic acidosis (MALA) is controversial. If severe metabolic acidosis is present, sodium bicarbonate may be administered, but there are theoretical disadvantages to its use [12]. These disadvantages include leftward shift of the hemoglobin dissociation curve, excess sodium load, rebound metabolic alkalosis, disturbances in serum potassium and calcium, decreased myocardial contractility, increased carbon dioxide production, and reflex vasodilation after bolus injection [11]. (See "Bicarbonate therapy in lactic acidosis".)

Extrapolating from other clinical scenarios, we suggest limiting the use of sodium bicarbonate to patients with severe metabolic acidosis (arterial pH below 7.1, or below 7.2 in patients with severe acute kidney injury), with the aim being to maintain the pH above 7.1 (or above 7.3 in patients with severe acute kidney injury), until the acute toxicity resolves.

Extracorporeal removal — Hemodialysis has been used successfully in patients with MALA that developed from chronic use or acute overdose [8,12,30-32]. We concur with the suggestions of the Extracorporeal Treatments in Poisoning Workgroup and recommend hemodialysis for patients with any of the following findings associated with severe metformin poisoning from chronic use or acute overdose [8]:

●Severely elevated serum lactate concentration (>20 mmol/L)

●Severe metabolic acidosis (pH ≤7.0)

●Failure to improve (as determined by pH, lactate concentration, or clinical status) with supportive care and bicarbonate therapy within two to four hours.

Although evidence is limited, we suggest hemodialysis for patients with any of the following findings:

●Elevated serum lactate concentration between 15 to 20 mmol/L

●Metabolic acidosis (pH of 7.0 to 7.1)

●Comorbidities:

•Shock or persistent hemodynamic instability requiring vasopressor therapy despite acute administration of IV boluses of isotonic crystalloid totalling 30 mL/kg  

•Kidney injury – Creatine >2 mg/dL (adults), or >1.5 mg/dL (elderly), or 2 times upper limit of normal (children), or chronic kidney disease (stage 3b or higher with eGFR <45 mL/min/1.73 m², oliguria, or anuria)

•Liver failure – liver injury with coagulopathy (INR >1.5) and any degree of encephalopathy

•Decreased level of consciousness

For critically ill patients who do not meet any of the above criteria, (eg, those with lactate concentrations >15 mmol/L, or pH 7.0 to 7.1 ), or who have important comorbid conditions (eg, kidney insufficiency, liver failure, decreased level of consciousness), it is important to obtain early consultation with a medical toxicologist and a nephrologist, and to coordinate care with these specialists, as such patients may progress quickly to needing hemodialysis [8].

Hemodialysis should be performed using a bicarbonate buffer, as the benefits of hemodialysis lie in correcting the metabolic acidosis much more so than in removing metformin. Treatment may need to be repeated should metabolic derangements recur. Hemodialysis may be discontinued when the lactate concentration is <3 mmol/L and the pH is >7.35 [8].

For patients with severe metformin poisoning requiring extracorporeal removal, hemodialysis is the preferred approach if the hemodynamics are adequate. Continuous hemodialysis (>15 hours) has been used successfully in extremely ill patients. If the patient is hemodynamically unstable, CVVH or CVVHD should be considered. Continuous venovenous hemofiltration (CVVH) has been performed in patients with metformin overdose [12,33]. According to case reports, the clearance of drug by CVVH was less than that generally reported to occur with conventional hemodialysis [30,33]. Therefore, CVVH should only be considered in patients who are too hemodynamically unstable to tolerate hemodialysis.

Although there are no randomized trials of prolonged renal replacement therapy in severe metformin poisoning, retrospective series and case reports support this approach when necessary [25,33-35].

No antidotal treatment — There are no antidotes for metformin toxicity.

DISPOSITION — The onset of lactic acidosis may take several hours, so patients reporting an acute ingestion should be observed for at least six to eight hours [3,36]. Patients who are well appearing and who have a normal acid-base status after six to eight hours may be discharged or transferred to the care of a psychiatrist.

If a patient deteriorates despite appropriate supportive care, the clinician should promptly consult nephrology regarding the possibility of hemodialysis. During this consultation, the clinician should convey to the nephrologist both the patient's clinical condition and, if available, serial acid-base determinations to help document the patient's deterioration.

Patients may present with a mild lactate elevation or mildly increased anion gap, but have normal vital signs and an unremarkable physical examination. Such patients may be discharged home with careful instructions to stop taking their metformin and to see their primary clinician within the next several days if the laboratory abnormalities are minor and resolve on repeat evaluation after a brief period (approximately six hours) of uneventful observation. Asymptomatic patients with persistent abnormalities (metabolic acidosis; elevated lactate) and symptomatic patients should be observed using the same guidelines described for acute ingestions, or they should be admitted to the hospital for observation.

PEDIATRIC CONSIDERATIONS — The number of pediatric patients with Type II diabetes is increasing, likely as a result of the pediatric obesity epidemic. Metformin is one of only a few drugs approved for the treatment of Type II diabetes in this population. It is logical to treat pediatric metformin toxicity in the same manner as one would treat adults, and anecdotal success supports such therapy [37,38]. (See "Management of type 2 diabetes mellitus in children and adolescents".)

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have clinical and/or medical toxicologists available for bedside consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

●Pharmacology and kinetics – Biguanides are antihyperglycemic agents (not hypoglycemic agents) since they promote euglycemia. Metformin absorption occurs primarily in the intestine, and the drug is excreted unmetabolized from the kidneys. It may accumulate in renal failure. (See 'Pharmacology' above and 'Kinetics' above.)

●Clinical features of toxicity – Signs and symptoms can include nausea and abdominal pain, and tachycardia, hypotension, tachypnea, and altered mental status in patients with severe lactic acidosis. (See 'Clinical features of Toxicity' above.)

•Hypoglycemia – Metformin can contribute to hypoglycemia when in combination with other hypoglycemic drugs but is alone unlikely to cause hypoglycemia. (See 'Hypoglycemia' above.)

•Lactic acidosis – Metformin-associated metabolic acidosis (MALA) is the major toxicity of metformin. MALA may occur in patients with acute metformin overdose and those taking metformin who develop a precipitating illness that causes tissue hypoxemia or kidney injury and impaired metformin elimination. Risk factors include renal insufficiency, liver disease, alcohol use, heart failure, and history of lactic acidosis during metformin therapy. (See 'Lactic acidosis' above.)

In patients who develop MALA from a precipitating illness, mortality correlates with the severity of the underlying medical conditions. In patients with MALA from acute metformin overdose, death correlates with high plasma lactate and low serum pH. (See 'Outcomes' above.)

●Evaluation – Routine evaluation of any acutely poisoned patient should include fingerstick glucose, acetaminophen and salicylate concentrations, electrocardiogram, and pregnancy test in females of childbearing age. Specific laboratory testing in cases of known or suspected metformin toxicity includes serum chemistries, arterial or venous blood gas, and serum lactate concentration (to confirm the metabolic acidosis is in fact a lactic acidosis). (See 'Studies to obtain' above.)

Obtaining a serum metformin concentration is unhelpful in most cases because few hospitals perform the test, and the concentration often does not correlate with the severity of the poisoning or patient outcome. If the test is available, an undetectable concentration excludes metformin as the cause of lactic acidosis in most cases. (See 'Role of metformin concentration' above.)

●Diagnosis – Metformin overdose is diagnosed by history of intentional metformin ingestion. MALA is diagnosed with an elevated serum lactate concentration in conjunction with taking metformin. The priority in diagnosis is identifying the presence of lactic acidosis and any precipitating illnesses. Distinguishing whether metformin is causing or contributing to the acidosis and clinical picture does not alter management, thus the term "metformin-associated" lactic acidosis). An extremely elevated lactate concentration (ie, >8 mmol/L) suggests that metformin is contributing to the clinical presentation. (See 'Diagnosis' above.)

●Management – A summary table to facilitate emergency management of metformin intoxication is provided (table 1). Care is mainly supportive, with hemodialysis used to treat MALA. There is no antidote for metformin toxicity. (See 'Management of overdose or toxicity' above.)

•Supportive care – Patients with metformin toxicity rarely require tracheal intubation. Hyperpnea and tachypnea may reflect compensation for a metabolic acidosis and may not represent impending respiratory failure. If intubation is required, the clinician should pay special attention to ventilator management. Minute ventilation sufficient to compensate for any underlying acidosis should be maintained and arterial blood gas results checked frequently until the patient is stabilized. Persistent hypotension suggests profound toxicity. (See 'Airway, breathing, circulation' above.)

•Gastrointestinal (GI) decontamination – In patients with acute metformin ingestion, we suggest GI decontamination with activated charcoal (AC) be performed (Grade 2C). AC should not be given to patients with toxicity from chronic use. The clinician must assess aspiration risk before any attempts to administer AC. (See 'Gastrointestinal decontamination' above.)

•Hypoglycemia – Treat hypoglycemia with dextrose 0.5 to 1 g/kg IV, followed by a meal if food is not contraindicated. (See 'Hypoglycemia' above.)

•MALA – In patients with severe metabolic acidemia (ie, arterial pH less than 7.15), we suggest administering sodium bicarbonate (Grade 2C). A reasonable goal is to maintain the pH above 7.15 until the acute toxicity resolves. (See 'Sodium bicarbonate' above and "Bicarbonate therapy in lactic acidosis".)

In patients with MALA and any of the following, we recommend hemodialysis (Grade 1C):

-Lactate concentrations >20 mmol/L

-Severe metabolic acidosis (pH ≤7.1)

-Failure to improve within two to four hours despite appropriate supportive care and bicarbonate therapy

In patients with MALA and any of the following, we suggest hemodialysis (Grade 2C):

-Lactate concentrations between 15 to 20 mmol/L

-Metabolic acidosis with pH 7.0 to 7.1

-Presence of comorbid conditions (shock, kidney impairment, liver failure, or decreased level of consciousness)

Hemodialysis has been used successfully in patients with MALA due to chronic use or acute overdose. Early consultation with a medical toxicologist and a nephrologist should be obtained for any patient with signs of severe toxicity, acidosis, or for when considering hemodialysis. (See 'Extracorporeal removal' above.)

●Disposition – Patients reporting an acute ingestion should be observed for at least six to eight hours. Patients who are well appearing and who have a normal acid-base status after six to eight hours may be discharged or transferred to the care of a psychiatrist.

If a patient deteriorates during a period of observation, the clinician should promptly consult nephrology regarding the possibility of hemodialysis. Serial acid-base determinations help document the patient's deterioration. (See 'Disposition' above.)

●Pediatric considerations – We treat children with metformin overdose in the same manner as adults. (See 'Pediatric considerations' above.)