INTRODUCTION — Sulfonylurea agents are commonly used in the treatment of diabetes mellitus. When used appropriately, they promote euglycemia, although hypoglycemia can occur if clearance is impaired or the patient does not eat. Sulfonylureas often cause hypoglycemia with overdose or when ingested by nondiabetic patients.
The hypoglycemic effects of the sulfonamide antibacterial agents were first discovered in the 1940s. The sulfonylurea medications were first used to treat diabetes mellitus type 2 in 1954, and they remain in widespread use today [1]. Sulfonylureas may be used alone when diet control has failed or in combination with other oral drugs.
Patients over 65 years, those taking multiple medications, and those who are frequently hospitalized are at increased risk for hypoglycemia [1,2]. Sulfonylurea-related hypoglycemia may also be seen in the setting of unintentional ingestion. Ingestion of a single sulfonylurea pill (ie, 2 mg) by a toddler can cause hypoglycemia [3,4].
The management of sulfonylurea toxicity will be reviewed here. The therapeutic use of sulfonylureas and other antihyperglycemic agents, the toxicology of other antihyperglycemic agents such as metformin, and the general clinical management of drug intoxication are discussed separately:
●(See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)
●(See "Metformin poisoning".)
●(See "General approach to drug poisoning in adults".)
PHARMACOLOGY AND TOXICOLOGY — Sulfonylurea medications inhibit ATP-sensitive potassium channels in pancreatic beta cell membranes. These potassium channels normally allow for potassium efflux from the cell. Inhibition leads to elevated intracellular potassium concentrations, which results in depolarization. Depolarization causes calcium influx, which activates the secretory system that releases insulin. Sulfonylureas also promote exocytosis of insulin through distinct mechanisms involving direct binding of pancreatic beta cell receptors. In summary, sulfonylurea medications promote hypoglycemia by increasing the release of endogenous insulin [5-7].
The toxicity of sulfonylurea agents is a direct extension of their normal pharmacology. When used inappropriately (in overdose or in patients without diabetes), hypoglycemia can result.
Several drug and patient related factors increase the risk of hypoglycemia. Sulfonylurea agents with longer durations of action (eg, chlorpropamide and glyburide) are more likely to cause such reactions [1,8]. Impaired drug clearance contributes to toxicity in some cases, and renal insufficiency is associated with a fourfold risk of hypoglycemia in patients taking sulfonylureas.
Drug interactions may also cause hypoglycemia through a number of mechanisms, including decreased hepatic metabolism, increased hypoglycemic activity, and inhibition of membrane transporters (table 1) [1,9-13]. Certain antibiotics and antifungals are associated with increased risk of hypoglycemia when taken with sulfonylureas [14].
Specific interactions of sulfonylureas with other medications may be determined using the drug interaction tools included with UpToDate. These tools can be accessed by using the following link (Lexicomp drug interactions) or the “Drug Interactions” tab on the UpToDate home page.
KINETICS — Sulfonylureas possess a broad range of pharmacokinetic properties (table 2). In overdose, their onset of action remains unchanged, but their duration of action increases [15]. Peak plasma concentrations are generally achieved within eight hours of an acute ingestion, but may be delayed in overdose.
Sulfonylureas are metabolized by the liver. Some agents have active metabolites that are renally excreted (table 3).
The sulfonylureas are extensively protein bound [1]. The duration of activity, hepatic metabolism, and renal excretion all have implications in the management of patients presenting with sulfonylurea related hypoglycemia.
HISTORY AND PHYSICAL EXAMINATION — If possible, clinicians should ask patients about the amount, timing, and reason for any ingestion, what drug was taken, and coingestants including other diabetic medications. Coingestants may mask autonomic symptoms of sulfonylurea overdose. The clinician should attempt to identify any recent illness that may have triggered sulfonylurea-induced hypoglycemia. Age greater than 65 years, taking multiple medications, frequent hospitalization, renal insufficiency, and poor management of diabetes have been associated with sulfonylurea-induced hypoglycemia [1,2,16].
The remainder of the history and physical examination should focus on identifying the manifestations of hypoglycemia, often divided into neuroglycopenic and autonomic dysfunction. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)
Neuroglycopenia describes insufficient brain glucose. Common symptoms include confusion, difficulty speaking, dizziness, hemiparesis, seizures, or coma [17]. In short, neuroglycopenia can mimic virtually any neurologic condition.
Autonomic symptoms are caused by counterregulatory hormones, especially epinephrine, and include anxiety, nausea, sweating, and palpitations [18,19].
According to one retrospective chart review of 59 patients, the most common neuroglycopenic symptoms are confusion (83 percent) and personality change (64 percent), while the most common autonomic complaints are diaphoresis (69 percent) and tremulousness (24 percent) [17].
In infants and young children, the signs of hypoglycemia are frequently nonspecific. They may include irritability, lethargy, abnormal behavior, and with severe hypoglycemia can progress to seizure and coma. Autonomic symptoms are less prominent. With repeated episodes of hypoglycemia, severe manifestations can appear suddenly. (See "Approach to hypoglycemia in infants and children".)
There is no consistent chronologic order to the evolution of hypoglycemic symptoms.
LABORATORY EVALUATION — When hypoglycemia is absent following an unintentional exposure, additional testing is generally unnecessary. Patients with known or suspected sulfonylurea poisoning should have a serum creatinine measured, as a decrease in renal clearance may contribute to toxicity. Serial measurements of serum glucose and baseline measurements of serum electrolytes are appropriate. Further testing is determined clinically. As an example, urine myoglobin and serum creatine kinase are appropriate tests in a patient found on the ground and unresponsive, and thought to be at risk for rhabdomyolysis.
Routine laboratory evaluation of any poisoned patient, particularly those with a suspected intentional overdose, includes the following:
●Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status. This is particularly important in patients who have taken sulfonylurea agents.
●Acetaminophen and salicylate concentrations, to rule out these common coingestions.
●Electrocardiogram, to rule out conduction system poisoning by coingestants that effect the QRS or QTc intervals.
●Pregnancy test, when appropriate.
DIAGNOSIS — The diagnosis of sulfonylurea poisoning is made clinically on the basis of a history of overdose or exposure to sulfonylureas and confirmatory clinical and laboratory findings of hypoglycemia, including alterations in mental status (eg, confusion, difficulty speaking, hemiparesis, seizures, coma) and autonomic signs and symptoms (eg, anxiety, sweating, palpations). In the case of pediatric sulfonylurea poisoning, a careful history may reveal a missing tablet belonging to an adult caregiver. In adult poisoning, patients may give a history of intentional overdose.
In most cases, patients with sulfonylurea poisoning present with undifferentiated hypoglycemia. If available, a medication list may reveal the possibility of sulfonylurea poisoning. Hypoglycemia in the context of a history of sulfonylurea use is sufficient to establish a clinical diagnosis of sulfonylurea poisoning. All suspected cases of sulfonylurea poisoning should be treated empirically. (See 'Management' below.)
DIFFERENTIAL DIAGNOSIS — If the history is unclear, the clinician should consider other causes of hypoglycemia before establishing the diagnosis of sulfonylurea poisoning. However, consideration of the differential diagnosis must not delay the treatment of acute hypoglycemia. The differential diagnosis of low blood glucose is broad and discussed in detail separately; alternative diagnoses of particular relevance to the patient with sulfonylurea poisoning are discussed briefly below. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach" and "Approach to hypoglycemia in infants and children".).
A number of diseases (table 4) and medications (table 5) can cause hypoglycemia. Diseases that increase insulin secretion (eg, insulinomas) or decrease insulin availability (eg, insulin antibodies or insulin receptor antibodies) can cause hypoglycemia. Antibodies can cause hypoglycemia when they function as insulin receptor agonists or, rarely, when they bind insulin and prolong its duration of activity [20]. In addition, deficiencies in cortisol or glucagon, as well as severe illness from sepsis, hepatic failure, or malnutrition may cause hypoglycemia. However, patients with severe, acute presentations of such deficiencies or diseases are generally ill appearing and manifest signs and symptoms of those conditions in addition to signs and symptoms (such as confusion and autonomic findings) attributable to sulfonylurea poisoning. Prominent features of adrenal crisis include fever and abdominal pain; septic patients are often febrile with abnormal vital signs and a source of infection; hepatic failure may manifest with abdominal complaints (pain, vomiting, distension), characteristic laboratory abnormalities (elevated PT and Bilirubin), jaundice, and encephalopathy.
Drugs such as insulin, meglitinides, or alcohol may cause hypoglycemia. Rarely, insulin is surreptitiously administered with the intent to harm. If a patient is taking insulin and a sulfonylurea, it may be impossible to determine the degree to which each drug contributed.
Laboratory results can be used to support the diagnosis but should not delay treatment. Because sulfonylureas cause release of endogenous insulin, proinsulin and c-peptide concentrations will be elevated along with insulin concentrations. Very rarely, individuals ingest illegally obtained sulfonylureas because the tablets have a similar appearance to misused substances such as diazepam or oxycodone. Confirmatory sulfonylurea assays may be available in many institutions, but usually require several days for results and thus, play no role in acute clinical management.
MANAGEMENT
Hypoglycemia — When hypoglycemia is recognized, intravenous dextrose (D-glucose) is administered (0.5 to 1 g/kg IV) to increase blood glucose acutely. Symptomatic hypoglycemia from intentional sulfonylurea overdose is treated with both dextrose and octreotide; the role of octreotide in hypoglycemia associated with therapeutic use of sulfonylureas is unclear. (See 'Symptomatic intentional overdose' below and 'Unintentional single-episode hypoglycemia' below.)
In adults, the initial treatment is generally 25 g (50 mL) of 50 percent dextrose (D50W) solution. In infants and children, a weight-based bolus of dextrose (0.5 to 1 g/kg) is given IV. Children are treated with a 25 percent (D25W) or 10 percent (D10W) dextrose solution, and neonates with a 10 percent dextrose solution. Doses of dextrose may be repeated.
Basic pediatric dosing is as follows:
●D10W: Give 5 to 10 mL/kg
●D25W: Give 2 to 4 mL/kg
●D50W: Give 1 to 2 mL/kg
If thiamine deficiency (from alcoholism or other forms of malnutrition) is suspected, parenteral thiamine (100 mg IV) is given in conjunction with glucose. (See "Wernicke encephalopathy".)
Glucagon (5 mg) given intramuscularly (IM) raises serum glucose slightly and may be used as a temporizing measure while IV access is obtained, but it is not a substitute for dextrose [21]. The efficacy of glucagon is dependent upon hepatic glycogen stores, which may be depleted in the setting of prolonged hypoglycemia [15]. The short duration of action of glucagon further limits its effectiveness.
Once clinical euglycemia is established based on clinical findings, and generally accompanied by a serum glucose ≥60 mg/dL (3.3 mmol/L), the patient should be fed a calorie-rich meal. Fifty mL of 50 percent dextrose in sterile water (D50W) contains only 25 g of dextrose or 100 calories, whereas food provides a calorie-rich and longer lasting source of glucose.
Further treatment and disposition vary depending on the class of agent causing the toxicity and the severity of symptoms.
Intoxication — The clinician is most likely to encounter one of three possible intoxication scenarios: a patient with a sulfonylurea overdose and symptomatic hypoglycemia; a patient who develops a hypoglycemic episode with therapeutic use of a sulfonylurea agent; and the asymptomatic (usually pediatric) patient with an acute exposure and a normal serum glucose.
Symptomatic intentional overdose — The patient with a sulfonylurea overdose and symptomatic hypoglycemia should be treated with both intravenous dextrose and octreotide. Intravenous dextrose is administered, as described above, to raise the blood glucose acutely, thereby increasing glucose delivery to the brain (see 'Hypoglycemia' above). Octreotide is a somatostatin analog that inhibits insulin release from pancreatic beta-islet cells.
Intravenous dextrose, while crucial for resuscitation, should not be used as monotherapy for a sulfonylurea overdose. When given alone, IV dextrose may cause a transient hyperglycemia that triggers increased insulin release, leading to recurrent episodes of hypoglycemia. This increase in insulin release can be minimized by octreotide. Octreotide dosing is as follows:
●In adults, the dose of octreotide is 50 to 100 mcg administered by intramuscular, or subcutaneous, injection every six hours.
●In children, the dose of octreotide is 1 to 1.5 mcg/kg (up to 50 mcg) every six hours.
Octreotide may also be given as an IV bolus over several minutes or by continuous IV infusion [22]. In almost all cases, intermittent intramuscular and subcutaneous dosing is sufficient and IV infusion is unnecessary to maintain normoglycemia.
Serum glucose should be periodically monitored to identify any recurrence of hypoglycemia. The optimal interval is not known. Once the initial hypoglycemia is corrected, we suggest measuring blood glucose twice more at 30 minute intervals. If the patient maintains euglycemia, serum glucose can be checked every four to six hours thereafter.
In our experience, this approach is usually sufficient to prevent further hypoglycemia and no additional dextrose is needed. If desired, a dextrose infusion may be provided as follows:
●Pediatric dextrose infusion: 6 to 9 mg/kg per minute. The rate of glucose infusion can be calculated as follows:
Rate of infusion (mg/kg per minute) = (Percent dextrose in solution x 10 x rate of infusion [mL per hour]) ÷ (60 x weight [kg])
●Adult dextrose infusion: 75 to 100 mL/hour of a 5 percent dextrose solution (D5W)
Octreotide should be administered for 24 hours. After octreotide is discontinued, the patient is monitored for hypoglycemia for another 24 hours to ensure there is no remaining drug or active metabolite. If hypoglycemia recurs during this period, we suggest restarting octreotide therapy for another 24 hours. In addition, two serum glucose measurements should be obtained 30 minutes apart during the first hour, and every four to six hours thereafter, provided euglycemia is maintained.
A small number of controlled trials and multiple case reports describe successful treatment of sulfonylurea-related hypoglycemia with octreotide in adult diabetic and nondiabetic patients [1,23-27]. A retrospective review of nine adult patients treated for sulfonylurea-related hypoglycemia showed that 2.9 ampules of D50W were needed for each patient before octreotide treatment but only 0.2 ampules thereafter [23]. The risk for hypoglycemia before octreotide treatment was 27 times the risk of hypoglycemia after treatment. A small, limited randomized trial found that patients treated with a single dose of octreotide in addition to standard care maintained higher serum glucose over eight hours and sustained fewer episodes of hypoglycemia than patients treated with standard care alone [28].
Children also benefit from octreotide therapy. A review of 121 pediatric cases involving children less than six years reported that treatment with octreotide substantially reduced hypoglycemic episodes (median of 2 [range 0-9] hypoglycemic events before octreotide versus median of 0 [range 0-5] after octreotide) and caused no adverse effects. Most patients (82 percent) did not develop hypoglycemia after treatment, but 18 percent experienced hypoglycemia after the first dose (median five hours later) [29].
Several mechanisms of action have been proposed for octreotide, but the most important is thought to be a G-protein-mediated decrease in calcium influx through voltage-gated channels in pancreatic beta islet cells. Decreased calcium influx diminishes calcium-mediated insulin release [30]. The drug is rapidly and completely absorbed when given subcutaneously, reaching 100 percent bioavailability within 30 minutes [31].
Octreotide has replaced diazoxide as a treatment for sulfonylurea-induced hypoglycemia [15,32]. Diazoxide hyperpolarizes the islet cell membrane, inhibiting calcium influx, and thus, the calcium-dependent release of insulin. A study comparing dextrose, diazoxide, and octreotide in normal volunteers showed that octreotide produces a significantly greater decrease in insulin secretion and glucose requirements [32]. Diazoxide can also cause hypotension.
In the presence of an acute overdose (ie, within two hours), activated charcoal (AC) may be given to prevent absorption of the sulfonylurea. Charcoal should be withheld in patients who are sedated and may not be able to protect their airway, unless endotracheal intubation is performed first. Endotracheal intubation should not be performed solely for the purpose of giving charcoal. (See "Gastrointestinal decontamination of the poisoned patient".)
Serum electrolytes should also be obtained. Chlorpropamide has been associated with dose-independent symptomatic hyponatremia related to inappropriate secretion of antidiuretic hormone [33]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Drugs'.)
There are limited data on hemodialysis for sulfonylurea ingestions. The drugs exhibit high protein binding which theoretically makes hemodialysis ineffective. There are a few case reports of hemoperfusion being used successfully in a sulfonylurea overdose [34,35].
Unintentional single-episode hypoglycemia — Management of the patient with a single episode of hypoglycemia during therapeutic sulfonylurea use (not overdose) is less straightforward. Intravenous dextrose is appropriate to correct symptomatic hypoglycemia, but the role for octreotide is less clear. We recommend feeding such patients a calorie-rich meal, holding their sulfonylurea medication, and observing them in the hospital for 24 hours. Because we recommend up to 24 hours of additional glucose monitoring following the last administration of octreotide, we do not suggest octreotide therapy for a single episode of hypoglycemia under these circumstances.
If the patient remains euglycemic during the 24 hour observation period, we believe that the patient may be safely discharged. If the patient develops a second episode of hypoglycemia, we recommend that octreotide be administered in the same manner and monitoring schedule as described above for patients with an overdose. (See 'Hypoglycemia' above.)
The management of patients who present to their primary care physicians (PCP) with mild symptoms of hypoglycemia during therapeutic sulfonylurea use may differ from that of patients who present to the emergency department. PCPs who know the patient well may elect to discharge the patient home after a thorough evaluation and a period of observation, provided the following criteria are met:
●Symptoms are mild and resolve rapidly and completely following simple treatment (eg, juice and a meal), and do not recur over a few hours of observation.
●There is a clear history of inadequate food intake preceding the development of symptoms.
●Serum glucose is maintained above 80 mg/dL (4.4 mmol/L) over a few hours of observation.
●History, physical examination, and possibly laboratory studies (eg, BUN and creatinine) do not raise concerns about comorbid disease or impaired drug clearance.
●Responsible caretakers will remain with the patient for the next 24 hours to ensure that finger stick blood sugars are monitored closely (eg, every four hours), remain over 80 mg/dL (4.4 mmol/L), and that symptoms do not recur.
●Appropriate follow-up is arranged.
Observation in the hospital is indicated if the patient does not meet all these criteria, or if the clinician has concerns about the patient's condition or whether appropriate monitoring can be performed at home.
Pediatric considerations — The management of an asymptomatic, euglycemic child presenting with a history of a sulfonylurea exposure is challenging. Ingestions of a single sulfonylurea pill as small as 2 mg can cause hypoglycemia in young children. Activated charcoal should be given if it is within two hours of the ingestion and the patient will tolerate it. Activated charcoal is unlikely to be effective in symptomatic children since hypoglycemia from sulfonylurea often occurs hours after the ingestion.
In an asymptomatic child with a sulfonylurea exposure, we recommend in-hospital observation for 12 to 24 hours. If a 12-hour observation would lead to discharge at night, patients should be observed until the morning. Hypoglycemia (if present) will typically occur within eight hours although delayed hypoglycemia has occurred [3,4,36-39]. If the patient becomes hypoglycemic, standard treatment is provided. (See 'Hypoglycemia' above.)
The dose of sulfonylurea necessary to cause hypoglycemia in small children is difficult to determine based on available evidence, and will depend on a range of factors, such as when the child last ate, whether the child is ill or malnourished, and the size of the child. It is best to err on the side of caution and observe the child in the hospital if any doubt exists about the nature of the ingestion.
ADDITIONAL RESOURCES
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. 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".)
SUMMARY AND RECOMMENDATIONS
●Pharmacology – Sulfonylurea agents are commonly used to treat of diabetes mellitus by increasing insulin release but can also cause hypoglycemia. Risk factors for hypoglycemia from therapeutic use include (see 'Pharmacology and toxicology' above and 'Kinetics' above):
•Age over 65 years
•Taking multiple medications
•Frequent hospitalization
•Use of agents with longer durations of action (eg, chlorpropamide and glyburide)
•Impaired drug clearance (eg, renal or hepatic dysfunction)
●History and physical examination – Inquire about the amount, timing, and reason for any ingestion, what drug was taken, and co-ingestants, including other diabetic medications. Hypoglycemia generally manifests with neurologic and autonomic symptoms. Among the most common are confusion, personality change, diaphoresis, and tremulousness, but symptoms can be masked by co-ingestants. (See 'History and physical examination' above.)
●Laboratory evaluation – In a patient with an intentional overdose or at risk for poisoning from other agents, obtain the following studies: fingerstick glucose, serum electrolytes, acetaminophen and salicylate concentrations, serum creatinine, electrocardiogram, and a pregnancy test, when appropriate. (See 'Laboratory evaluation' above.)
●Management
•Hypoglycemia – When hypoglycemia is recognized, administer intravenous (IV) dextrose (0.5 to 1 g/kg IV) to increase blood glucose acutely. In adults, the initial bolus is generally given as 25 g (50 mL) of a 50% dextrose (D50W) solution. In children, a 25% dextrose solution is used, while in infants and neonates, a 10% dextrose solution is used. (See 'Hypoglycemia' above.)
After treatment, obtain serial measurements of fingerstick glucose twice more at 30-minute intervals, and if the patient maintains euglycemia, serum glucose can be checked every four to six hours thereafter.
•Intentional overdose – In a patient with a sulfonylurea overdose and symptomatic hypoglycemia, we suggest immediate treatment with octreotide (Grade 2C) in addition to IV dextrose instead of IV dextrose alone. In adults, the dose of octreotide is 50 to 100 mcg administered by intramuscular or subcutaneous injection every six hours; in children the dose is 1 to 1.5 mcg/kg (up to 50 mcg) every six hours. (See 'Symptomatic intentional overdose' above.)
•Hypoglycemia during therapeutic dosing – In a patient with a single episode of hypoglycemia during therapeutic sulfonylurea use (not overdose), treatment consists of IV dextrose followed by a calorie-rich meal, discontinuation of sulfonylurea medications, and 24 hours of in-hospital observation with close monitoring of the serum glucose. If the patient develops a second episode of hypoglycemia, we suggest treating with octreotide in the same manner as described above for a patient with an overdose. (See 'Unintentional single-episode hypoglycemia' above.)
Primary care physicians may elect to discharge home patients they know well who present to the clinic with mild symptoms of hypoglycemia during therapeutic sulfonylurea use, provided symptoms are mild and resolve, there is a clear history of inadequate food intake prior to hypoglycemia, serum glucose is maintained above 80 mg/dL, there is a responsible caretaker, and follow-up is arranged. (See 'Unintentional single-episode hypoglycemia' above.)
●Pediatric consideration – In an asymptomatic child with a sulfonylurea exposure, we recommend in-hospital observation for 12 to 24 hours. If a 12-hour observation would lead to discharge at night, patients should be observed until the morning. Delayed hypoglycemia has occurred following ingestion of a number of medications, and a single sulfonylurea pill as small as 2 mg can cause hypoglycemia in a young child. If the patient becomes hypoglycemic, standard treatment is provided. (See 'Pediatric considerations' above and 'Hypoglycemia' above.)
