Oral Hypoglycemic Toxicity 

Oral Hypoglycemic Toxicity 

• Oral hypoglycemic toxicity is a spectrum of disease associated with antidiabetic medication ingestion
• Highest risk medication class for significant hypoglycemia after ingestion is sulfonylureas, which feature a long half-life and duration of action⁶⁸
  • These patients should generally be admitted to the hospital for serial monitoring given the risk of recurrent hypoglycemia¹
• Meglitinides can also cause hypoglycemia in a similar mechanism to sulfonylureas, but have a much shorter duration of action and are thus less concerning in overdose⁷
• Metformin can result in life-threatening lactic elevation and metabolic acidosis, and rarely can cause hypoglycemia if overdosed⁷
• Several other classes of antidiabetic medications are on the market today, but are generally lower risk in overdose with only occasional reports of hypoglycemia¹
• Treatment of hypoglycemia involves oral and IV dextrose. IV octreotide should be employed in sulfonylurea overdose and can also be considered in meglitinide overdose when hypoglycemia occurs⁴⁸
• Activated charcoal should be given to appropriately selected patients with sulfonylurea, meglitinide, and metformin overdose⁵²
• Hemodialysis is indicated for severe acidosis secondary to metformin toxicity⁴⁸

Alarm Signs and Symptoms

• Confusion, high respiratory rate, and hypotension can signify significant acidosis and lactate elevation in the setting of metformin overdose or chronic metformin toxicity
• Seizures, hypotension, and ventricular tachycardia can signify severe hypoglycemia associated with sulfonylurea toxicity

• Oral hypoglycemic toxicity involves the adverse effects from the ingestion of diabetic medications
• Severity and presentation are dependent on several factors, with the agent ingested and amount of ingestion being paramount
• Oral diabetic medications can be broadly subdivided into those that are hypoglycemic agents and those that are antihyperglycemic agents, with the former being much more likely to cause hypoglycemia after ingestion¹
• This review will focus on the oral diabetic agents that cause hypoglycemic toxicity, while also touching briefly on other antidiabetic medication classes that do not cause hypoglycemia

Epidemiology

• In 2020, there were more than 16,000 exposures to these medications reported to the American Association of Poison Control Centers. Among these, roughly 60% were related to metformin, 20% related to sulfonylurea agents, and 20% related to other classes²

Etiology and Risk Factors

What causes this condition?

• Toxicity of oral hypoglycemic medications will often occur in the setting of intentional overdose or accidental ingestion
  • Accidental ingestions occur commonly in children, and unexplained hypoglycemia in a child should raise suspicion for oral hypoglycemic exposure³
    • As little as 1 sulfonylurea pill ingested by a child has caused significant hypoglycemia⁴
  • Oral hypoglycemic toxicity has also been reported secondary to pharmacy dispensing errors⁵
  • Reduced renal function may place patients at higher risk for developing hypoglycemia from sulfonylurea ingestion and MALA (metformin-associated lactic acidosis) from metformin ingestion⁶
• Sulfonylurea and meglitinide classes are highest risk to cause hypoglycemia among oral agents to treat diabetes
  • Sulfonylureas stimulate insulin secretion from pancreatic β-cells. They feature a long half-life and duration of action, making these a high risk for prolonged effects in overdose
  • Meglitinides also stimulate insulin secretion from the pancreas. They have a shorter half-life and duration of action than do sulfonylureas⁷
• Other agents to treat diabetes confer a low risk of hypoglycemia (unless used in combination with insulin or an insulin secretagogue)
  • Biguanides inhibit hepatic gluconeogenesis and oppose the action of glucagon. Metformin is the only biguanide class medication currently available in most countries
  • Thiazolidinediones increase insulin sensitivity in the peripheral tissues
  • α-Glucosidase inhibitors reduce the metabolism of sucrose to glucose and fructose by competitively inhibiting enzymes in the intestinal brush border cells
  • Dipeptidyl peptidase 4 inhibitors prevent the breakdown of the incretin hormone glucagonlike peptide 1, leading to enhanced insulin secretion and delayed gastric emptying
  • SGLT-2 (sodium-glucose cotransporter 2) inhibitors reduce the function of SGLT-2, which results in a reduction in the resorption of glucose in the proximal renal tubule. This results in increased urinary excretion of glucose
  • Semaglutide, a glucagonlike peptide 1 receptor agonist, potentiates glucose-dependent insulin secretion

Hypoglycemic agents, risk of hypoglycemia, and other clinical associations

Antidiabetic medication class and example drugs8	Mechanism of action	Risk of hypoglycemia	Class-specific considerations
Sulfonylureas (glipizide, glyburide, glimepiride)	Stimulate insulin secretion from pancreatic β-cells	Yes	Long half-life. Increased risk of toxicity in renal impairment
Meglitinides (repaglinide, nateglinide)	Stimulate insulin secretion from pancreatic β-cells	Yes	Short half-life. Increased risk of toxicity in hepatic impairment
Biguanides (metformin, phenformin)	Inhibit hepatic gluconeogenesis and oppose the action of glucagon	Rarely9	Elevated lactic acid and metabolic acidosis can occur
Thiazolidinediones (rosiglitazone, pioglitazone)	Increase insulin sensitivity in the peripheral tissues	No	Hepatic injury in chronic therapy can occur
α-Glucosidase inhibitors (acarbose, miglitol)	Reduce the metabolism of sucrose to glucose by competitively inhibiting enzymes in the intestinal cells	No	Diarrhea and abdominal pain can occur
Dipeptidyl peptidase 4 inhibitors (alogliptin, sitagliptin)	Decrease glucagon release and increase insulin secretion	No	Rarely, hypersensitivity reactions can occur
SGLT-2 inhibitors (canagliflozin, dapagliflozin)	Reduce the function of SGLT-2, which is expressed in the proximal renal tubule	No	Risk of euglycemic diabetic ketoacidosis
Dopamine agonist (bromocriptine)	Decreases insulin resistance and hepatic glucose production	No	Nausea is most common adverse effect
Bile acid sequestrant (colesevelam)	May improve glucose metabolism through the incretin pathway	No	Constipation can occur
Glucagonlike peptide 1 receptor agonist (semaglutide)	Potentiates glucose-dependent insulin secretion	Rarely10	Nausea, vomiting, and diarrhea can occur

Caption: SGLT-2, sodium-glucose cotransporter 2.

Risk Factors

• Risk factors for toxicity from intentional overdose of oral hypoglycemic agents
  • Psychiatric illness
    • Depression rates are higher in the diabetic population, suggesting an increased risk of intentional overdose in this population¹¹
  • Exposure or access to oral hypoglycemic medications
  • Prior self-harm attempts or a history of overdose
• Risk factors for toxicity from therapeutic dosages of oral hypoglycemic agents
  • Large amount of agent ingested
  • Concomitant or preexisting renal insufficiency
  • Concomitant or preexisting liver disease
  • Coexistent disease processes such as alcohol use disorder, sepsis, and starvation
  • Older age⁶
  • Concomitant insulin usage⁶
  • Unanticipated drug-drug interactions¹²
    • Sulfonylurea drugs are metabolized by the cytochrome P450 2C9 pathway, meaning that inhibitors of this pathway can increase the risk of hypoglycemic toxicity¹³
      • Common drugs that have been implicated include trimethoprim, metronidazole, and fluconazole¹⁴

Diagnosis

Approach to Diagnosis

• Diagnosis is suspected based on the following:
  • Likely or confirmed hypoglycemic event
  • History suggestive of medication ingestion, particularly intentional overdose
  • Review of patient medication list that confirms prescription for oral hypoglycemic agents
  • Patient access to sulfonylurea or meglitinide medications, including if these are used by a family member
• Always consider oral hypoglycemic toxicity in cases of hypoglycemia of unknown etiology¹⁵
• Laboratory studies that are obtained in all cases of suspected oral hypoglycemia include serum glucose level and a basic chemistry panel¹
  • Note that hypoglycemia is generally defined as a measured plasma glucose level 70 mg/dL or less¹⁶
  • It is critical to obtain serial glucose levels in cases of oral hypoglycemic toxicity, particularly if sulfonylurea toxicity is suspected or confirmed
• Optional laboratory studies, depending on specific circumstances, include:
  • Blood gas analysis and lactate level, if MALA (metformin-associated lactic acidosis) is suspected¹⁷
  • Urinalysis can assess for glycosuria if SGLT-2 inhibitor ingestion is suspected; however, this is a nonspecific finding¹⁸
  • A hypoglycemia evaluation with hormone and drug levels (eg, sulfonylurea panel, and insulin and C peptide levels), if cause is unknown, or if sulfonylurea ingestion is suspected

Workup

History

• Earlier medical history or current medical issues
  • Known history of intentional overdose
  • Known access to oral hypoglycemic medications
  • Known preexisting psychiatric illness or earlier history of overdose
  • Worsening depression or mental health disease, particularly in the setting of known access to medications
• Symptoms
  • Reported symptoms of resultant hypoglycemia can include dizziness, blurry vision, headache, confusion, nausea, dyspnea, and palpitations
  • Patients with metformin toxicity and MALA (metformin-associated lactic acidosis) can complain of abdominal pain, nausea, vomiting, and diarrhea²⁰
• Overdose-related history
  • Additional history provided by others, such as emergency medical services or family members, can be critical in obtaining accurate history of medication access or ingestion
  • Time of ingestion is helpful in determining if decontamination is indicated and assessing the risk of worsening symptoms upon presentation
  • In rare cases involving sulfonylurea ingestion, the onset of hypoglycemia can be delayed by 11 to 21 hours¹
  • As little as 1 sulfonylurea pill has been demonstrated to cause clinically significant hypoglycemia in toddlers¹

Physical Examination

• Hypoglycemia can result in mild or severe examination findings dependent on severity³
  • Mild hypoglycemia can result in diaphoresis, agitation, confusion, lethargy, emesis, and tachycardia
  • Moderate hypoglycemia can result in obtundation, coma, and seizures
  • Severe hypoglycemia can result in status epilepticus, hypotension, cerebral edema, and ventricular tachycardia
  • Infants may show feeding difficulty⁷
• Metformin toxicity may induce a metabolic acidosis (MALA), which can result in hypotension, increased respiratory rate, confusion, and lethargy²²

Laboratory Tests

• Serum or capillary blood glucose level
  • Glucose testing is mainstay of hypoglycemia laboratory assessment and should be deployed rapidly in any case of suspected oral hypoglycemia toxicity
  • “Fingerstick” bedside glucose is often preferable given the immediate availability of the result but should be confirmed by a laboratory-based measurement if possible¹⁶
  • Hypoglycemia is defined as a measured plasma glucose level 70 mg/dL or less¹⁶
• Basic metabolic panel
  • Is obtained to assess bicarbonate level, electrolyte levels, and kidney function
• Lactic acid levels and blood gas analysis
  • Metabolic acidosis and elevated lactate levels could be suggestive of metformin toxicity and MALA¹⁷
    • Patients with renal impairment are particularly at risk
  • Generally, rates of lactic acidosis associated with metformin usage are low, particularly if there are no preexisting comorbidities²³
  • One study demonstrated MALA in 9.1% of metformin mono-overdose case²⁴
  • When MALA does occur, the resultant degree of acidosis can be significant²⁵
• Urinalysis
  • May show glycosuria in SGLT-2 exposure,¹⁸ although this is nonspecific
• Medication-specific testing and serum concentrations
  • An oral hypoglycemic screen to assess for serum concentrations of specific medications may be available onsite at certain centers, but most often blood must be collected for analysis at “send-out” commercial laboratories
    • Results of these will not be available in a timely manner, and clinical care and treatment must proceed in the absence of this data
    • In addition, serum concentrations do not always correlate with the severity of poisoning²⁷
  • Aspirin and acetaminophen levels should be obtained in the setting of intentional overdose to assess for these coingestions
• Hypoglycemia evaluation
  • If the cause of hypoglycemia is unclear, pancreatic β-cell hormone levels (eg, insulin and C peptide) may be measured to determine if the hypoglycemia is due to exogenous sources, or to autonomous, endogenous production of insulin. Collection and processing of such sampling requires meticulous care
  • Sulfonylurea medications cause release of endogenous insulin, and thus increased insulin levels, proinsulin levels, and C peptide levels can be present in sulfonylurea-induced hypoglycemia³⁰

Imaging Studies

• Not routinely recommended or indicated
• If there is concern for an associated aspiration event, then a chest x-ray is considered
• If significant altered mental status is present, and the clinical and laboratory findings do not reliably suggest oral hypoglycemic toxicity as the cause, then neuroimaging is considered

Other Diagnostic Tools

• ECG is obtained in the setting of overdose, because the presence of coingestants could result in conduction system toxicity
• Findings on ECG reflective of this could include prolongation of the QRS complex and PR interval

Differential Diagnosis

Differential Diagnosis: Hypoglycemia and MALA.

Condition	Description	Differentiated by
Differential diagnosis for hypoglycemia
Sepsis	Organ dysfunction in the setting of infection, which can lead to resultant hypoglycemia	Clinical suspicion for infection or infectious source identification
Exogenous insulin toxicity	Hypoglycemia may result from iatrogenic insulin utilization	Presence of insulin on home medication list or access to insulin should raise suspicionLaboratory testing will show high plasma insulin levels in concert with low plasma C peptide levels if samples are drawn at the time of hypoglycemic event15
Adrenal insufficiency	Hypoglycemia may sometimes occur secondary to cortisol deficiency, which results in increased insulin sensitivity	Clinical symptoms suggestive of adrenal insufficiency (eg, weakness, fatigue, weight loss, abdominal pain)Laboratory testing will show a low morning serum cortisol level31
Alcohol usage	Hypoglycemia can occur secondary to impairment of gluconeogenesis, reduction of counterregulatory hormone production, and malnutrition32	Clinical history suggestive of alcoholismElevated alcohol level may be present on laboratory testing
Insulinoma	Hypoglycemia may result from increased endogenous insulin production	Laboratory testing will show increased plasma insulin levels, increased C peptide levels, and increased proinsulin levels at the time of symptomatic and laboratory confirmed hypoglycemia15
Malnutrition	Depleted glycogen stores can result in hypoglycemia	History and examination suggestive of malnutrition (eg, significant weight loss over time, loss of muscle mass)Laboratory testing may show low albumin and low prealbumin levels (but require cautious interpretation)33
Liver failure	Associated with decreased glycogen stores and impaired insulin uptake and insulin degradation. These may result in subsequent hypoglycemia34	History and examination suggestive of liver failureFindings of cirrhosis or ascites on physical examination or bedside ultrasoundLaboratory findings will show elevated bilirubin, low platelets, and elevated PT/INR and PTT
Renal failure	Hypoglycemia may result from impaired gluconeogenesis, impaired glycogenolysis, and decreased insulin degradation in peripheral tissues35	History and examination suggestive of renal failureLaboratory findings will show reduced GFR, elevated creatinine, and elevated BUN level
Differential diagnosis for MALA
Toxic alcohol ingestion	Ingestion of ethylene glycol or methanol can result in an anion gap metabolic acidosis that may also result in an elevated lactic acid levelThis could produce laboratory findings similar to MALA	Laboratory findings may show an elevated osmolal gap37Lactate level is generally only mildly elevated. However, a falsely high lactate level may result when using blood gas analyzers or point of care testing due to the laboratory instrument failing to differentiate between lactate and glycolate or glyoxylate37
Mesenteric ischemia	Tissue hypoxia of the intestine leading to elevated lactic acid levels38	History and examination should suggest ischemia colitis, which is associated with significant abdominal pain, blood in the stool, and pain out of proportion to examination
Salicylate toxicity39	Associated with an anion gap metabolic acidosis that may also result in an elevated lactic acid level	Laboratory findings will show an elevated salicylate levelA mixed respiratory alkalosis and metabolic acidosis may be presentPresence of tachypnea, tinnitus, confusion, hypotension, and seizures may help raise suspicion for salicylate toxicity in the correct clinical scenario

Caption: MALA, metformin-associated lactic acidosis; PT, prothrombin time; PTT, partial thromboplastin time.

Treatment

Approach to Treatment

• Initial management of patients with significant illness secondary to oral hypoglycemic toxicity is to manage the airway, breathing, and circulation (similar to all critically ill patients)⁴⁰
  • One of the first steps is to establish large bore IV access for patients who present with critical illness associated with oral hypoglycemic toxicity
• Specific management strategies after initial stabilization depend upon the suspected or known oral hypoglycemic ingested and the ensuing acute complication(s)
  • Immediate concern for sulfonylureas and, to a lesser extent, meglitinide toxicities is hypoglycemia¹
  • Realize that ongoing treatment of sulfonylurea-induced hypoglycemia can be complex, because poisoning may be refractory to the routine treatments rendered for hypoglycemia¹
  • Kinetics are an important consideration. It is critical for the clinician to be aware that sulfonylurea medications are highest risk for delayed peak plasma concentrations and a prolonged duration of action¹

Pharmacokinetics of oral hypoglycemics.

	Sulfonylurea	Meglitinide	Metformin
Peak serum concentration	1-8 hours	30-60 minutes	3 hours
Half-life	3-36 hours	1-2 hours	2-6 hours
Duration of action	Up to several days	Up to several hours	Up to several hours

Caption: Data from many references.7

Sulfonylurea Toxicity

• Main methods to treat hypoglycemia resulting from sulfonylurea toxicity include IV dextrose, glucagon, and octreotide
• Administer IV dextrose expeditiously for symptomatic sulfonylurea-induced hypoglycemia¹
  • IV dextrose boluses may provoke rebound hypoglycemia, and thus oral glucose is preferred in the asymptomatic or mildly symptomatic patient⁴⁸
  • IV dextrose infusion may be preferable to boluses in a mildly symptomatic patient given this risk of rebound hypoglycemia
• If IV access cannot be immediately obtained, intramuscular glucagon can be employed, but this does not reliably increase serum glucose level to an adequate level and should be followed by dextrose when access is established⁴⁹
• After initial immediate treatment of hypoglycemia, IV or subcutaneous octreotide should be given alongside IV dextrose in cases of symptomatic hypoglycemia from sulfonylurea toxicity⁵⁰
• Activated charcoal can be given for large overdoses to reduce absorption but should be done within 2 hours of ingestion⁵²
• Hemodialysis is typically not indicated in sulfonylurea toxicity, because these agents are highly protein bound rendering it ineffective⁴⁸
• Most patients with known or suspected sulfonylurea toxicity should be admitted to the hospital for serial monitoring of blood glucose level because of the high risk of recurrent hypoglycemia¹
• After initial stabilization, give a full meal that is inclusive of complex carbohydrates, proteins, and fats
  • This will provide a source of endogenous glucose that is of longer duration than simple carbohydrates alone

Meglitinide Toxicity

• Approach to managing meglitinide toxicity is similar to sulfonylurea toxicity, but meglitinides theoretically have less potential for profound and prolonged hypoglycemia, as compared with sulfonylureas, because of their shorter duration of action⁵⁶
• For acute, symptomatic hypoglycemia, administer IV dextrose⁷
• If IV access cannot be immediately secured, can give intramuscular glucagon, but this is not routine⁴⁹
• Octreotide is generally unnecessary for meglitinide toxicity, owing to the short duration of action, but it is effective and can be employed⁵⁸
• Activated charcoal is recommended for large overdose cases if it can be given within 1 to 2 hours after ingestion⁷

Biguanide (Metformin) Toxicity

• Metformin toxicity can be seen in cases of acute overdose or when impairment in renal function leads to reduced elimination⁴⁸
• MALA (metformin-associated lactic acidosis) is the primary concern in metformin toxicity, though hypoglycemia can also rarely occur⁹
  • Correction of acidosis, through supportive measures, is central to treatment¹
  • Volume resuscitation, hemodynamic support, and management of electrolyte derangements should begin promptly⁴⁸
  • Sodium bicarbonate injection is controversial; it is recommended by some experts only in those patients with severe metabolic acidosis⁴⁸
• Aside from acidosis, treat hypoglycemia, if it occurs, with IV dextrose³
• Hemodialysis is effective in acute overdose and toxicity associated with chronic usage
  • Hemodialysis is recommended in cases of MALA with significant acidosis (pH less than 7), lactate level more than 20 mmol/L, shock, decreased level of consciousness, and failure of standard supportive measures⁶⁰
• Switch to activated charcoal for appropriate cases where the patient is protecting their airway or has been intubated, including late in overdose (beyond 1-2 hours). Activated charcoal is expected to bind biguanides⁷
• Methylene blue has been proposed as a therapy in severe MALA refractory to standard supportive therapy while hemodialysis is being arranged⁴⁸

Drug Therapy

• Sulfonylurea toxicity
  • IV dextrose is the first action for symptomatic sulfonylurea-induced hypoglycemia or for asymptomatic patients if glucose level is less than 60 mg/dL⁷
    • Initial dose is 50 mL bolus of 50% dextrose IV in adults¹
      • This provides 25 g of glucose
    • In children, the recommended bolus dose is 2 mL/kg of 25% dextrose in water IV¹
    • In infants, the recommended bolus dose is 2 to 4 mL/kg of 10% dextrose in water IV¹
    • Bolus dose of dextrose can then be followed by a 5% to 10% dextrose in water IV infusion
  • Oral glucose is recommended for patients with hypoglycemia due to sulfonylurea toxicity or overdose, who are asymptomatic
    • Some evidence suggests that administration of IV dextrose boluses can lead to increased insulin release and resultant rebound hypoglycemia⁴⁸
      • Therefore, oral consumption of glucose is preferable for the asymptomatic patients with mild hypoglycemia; IV dextrose is reserved for the symptomatic patient or when the glucose level falls below 60 mg/dL⁷
      • This increased insulin release may be attenuated by concomitant octreotide administration⁶³
  • Intramuscular glucagon can raise serum glucose levels slightly and can be used when IV access has not yet been obtained, though is not otherwise routinely recommended⁴⁹
    • A dose of 1 mg of intramuscular glucagon is recommended for adults and children more than 25 kg or older than 6 years with unknown weight; 0.5 mg is recommended for children less than 25 kg or younger than 6 years⁴⁷
    • Intranasal glucagon is not readily available but has shown similar efficacy as intramuscular glucagon⁶⁴
  • Octreotide should be given in addition to dextrose in cases of hypoglycemia secondary to sulfonylurea overdose
    • Octreotide is a long-acting, synthetic somatostatin analog that suppresses insulin secretion⁵⁰
      • It should be given alongside IV dextrose in cases of symptomatic hypoglycemia from sulfonylurea overdose and has been shown to reduce the number of subsequent hypoglycemic episodes and increase glucose levels⁴⁸
        • Dose is 50 to 100 mcg IV or subcutaneously every 6 to 12 hours in adults and 1 to 2 mcg/kg IV or subcutaneously every 6 to 12 hours in children⁵⁰
        • Administration of octreotide should continue for approximately 24 hours (approximately 3-4 doses)⁶⁵
    • Octreotide has been shown to be beneficial in sulfonylurea-induced hypoglycemia in maintenance dose cases and those with intentional overdose⁵⁰
  • Activated charcoal can bind to sulfonylurea medications and reduce absorption⁵²
    • Should be considered if within 2 hours of ingestion for immediate-release sulfonylureas and there is no concern regarding inadequate airway protection⁵⁴
• Meglitinide toxicity
  • Meglitinides have a faster onset and shorter duration of action, and are thus thought to have less potential for profound and prolonged hypoglycemia than sulfonylureas⁵⁶
  • In patients who do have documented hypoglycemia in the setting of meglitinide toxicity, IV dextrose should have employed⁷
    • IV 10% dextrose infusion can be used to maintain glucose level at more than 80 mg/dL
    • Bolus doses of 50% dextrose by injection and oral dextrose supplementation can be used if needed
  • Intramuscular glucagon can raise serum glucose levels slightly and can be used when IV access has not yet been obtained, though is not otherwise routinely recommended⁴⁹
    • A dose of 1 mg of intramuscular glucagon is recommended for adults and children more than 25 kg or older than 6 years with unknown weight; 0.5 mg is recommended for children less than 25 kg or younger than 6 years⁴⁷
  • Octreotide is effective and can be employed, but would not generally be needed given the short duration of actions of these medications⁵⁸
  • Activated charcoal is expected to bind meglitinides and should be given in large overdose cases within 1 to 2 hours⁷
• Biguanide (metformin) toxicity
  • Metformin has an elimination half-life that ranges from 2 to 6 hours in therapeutic usage, though this is more variable in overdose⁴²
  • Peak plasma concentrations occur within about 3 hours of administration⁴⁴
    • Clearance can be significantly decreased in the setting of renal impairment⁴⁵
  • Metformin toxicity can be seen in cases of acute overdose or when impairment in renal function leads to reduced elimination⁴⁸
  • MALA is the primary concern in metformin toxicity, though hypoglycemia can also rarely occur⁹
    • Hypoglycemia should be treated with IV dextrose if it does occur³
    • Correction of acidosis is central to treatment of MALA
      • Sodium bicarbonate is recommended by some experts, with initial dose recommendations of 1 to 2 mEq/kg⁷
        • However, sodium bicarbonate in this setting is controversial and is recommended by some only in those patients with severe metabolic acidosis⁴⁸
        • In addition, administration of sodium bicarbonate has not been shown to improve survival and has the potential to worsen intracellular acidosis and cause reflex vasodilation after bolus injection²⁶
  • Hemodialysis may be used to enhance elimination of metformin
    • Hemodialysis is effective in acute overdose and toxicity associated with chronic usage
    • It is recommended in cases of MALA with significant acidosis (pH less than 7), lactate level more than 20 mmol/L, shock, decreased level of consciousness, and failure of standard supportive measures⁶⁰
  • Activated charcoal is expected to bind biguanides and should be considered in appropriate cases in overdose
    • This includes late in overdose, because metformin can remain in the gut for several hours⁷
  • Methylene blue has been proposed as a therapy in severe MALA refractory to standard supportive therapy while hemodialysis is being arranged⁴⁸
    • There is limited evidence regarding dosage of methylene blue in this setting, though 1 to 2 mg/kg bolus followed by a low-dose infusion has been reported previously⁶¹

Treatment Procedures

Hemodialysis

• Hemodialysis may be used to enhance elimination of metformin
  • Hemodialysis is effective in acute overdose and toxicity associated with chronic usage
  • It is recommended in cases of MALA with significant acidosis (pH less than 7), lactate level more than 20 mmol/L, shock, decreased level of consciousness, and failure of standard supportive measures⁶⁰
• Hemodialysis is indicated for in cases of MALA with significant acidosis (pH less than 7), lactate level more than 20 mmol/L, shock, decreased level of consciousness, and failure of standard supportive measures⁶⁰
• Hemodialysis is not indicated in sulfonylurea or meglitinide poisoning, because they are highly protein bound which makes hemodialysis largely ineffective⁴⁸

Admission Criteria

• Sulfonylurea toxicity
  • In patients exposed to sulfonylureas who experience subsequent hypoglycemia, admission to the hospital for serial monitoring for at least 24 hours is recommended¹
    • This includes pediatric patients in whom delayed hypoglycemia after sulfonylurea exposure has been reported⁵⁵
  • A patient with exposure to sulfonylureas who presents without hypoglycemia should be observed for a minimum of 8 hours¹
• Meglitinide toxicity
  • Given the short half-life, meglitinide-associated hypoglycemia would not be expected to be as prolonged as sulfonylurea-associated hypoglycemia
    • However, serial monitoring and consideration of admission should still be employed for patients who do experience hypoglycemia¹
• Biguanide (metformin) toxicity
  • Patients who are asymptomatic with an acute overdose should be observed and serially monitored for approximately 6 to 8 hours⁶⁸
  • Pediatric patients who are asymptomatic with a suspected overdose should be observed for 12 hours⁶⁹
  • Patients who develop hypoglycemia, hemodynamic decompensation, or significant acidosis or lactate elevation should be admitted to the hospital for further care

Follow-up

Monitoring

• Frequent glucose monitoring, every 15 to 60 minutes dependent on severity, for oral hypoglycemic toxicity should occur in cases of hypoglycemia or suspected hypoglycemia⁶⁸
• Monitoring of acidosis and lactate level should be employed in MALA (metformin-associated lactic acidosis). Dependent on severity, this involves a recheck of acidosis and lactate every 30 to 180 minutes
• Frequent mental status monitoring and vital sign monitoring should be employed in all patients with oral hypoglycemic toxicity

Complications

• Complications of untreated hypoglycemia can include seizures, coma, and death
• Complications of untreated MALA can include hypotension, cardiovascular collapse secondary to profound acidosis, and death

Prognosis

• Prognosis is generally favorable for oral hypoglycemic toxicity, particularly with prompt correction and monitoring of hypoglycemia²
  • Among approximately 16,000 exposures reported to the American Association of Poison Control Centers in 2020, there were only 21 mortalities, 19 of which were related to metformin²
  • However, intentional ingestions of sulfonylureas can still carry significant consequence, with 1 study of 101 adults having 5 fatalities and 5 cases of permanent neurologic insult⁷⁰
  • In addition, MALA can be associated with high mortality when it does occur, with 1 series of 49 patients suffering a 45% mortality rate²⁷

Referral

• If available, discussion with a poison control center and toxicologist is prudent for oral hypoglycemic toxicity cases

Screening and Prevention

Prevention

• Mainstay of prevention is education and awareness of the potential for hypoglycemia in conjunction with antidiabetic medications
  • This involves education to patients regarding the prompt recognition and treatment of hypoglycemic symptoms, such as tremulousness, palpitations, diaphoresis, paresthesias, confusion, and altered mental status⁷¹
  • Particular educational attention should be given to patients who are taking sulfonylurea medications, because the risk of hypoglycemic toxicity is highest in this cohort
  • Education on regular blood glucose level monitoring, avoidance of skipped meals, and avoidance of excessive alcohol consumption should also be considered
• Patients and clinicians should be aware of the potential for drug-drug interactions that may increase the hypoglycemic effects of sulfonylureas, particularly common drugs that affect the cytochrome P450 2C9 pathway
• Clinicians and patients should be aware of the potential for comorbidities such as renal disease or liver dysfunction to prolong the effects of oral antidiabetic medications

References

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5.Shumak SL et al. Recurrent hypoglycemia secondary to drug-dispensing error. Arch Intern Med. 1991;151(9):1877-1878.

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9.Joseph CMC. Symptomatic hypoglycemia during treatment with a therapeutic dose of metformin. Am J Case Rep. 2021;22:e931311.

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10.Wright EE Jr et al. Clinical review of the efficacy and safety of oral semaglutide in patients with type 2 diabetes considered for injectable GLP-1 receptor agonist therapy or currently on insulin therapy. Postgrad Med. 2020;132(suppl 2):26-36.

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11.Kaminer Y et al. Attempted suicide by insulin overdose in insulin-dependent diabetic adolescents. Pediatrics. 1988;81(4):526-528.

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12.Gunaratne K et al. Unintentional sulfonylurea toxicity due to a drug-drug interaction: a case report. BMC Res Notes. 2018;11(1):331.

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13.Tateishi H et al. Hypoglycemia possibly caused by CYP2C9-mediated drug interaction in combination with bucolome: a case report. J Pharm Health Care Sci. 2021;7(1):39.

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14.Tirkkonen T et al. Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide. J Intern Med. 2010;268(4):359-366.

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15.Cryer PE et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94(3):709-728.

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