Overdose of Oral Antidiabetic Medications and Insulin
August 26, 2012
Overdose of Oral Antidiabetic Medications and Insulin
Authors:
Diana Strasburger, MD, RDMS, Attending Physician, Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, IL.
Janna H. Villano, MD, Resident Physician, Department of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, IL.
Peer Reviewer:
Gina Piazza, DO, Associate Professor of Emergency Medicine, Georgia Health Sciences University, Augusta, GA.
Sandra M. Schneider, MD, Editor
Treating the hypoglycemia and metabolic derangements caused by antidiabetic medications, especially in massive overdose, are dynamic as new agents are introduced. Emergency physicians should know potential pitfalls in order to effectively and safely manage these patients, avoiding rebound hypoglycemia and premature discharge without appropriate monitoring. This article will review the clinical presentation and management of toxicity from commercially available antidiabetic agents in the United States, including oral hypoglycemic agents such as sulfonylureas and oral antihyperglycemic agents such as biguanides, as well as novel antidiabetic agents and insulin.
Introduction
Diabetes mellitus (DM) is an ever-increasing epidemic facing the current health care system. Its prevalence is increasing worldwide from an estimated 30 million in 1985 to 150 million in 2000, 171 million in 2007, and an anticipated 366 million in 2030.1,2 Medications used to treat diabetes are diverse, and often patients use multiple classes of medications to obtain euglycemia. Oral preparations can be divided into two categories based on their pharmacodynamics and effect or lack of an effect on insulin: hypoglycemic agents such as sulfonylureas and meglitinides; and antihyperglycemic agents such as biguanides, alpha-glucosidase inhibitors, and thiazolidinediones, along with newer agents such as DPP-4 inhibitors, incretin mimetics, and synthetic analogues. Available antidiabetic agents are listed in Table 1, and insulin preparations are listed in Table 2.3-5
Table 1: FDA-approved Antidiabetic Medications3,4*
Generic Name |
Brand Name |
Duration of Action |
* Combined commercially available products are also available, though not listed above. |
||
First-generation sulfonylureas |
||
Acetohexamide |
Dymelor |
Up to 16 hours |
Chlorpropamide |
Diabinese |
Up to 72 hours |
Tolazamide |
Tolinase |
Up to 24 hours |
Tolbutamide |
Orinase |
Up to 12 hours |
Second-generation sulfonylureas |
||
Glipizide |
Glucotrol |
24 hours |
Glyburide |
Diabeta |
24 hours |
Glimepiride |
Amaryl |
24 hours |
Short-acting insulin secretagogues |
||
Nateglinide |
Starlix |
Up to 4 hours |
Repaglinide |
Prandin |
Up to 4 hours |
Biguanides |
||
Metformin |
Glucophage |
Up to 24 hours |
Metformin ER |
Glucophage XR |
Up to 24 hours |
Thiazolidinediones |
||
Pioglitazone |
Actos |
24 hours |
Rosiglitazone |
Avandia |
24 hours |
Alpha-glucosidase inhibitors |
||
Acarbose |
Precose |
1-3 hours |
Miglitol |
Glyset |
1-3 hours |
Dipeptidyl-peptidase 4 inhibitors |
||
Sitagliptin |
Januvia |
24 hours |
Saxagliptin |
Onglyza |
24 hours |
Linagliptin |
Trajenta |
12 hours |
Incretin mimetic |
||
Exenatide |
Byetta |
t1/2 2.5 hours |
Liraglutide |
Victoza |
13 hours |
Amylinomimetic |
||
Pramlintide |
Symlin |
3 hours |
Table 2: FDA-approved Antidiabetic Medications: Insulin5
Generic Name |
Brand Name |
Peak Action |
Effective Duration |
* Combined commercially available products are available for several diabetic medications. |
|||
Rapid-acting insulin |
|||
Lispro |
Humalog |
30-90 min |
3-5 hr |
Aspart |
Aspart |
30-90 min |
3-5 hr |
Glulisine |
Apidra |
30-90 min |
3-5 hr |
Short-acting insulin |
|||
Regular |
Humulin R Novolin R |
2-3 hr |
5-8 hr |
Intermediate-acting insulin |
|||
NPH |
Humulin N Novolin N |
4-10 hr |
10-16 hr |
Lente |
Humulin L Novolin L |
4-12 hr |
12-18 hr |
Long-acting insulin |
|||
Glargine |
Lantus |
Peakless |
20-24 hr |
Detemir |
Levemir |
6-14 hr |
16-20 hr |
In 2010, the American Association of Poison Control Centers (AAPCC) reported 19,917 total exposures to antidiabetic medications, including insulin. Of these exposures, 11,399 single exposures were reported. More than 53% of these were due to oral medications, and 46.5% were attributed to insulin. Sixty-seven percent of the single exposures occurred in adults older than the age of 20 years, while 20% occurred in children younger than the age of 5 years. Nine percent of toxic exposures were reported as intentional, while 91% included unintentional and adverse medication reactions. Of the single exposures, 113 major adverse events and 6 deaths were reported.6
A retrospective study looked at adverse events related to insulin at 9 poison centers in 4 states and showed an increase of insulin exposures of 279% (from 170 to 645 patients per year) from 2000 to 2009. Of the insulin exposures, 2584 (68%) were classified as unintentional therapeutic errors.7
The management of hypoglycemic drugs is based on restoring and maintaining euglycemia, while management of antihyperglycemic medications focuses on supportive care and correction of metabolic derangements. Nondiabetics have a greater morbidity and mortality from an insulin or sulfonylurea overdose, while those with DM have more significant outcomes with biguanide overdose.8-11
Consider intentional overdose in cases of unexplained hypoglycemia and treat, if present, concomitant psychiatric illnesses. In some cases it may not be initially evident that the episode of hypoglycemia is a suicidal attempt. The prevalence of depression is higher in patients with multiple medical comorbidities, including DM, than in the general population.8,12
Hypoglycemia
For general purposes, hypoglycemia is defined as a blood glucose level less than 70 mg/dL. An individual, however, may not demonstrate symptoms until levels are significantly lower. True hypoglycemia has symptoms known or likely to be caused by hypoglycemia, low plasma glucose measured at the time of symptoms, and relief of symptoms when the glucose is raised to normal range.13
Symptoms of hypoglycemia are summarized in Table 3.8 In some cases, the patient may appear to be in no distress and without neurologic deficits; however, hypoglycemic patients have the potential to quickly deteriorate from confusion to lethargy and coma with seizures.8 If hypoglycemia is prolonged, cerebral edema can occur.
Table 3: Symptoms of Hypoglycemia8
Mild |
Moderate |
Severe |
Diaphoresis |
Obtundation |
Status epilepticus |
The differential diagnosis of hypoglycemia is broad, including therapeutic dosages of insulin or insulin secretagogues; alcohol abuse or alcoholic ketoacidosis; sepsis; hormonal deficiency; hepatic, renal, or cardiac failure; endogenous hyperinsulinism caused by insulinoma or non-islet cell tumor; and accidental, surreptitious, or malicious hypoglycemia.13
Approach to the Poisoned Patient
The management of a patient poisoned with antidiabetic medications follows the general guidelines for all poisoned patients in terms of stabilization, history/physical exam, and laboratory tests. This section will emphasize those aspects unique to these agents. Clinical conditions may change rapidly and, therefore, vital signs should be monitored, bedside glucose measurements repeated frequently, and level of consciousness reassessed often.14
The presentation of the patient may range from normal to coma.14,15 The skin should be examined for possible needle injection sites. A physician may consider ordering an insulin level and C-peptide as additional diagnostic modalities in hypoglycemic patients who are not taking insulin. C-peptide levels differentiate endogenous from exogenous insulin in hypoglycemic patients. These levels, however, are not available in most emergency departments. The area poison control center should be contacted for additional assistance in suspected poisoned patients.
Intravenous glucose should be administered without delay if a bedside glucose level is low and hypoglycemia is confirmed, or if hypoglycemia cannot be quickly ascertained and the patient has clinical signs of hypoglycemia. Treatment options are listed in Table 4. Glucagon is used to treat hypoglycemia when intravenous access is not easily obtained.16 Follow treatment with a meal rich in carbohydrates and protein when possible. Bedside glucose measurements should be repeated as often as every 15 to 30 minutes while patients are hypoglycemic, and hourly when patients are euglycemic. Dextrose infusions are generally not used in insulin overdose, and in cases involving oral hypoglycemic agents, dextrose infusions can cause hypoglycemia. Their use should be discussed with a toxicologist or poison specialist.17 When used, continuous infusion of high concentration dextrose (> 10%) should be through a central line.16
Table 4: Treatment Options
Dextrose
|
Glucagon
Follow treatment with a meal rich in carbohydrates and protein when possible. |
Decontamination via use of activated charcoal is controversial due to lack of evidence of improvement in patient outcomes and risk of aspiration.18 With the exception of tolbutamide, the first-generation sulfonylurea agents do not seem to bind to activated charcoal, while second-generation agents seem to have a higher affinity.19,20 Use of ipecac is no longer recommended.21 Gastric lavage is generally not used, though it may be considered in a massive overdose if performed shortly after ingestion. There is little evidence that gastric lavage improves clinical outcomes.8,22-26 Cathartics and whole-bowel irrigation are generally not used.27,28 Hemodialysis has been used with success with biguanide overdose.29,30
Any patient with suspected intentional overdose should be evaluated by psychiatry and treated accordingly.
Oral Hypoglycemic Agents
Sulfonylureas. Introduction and Epidemiology. In 2010, the AAPCC reported 3998 total sulfonylurea exposures, with 1712 single medication exposures. This represents 28.9% of all exposures to antidiabetic medications, second only to biguanides. Of the single exposures, 85% were classified as unintentional, 10% as intentional, and 4% as adverse medication reactions. No deaths were attributed to single sulfonylurea exposure.6
Mechanism of Action and Pharmacology. Sulfonylureas are classified into first-, second-, and third-generation drugs, differentiated by shorter elimination half-lives and increased potency by weight in higher generations.29 These agents affect cellular metabolism, ultimately stimulating pancreatic beta cells to secrete stored insulin from secretory granules.31 They also decrease hepatic clearance of insulin.16,32 Sulfonylureas have a relatively low therapeutic index. They are rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations reached within two to four hours after therapeutic use.33,34 Hepatic metabolism converts sulfonylureas to active metabolites, which are renally excreted. The active metabolites account for their long duration of action, improving patient compliance and glycemic control. However, an overdose situation results in excessive pancreatic insulin release, subsequent refractory hypoglycemia, and unpredictable metabolism.29,32
Toxicity due to therapeutic use may be attributed to interactions with other medications, decreased metabolism, and decreased excretion.35 Patients older than 65 years, those taking multiple medications, or those who have frequent hospitalizations, renal insufficiency, and/or poor diabetic management are at heightened risk.36
History and Physical Exam. Symptoms of sulfonylurea toxicity and differential diagnosis mirror those of hypoglycemia. Neuroglycopenic effects, or symptoms caused by decreased brain glucose, may mimic many neurologic conditions and include mental status changes, difficulty speaking, dizziness, motor or sensory deficits, seizures, and coma. Symptoms of hypoglycemic autonomic dysfunction include anxiety, tremulousness, nausea, diaphoresis, and palpitations.37,38
Laboratory Evaluation. Ongoing and frequent assessment of blood glucose is the mainstay of evaluation.29 Assays to screen for sulfonylureas are commercially available.39 However, they are not available in most emergency departments and may produce false-negative results due to the large number of products available to patients.29,40,41
C-peptide levels are elevated in sulfonylurea exposure, both in therapeutic use and in overdose, due to sulfonylurea-induced endogenous pancreatic insulin release.42,43 Interpretation of elevated C-peptide levels in sulfonylurea toxicity is not affected by treatment of hypoglycemia; thus, these labs may be drawn after initial ED treatment.43 Insulin levels are elevated in sulfonylurea exposure. In therapeutic use, elevated insulin levels suggest medication-induced hypoglycemia rather than poor caloric intake.42 In one review, serum insulin concentrations 3.9 µIU/mL were consistent with sulfonylurea-induced hypoglycemia.43
Management. Patients with normal mental status may be given a carbohydrate-rich meal, while symptomatic adult patients with mental status changes should be given intravenous dextrose. Once mental status changes resolve, a meal should be provided to the patient. Glucagon exacerbates physiologic insulin release, which may exacerbate hypoglycemia in patients with sulfonylurea toxicity.4
Intravenous dextrose infusions are highly controversial and are associated with multiple complications. Dextrose stimulates insulin release, which is also potentiated by sulfonylurea use. This increase in insulin may lead to rebound hypoglycemia, which may be profound when the infusion is discontinued.17 In addition, dextrose infusions may cause phlebitis in patients.44,45 This practice is generally not recommended in management of sulfonylurea toxicity.
Use of activated charcoal is controversial in the overdose setting.46 Specifically, most first-generation sulfonylureas are not effectively bound by activated charcoal, though higher generations may have a higher affinity.29 Hemodialysis is not an effective means for enhanced elimination of sulfonylureas.47
Octreotide, though not FDA-approved for use in this capacity, has been reported as safe and effective in prevention of rebound hypoglycemia after sulfonylurea exposure.48-53 Octreotide is a somatostatin analog that acts by suppressing pancreatic insulin secretion.17,54,55 When administered subcutaneously (SC), it reaches peak effect within 30 minutes, with a half-life of 90 minutes and duration of action of 6 to 12 hours. Typical adult dosing is 50-100 mcg SC, though dosage intervals and indication are debated. Octreotide can also be given as an IV bolus over several minutes or by continuous infusion, though the SC route is preferred.56
A prospective, double-blind, placebo-controlled trial of octreotide versus standard therapy with IV dextrose and oral carbohydrates found that recurrent hypoglycemic episodes were significantly less frequent in patients who received octreotide. The authors recommend octreotide administration after the first treated hypoglycemic event.57 In this study, the effect lasted approximately 8 hours, so repeat dosing can be necessary. The authors of a review article suggested 50-100 mcg SC every 8 hours with supplemental dextrose for hypoglycemic episodes in patients for whom an initial dose of dextrose is insufficient.56 Further studies are required to define the ideal dosage and dosing interval.17,57
Hypoglycemia may recur in between administration of octreotide and its onset of action, so bedside glucose must be meticulously monitored. Multiple bedside glucose measurements should be obtained prior to patient transfer to a medical floor to avoid adverse effects of hypoglycemia during transfer.57
Octreotide is generally well tolerated, though side effects include injection site pain, nausea, abdominal pain, flatulence, and diarrhea. The dosages used for sulfonylurea-induced hypoglycemia are lower than for other indications for its use, such as massive upper gastrointestinal bleeding, and thus adverse effects are expected to be less frequent.56
Diazoxide historically has been used to treat sulfonylurea toxicity because it is a direct inhibitor of pancreatic insulin release.56,58 However, due its potential to cause hypotension, tachycardia, and electrolyte imbalances, it is no longer recommended.59
Disposition. Any patient with intentional overdose should be evaluated by psychiatry after medical clearance. Patients exposed to sulfonylureas who have normal vital signs, are asymptomatic, and do not experience hypoglycemia should be observed for at least 8 hours with serial bedside glucose measurements. Patients must remain euglycemic during the entire 8-hour observation period in order to be considered safe for discharge.29
A retrospective study suggests that diabetic patients who take supratherapeutic dosages of their own medications may monitor themselves at home with the following conditions: patients are exposed to immediate preparations only; administered only twice the usual daily dose or up to four times a single dose; they remain asymptomatic and euglycemic and have the ability to self-administer glucose or carbohydrate supplementation; and they call the poison control center to confirm safety of home monitoring.60 Patients who follow this model must disclose coingestants, check blood glucose every 30 to 60 minutes for 8 hours, be accompanied by a reliable friend or family member for the next 24 hours, and seek immediate health care should symptoms or hypoglycemia ensue. Patients who take supratherapeutic dosages of extended-release preparations should remain in the emergency department or hospital, even if they remain euglycemic.60
Patients who are exposed to sulfonylureas and develop hypoglycemia should be admitted to the hospital. This is necessary due to the agents' long duration of action, delayed clearance of medications and metabolites, exaggerated effect in overdose situations, and likelihood of recurrent episodes of hypoglycemia.61 Patients who remain euglycemic and asymptomatic for 24 hours may be safely discharged home or to a psychiatric unit.
Pediatric Exposures. Sulfonylurea agents can cause significant morbidity and mortality in pediatric patients with ingestions as small as one pill.62-64 Young children are at a greater risk for hypoglycemia due to decreased glycogen reserves, increased rate of glucose use, and impaired glycogenolysis and gluconeogenesis.65 In 2010, the AAPCC reported 979 single pediatric exposures to sulfonylureas, which encompassed 57% of total exposures. Ninety-two percent of pediatric exposures occurred in patients younger than 5 years old. There were no deaths.6
Delayed and refractory hypoglycemia has been reported after sulfonylurea exposure in pediatric patients.65,66 A retrospective chart review reported 44% of patients exposed developed hypoglycemia under 50 mg/dL. In this study, no patient with a known ingestion time developed hypoglycemia after 13 hours. The authors suggested observation for at least 16 hours, including an overnight fast for asymptomatic and euglycemic patients, with hourly bedside glucose measurements and no prophylactic dextrose.66 A retrospective poison center study found that prophylactic dextrose and feeding delayed the onset of hypoglycemia as much as 18 hours in pediatric patients.67
Pediatric patients with hypoglycemia should be treated with a carbohydrate-rich meal if they have normal mental status, and with IV dextrose with mental status changes. The initial recommended dose of dextrose in children is 2 mL/kg bolus of 25% dextrose in water IV, and in infants 2-4 mL/kg of 10% dextrose in water IV.29 Octreotide has been shown to be effective in reducing repeat hypoglycemic episodes in children, though the dosage and interval are not clearly defined. Extrapolated from adult dosages, pediatric dosages ranges from 1-2 mcg/kg up to 50 mcg, administered every 6 to 12 hours. Further studies are needed to develop optimal dosing and interval.65,68
Meglitinides. Meglitinides are non-sulfonylurea insulin secretagogues. Their mechanism of action is similar to sulfonylureas, but is mediated at a different binding site on the pancreatic beta cell. Repaglinide (Prandin) and nateglinide (Starlix) are two meglitinides approved by the FDA for use in diabetic patients. They have a much shorter duration of action compared to sulfonylureas and are thought to have less potential for prolonged hypoglycemia.69 While hypoglycemia has been reported in therapeutic dosages and in overdoses of meglitinides, limited experience suggests that the duration of hypoglycemia may be shortened compared to sulfonylureas.70-73
Octreotide has been advocated as a treatment for meglitinide-associated hypoglycemia and has been used with success in cases of nateglinide- and repaglinitide-associated hypoglycemia.71,72 Glucose alone has also been used. In a case of massive nateglinide overdose (3.42 g), the patient was treated with several intravenous glucose supplementations (totaling 100 g) and maintained euglycemia after 6 hours.73 Physicians should treat meglitinide exposures in a similar manner to sulfonylureas.29
Oral Antihyperglycemic Agents
Biguanides. Introduction and Epidemiology. Metformin is the only biguanide available in the United States and comprises more than one-third of all prescriptions of oral antidiabetic medications.74 Phenformin and Buformin are available internationally. Phenformin was recalled by the FDA in 1976 due to concerns over lactic acidosis.11 When used appropriately, metformin has a rare incidence of severe adverse outcomes with everyday use.75 However, many contraindications exist, including liver failure, renal insufficiency, and decompensated heart failure.76 Lactic acidosis remains the feared complication of biguanide poisoning, particularly in children and in patients with multiple comorbidities.77
In 2010, the AAPCC reported 7503 total toxic exposures of metformin, with 3464 single exposures. This represents 54.1% of all exposures to antidiabetic medications. Of the single exposures, 84% were unintentional, 13% were intentional, and 3% were adverse reactions. Six deaths were attributed to metformin in 2010.6,77
Mechanism of Action and Pharmacology. Biguanides act by limiting gluconeogenesis in the liver, as well as increasing insulin receptors in muscle tissue and increasing cellular glucose uptake.16,61 Biguanides alone have not been shown to increase insulin secretion from the pancreas or interfere with hormonal regulation of insulin secretion. Therefore, they should not cause hypoglycemia in therapeutic use or in overdose situations unless taken in combination with other antidiabetic agents.16,29,75
Metformin has a bioavailability of 40-60% and, in therapeutic use, is completely absorbed within six hours of oral ingestion. It has a large volume of distribution. Elimination half-life ranges from two to six hours in therapeutic use, though it becomes significantly less predictable in overdose.78,79 Peak plasma concentration occurs within approximately three hours of administration.80 Metformin is primarily eliminated by the kidneys; hence, clearance is decreased in patients with renal insufficiency.81
Metformin-Associated Lactic Acidosis (MALA). Lactic acidosis is the feared complication of metformin toxicity, both with therapeutic use and in overdose. MALA is most often described in patients with therapeutic toxicity or accidental poisoning.16,82,83 Incidence ranges from 1 to 10 cases per 100,000 patient-years for therapeutic use.77,84,85 Factors that increase metformin accumulation and lactic acidosis include renal dysfunction, impaired liver function, chronic cardiac or respiratory failure, sepsis, hemodynamic instability, and severe dehydration.84-89 MALA has been described in renal failure patients after missing a single dose of dialysis. It is suggested that metformin should be held for 48 hours after receiving contrast dye.29,90,91
Once MALA is established, circulatory failure and organ hypoperfusion contribute to lactic acid production and worsening acidosis.83,84,92
Development of anion gap metabolic acidosis and elevated lactate levels in acute intentional metformin overdose has been reported in the literature.77,92-96 Some authors have speculated that metformin itself may directly induce lactic acidosis in overdose situations.77,97,98
History and Physical Exam. Patients may complain of gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and anorexia. Patients with a greater toxicity may have somnolence, mental status changes, tachycardia, tachypnea, hypotension, hypothermia, oliguria, dysrhythmias, respiratory failure, and multisystem organ failure.82-84,89 Findings are largely attributed to acidosis.90
Laboratory Evaluation. In addition to standard labs for poisoning, physicians should obtain a serum lactate and an arterial blood gas. A bedside glucose should be obtained on patient arrival.
Metformin levels are not routinely recommended in these patients. They cannot be obtained in a timely fashion in most institutions. While an undetectable metformin level excludes metformin as a cause for lactic acidosis, serum concentration does not correlate with severity of poisoning.83 Therefore, the benefit to measuring metformin levels remains unclear.99
Management. Goals of management include correction of acidosis, elimination of the offending medication, reduction of lactate level, and treatment of concomitant disease. Care should be taken in ventilator management, as hyperpnea may be a compensatory mechanism for profound metabolic acidosis. As no antidote is available, treatment mainly consists of supportive care plus enhanced elimination.84,97
Enhanced elimination via extracorporeal techniques (hemodialysis) is a mainstay of treatment of severe metabolic acidosis associated with metformin poisoning.29 However, mixed outcomes are reported.92,95 Hemodialysis is recommended in cases with severe metabolic acidosis (pH < 7.1), large anion gap, lack of improvement with supportive care, hyperglycemia, renal insufficiency, and critical illness.75 Bicarbonate-buffered dialysate has been used with success in these patients.97
The optimal duration is unclear, though most studies suggest prolonged dialysis is most effective, in part due to rebound in drug levels due to cellular accumulation in some patients.79,84,97 Metformin levels do not correlate with dialysis duration.99
Continuous veno-venous hemofiltration (CVVH) should be considered in hemodynamically unstable patients. Though mixed reports exist, a recent review found no difference in drug removal between CVVH and hemodialysis.100 Multiple cases of unstable patients with severe metabolic acidosis successfully treated with CVVH have been reported.86,92,94,101,102 However, treatment failures have occurred.78 The combination of hemodialysis and CVVH to treat biguanide overdose has also been used with mixed success.100,103,104 Some authors suggest using plasma exchange, though more studies are needed.96,104
The use of intravenous sodium bicarbonate is not supported in biguanide poisoning because of the potential to worsen intracellular acidosis and hyperlactatemia, induce hyponatremia, shift the hemoglobin dissociation curve to the left, and cause reflex vasodilation after bolus injection.86,97,105 Even as a time-buying mechanism in severe acidosis, its use is likely inadequate; treatment should instead focus on extracorporeal elimination.84,106
Charcoal hemoperfusion is ineffective itself in the treatment of biguanide toxicity. While drug adsorption to charcoal may augment toxin removal by traditional hemodialysis, this is not standard practice, as metformin itself is easily dialyzed.84
Disposition. Asymptomatic patients with normal vital signs with ingestion of immediate-release preparations should be observed in the emergency department for a minimum of four to six hours.16,78,107 Patients with unclear history, ingestion of extended-release preparations, and polypharmacy ingestions require longer observation; peak plasma concentration of extended-release preparations may not be achieved for up to eight hours post-ingestion.108 After an appropriate observation period, asymptomatic patients without acidosis, hypoglycemia, or metabolic abnormalities may be discharged. Patients with unintentional overdose who have minimal lactate elevation, mild increase in anion gap, and normal vital signs should be observed. Patients with metabolic acidosis, lactate elevation, hypoglycemia (likely indicating coingestion), mental status changes, and significant symptomatology should be admitted to the intensive care unit.
Prognosis. A literature review found that higher metformin levels did not directly correlate with elevated lactate, decreasing serum pH, and increasing mortality.83 However, they found that no patient with nadir pH > 6.9 or peak lactate < 25 mmol/L died as a result of metformin toxicity. Survival has been reported in chronic metformin intoxication with greater acidosis.98
A retrospective study found that while lactate and metformin levels do not correlate with mortality, prothrombin time (PT), as a marker of liver dysfunction, was an independent predictor of death in MALA. The authors suggest that death is largely due to a patient's underlying health status and severity of multiorgan dysfunction.97 A review of case reports found that sepsis, circulatory shock, and end stage hepatic failure are the main predictors of poor prognosis.109
Patients with intentional overdose treated with prolonged hemodialysis, when appropriate, have a more favorable prognosis, compared to patients with unintentional toxicity, especially with the development of MALA, where mortality rates reach as high as 50%.82,97,110
Pediatric Exposure. Metformin is currently the only medication approved by the FDA to treat pediatric non-insulin-dependent diabetes. In 2010, 33% of single biguanide exposures occurred in pediatric patients, with 53% of pediatric exposures occurring in patients younger than 5 years of age.6 Ingestions of less than 10 mg/kg are not likely to cause hypoglycemia or severe metabolic acidosis.111 At higher doses, pediatric patients are treated similar to adults.92,94
Thiazolidinediones. Thiazolidinediones (TZDs), also referred to as glitazones, are oral antihyperglycemics that act by reduction in insulin resistance. Medications in the TZD class include troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos). In the United States, troglitazone was withdrawn from the market in 2000 due to drug-induced hepatitis. Since TZDs do not stimulate endogenous insulin release, hypoglycemia is not an expected side effect in overdose.61 In one case series of 48 patients who ingested pioglitazone or rosiglitazone, asymptomatic hypoglycemia (59 mg/dL) occurred in one patient. No other symptoms occurred.112 A poison control center analysis of 286 TZD overdose cases reported that 1.6% of the study population experienced hypoglycemia.113 Overdose risk of TZDs is unknown, but it is expected to be low, and no specific therapy aside from attentive supportive therapy is indicated at this time.61
Alpha-glucosidase Inhibitors. Alpha-glucosidase inhibitors are antidiabetic medications that prevent the metabolism and absorption of sucrose and complex carbohydrates at the small intestinal brush border. Acarbose (Precose) and miglitol (Glyset) are members of this class. This class of medications has limited systemic absorption and does not cause hypoglycemia.61 Supportive care remains the hallmark of overdose management at this time, and more research is required.
New Agents for Treatment of DM
GLP-1 is an incretin hormone that is deficient in patients with T2DM.114,115 It is secreted from L-cells in the intestine in response to oral nutrient intake and reduces blood sugar levels. GLP-1 is rapidly degraded by the enzyme DDP-4.114,116
FDA-approved incretin mimetics include exenatide (Byetta) and liraglutide (Victoza). FDA-approved DDP-4 inhibitors are sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Trajenta). Hypoglycemia may be associated with standard use of these agents in conjunction with sulfonylureas.114,117-120 Data concerning overdose of these agents are limited and appropriate supportive treatment is warranted.121-124 In a clinical study of exenatide toxicity, three patients with DM experienced a single overdose of 100 mcg SQ (10 times the recommended dose). One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration.125 In another case report of exenatide overdose, hypoglycemia did not occur.124
Pramlintide (Symlin) is an antihyperglycemic medication that augments endogenous release amylin, a pancreatic hormone deficient in diabetic patients. Pramlintide slows gastric emptying, promotes satiety, and inhibits glucagon release. It is currently used as an adjunct therapy for DM patients who use insulin. Data concerning overdose of these agents are limited.121-124
A number of potential therapies for DM are currently being investigated. These include sodium-glucose cotransporter (SGLT2) inhibitors, dual peroxisome proliferator-activated receptor (PPAR agonists), long-acting GLP-1 mimetics, long-acting insulin degludec, and inhaled insulin.114 Information about toxicity and potential for hypoglycemia are limited at this time.
Insulin
Introduction and Epidemiology. Hypoglycemia resulting from excess insulin may be associated with seizures, coma, permanent cognitive dysfunction, and death.1 Intentional insulin overdose is rare.
In the 2010 Annual Report of the American Association of Poison Control Centers, six deaths and 34 events with "major" morbidity were attributed to insulin exposure.6
Pharmacology and Development of Hypoglycemia. Commercially available preparations are listed in Table 3. Hypoglycemia can be prolonged and unpredictable based on the type of insulin administered, amount of insulin, single- or multiple-dose injections, and whether or not the patient is diabetic.126,127 With rapid-acting insulins, the critical time period for the development of hypoglycemia is one to three hours after administration. By comparison, development of hypoglycemia is unpredictable in long-acting preparations such as insulin glargine (Lantus). With a single large injection of insulin, a "depot effect" can be seen, which may result in delayed systemic absorption.126,128 Injection of large insulin doses will cause more severe hypoglycemia in nondiabetic patients than in diabetic patients.8-10
Laboratory Evaluation. Serial glucose measurements are critical for any patient suspected of insulin overdose. Insulin and C-peptide levels may be helpful. Under normal physiologic conditions, insulin and C-peptide are always released in equimolar amounts into circulation by the pancreas.129,130 In nondiabetic patients with hypoglycemia, insulin and C-peptide levels should be low. In the case of hypoglycemia caused by exogenous insulin administration, insulin levels will be elevated and C-peptide will be decreased.131
Management. The cornerstone of the management of insulin toxicity remains frequent glucose monitoring coupled with appropriate glucose repletion to avoid ongoing or recurrent hypoglycemia.132,133 In the hypoglycemic patient, initial management should be intravenous bolus of 50% dextrose in water (D50W) solution followed by an oral glucose load. As above, use of intramuscular glucagon should be considered when IV access or dextrose are unavailable. Glucagon requires adequate hepatic glycogen stores, which can be exhausted in the insulin overdose patient.8 Frequent bedside glucose measurements should be used to guide therapy. For refractory cases, a 25% or 50% dextrose drip in a central venous catheter with close ICU monitoring may be required. Meticulous monitoring and replacement of electrolytes is paramount; hypokalemia, hypomagnesemia, and hypophosphatemia are frequently present in insulin poisoning.134
The duration of monitoring and therapy is variable and depends on extent of hypoglycemia, symptoms, and preparation used. A pitfall of therapy is insufficient glucose administration and prematurely stopping monitoring of glucose levels and subsequent hypoglycemia.134 In a deliberate overdose, the dose of insulin used may be very high, leading to elevated and prolonged need for glucose.
The insulin glargine (Lantus) is long acting and does not have a prominent peak of activity, therefore creating a unique overdose situation. Published case reports suggest the need for prolonged therapy; dextrose infusion was required for 48-130 hours after an overdose, ranging from 26 to 2700 units of glargine. Patients with an overdose of insulin glargine should be admitted to the intensive care unit and closely monitored for hypoglycemia, seizures, electrolyte abnormalities, and respiratory distress.
Octreotide has not been specifically studied in insulin overdose, but could potentially be used as an adjunct in a massive insulin overdose or insulin glargine overdose.135 In an insulin overdose, octreotide potentially suppresses the secretion of endogenous insulin and prevents rebound hypoglycemia. However, there are no studies currently that support using octreotide in an insulin overdose.135
In massive insulin overdoses, surgical excision or aspiration of the injection site has been proposed to halt the anticipated hypoglycemic episodes in a massive insulin overdose. However, this practice is not routinely recommended.128,135
Prognosis and Disposition. The interval between insulin self-injection and initiation of therapy, and the duration of the hypoglycemic coma have been proposed as relevant prognostic factors.47,136 A delay in the initiation of dextrose infusion greater than six hours and duration of mechanical ventilation greater than 48 hours correlated with the severity of hypoglycemic encephalopathy.133
The duration of therapy may vary according to the patient and the amount and type of insulin injected. Treatment can be stopped when at least two successive blood glucose levels are greater than 100 mg/dL over an 8-hour period in a patient with normal mental status and vital signs.8 Longer-acting insulins such as insulin glargine warrant prolonged admission for serial glucose monitoring.
Summary
The toxicity of antidiabetic medications, including insulin, is highly variable and depends on the amount used, the specific medication's pharmacologic properties, patient comorbidities, and co-ingestants. Treatment is focused on supportive care, correction and prevention of hypoglycemia and metabolic derangements, and psychiatric evaluation, where appropriate. A toxicologist or poison control center should be called with overdose of these medications and will serve as a valuable resource in continued management.
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