53: Antidiabetics and Hypoglycemics George M. Bosse

HISTORY AND EPIDEMIOLOGYInsulin first became available for use in 1922 after Banting and Best successfully treated diabetic patients with pancreatic extracts.10 In an attempt to more closely simulate physiologic conditions, additional “designer” insulins with unique kinetic properties have been developed, including a rapid-acting basal insulin that mimics baseline insulin secretion known as lispro.67,140 Several oral delivery systems for insulin have been studied.94 However, the development of an oral delivery system for use in humans has not been successful because of poor intestinal absorption and degradation of the oral form of insulin by digestive enzymes. Using zonula occludens toxin, modulation of intestinal tight junctions in animal models significantly increases enteral absorption of insulin.42 An inhaled form of insulin was withdrawn from the market due to poor sales and inability to demonstrate better glucose control than short-acting insulins.90

The hypoglycemic activity of a sulfonamide derivative used for typhoid fever was noted during World War II.76 This discovery was verified later in animals. The sulfonylureas in use today are chemical modifications of that original sulfonamide compound. In the mid-1960s, the first generation sulfonylureas were widely used. Newer second generation drugs differ primarily in their potency.

Although insulin is widely used for treating diabetes mellitus, oral hypoglycemic exposures are more commonly reported to poison centers than are insulin exposures, based on 15 years of data from 1996 to 2010 (Chap. 136). In an older review of 1418 medication-related cases of hypoglycemia, sulfonylureas (especially the long-acting chlorpropamide and glyburide) alone or with a second hypoglycemic accounted for the largest percentage of cases (63%).130 Only 18 of the sulfonylurea cases in this series involved intentional overdose. However, hypoglycemia is reported in as many as 20% of patients using sulfonylureas.59 In a study of 99,628 emergency hospitalizations for adverse drug events in adults older than 65 years of age, 14% were due to insulin and 11% were due to oral hypoglycemics. The majority (95%) of the hospitalizations related to these groups of endocrine agents were due to hypoglycemia.19 Other causes of hypoglycemia are listed inTable 53–1.

TABLE 53–1.Causes of HypoglycemiaView Large|

Favorite Table|Download (.pdf)The biguanides metformin and phenformin were developed as derivatives of Galega officinalis, the French lilac, recognized in medieval Europe as a treatment for diabetes mellitus.8 Phenformin was used in the United States until 1977, when it was removed from the market because of its association with life-threatening metabolic acidosis with hyperlactatemia (64 cases/100,000 patient-years). However, phenformin still is available outside the United States.110

Development of the α-glucosidase inhibitors began in the 1960s when an α-amylase inhibitor was isolated from wheat flour.126 Acarbose was discovered more than 10 years later and approved for use in the United States in 1995. Troglitazone and repaglinide were approved for use in the United States in 1997. The US Food and Drug Administration subsequently directed the manufacturer of troglitazone to withdraw the product from the US market in 2000 because of associated liver toxicity. Exenatide, a synthetic form of a compound found in the saliva of the Gila monster, is an incretin mimetic. Liraglutide is a synthetic analog of human incretin. Other newer xenobiotics include the gliptins and the amylin analog pramlintide.

PHARMACOLOGYInsulin is synthesized as a precursor polypeptide in the β islet cells of the pancreas. Proteolytic processing

results in the formation of proinsulin, which is cleaved, giving rise to C-peptide and insulin itself, a double-chain molecule containing 51 amino acid residues. Glucose concentration plays a major role in the regulation of insulin release.116 Glucose is phosphorylated after transport into the β islet cell of the pancreas. Further metabolism of glucose-6-phosphate results in the formation of ATP. ATP inhibition of the K+ channel results in cell depolarization, inward calcium flux, and insulin release. After release, insulin binds to specific receptors on cell surfaces in insulin-sensitive tissues, particularly the hepatic, muscle, and fat cells. The action of insulin on these cells involves various phosphorylation and dephosphorylation reactions.

Figure 53–1 depicts the chemical structures of select antidiabetics. The sulfonylureas stimulate the β cells of the pancreas to release insulin and are often referred to as insulin secretagogues. They are ineffective in type 1 diabetes mellitus that results from islet cell destruction (Fig. 53–2). This stimulatory effect diminishes with chronic therapy. All the sulfonylureas bind to high-affinity receptor sensors on the pancreatic β cell membrane, resulting in closure of K+ channels.40,47,48 Inhibition of potassium efflux mimics the effect of naturally elevated intracellular ATP and results in insulin release. High-affinity sulfonylurea receptors also present within pancreatic β cells are postulated to be either located on granular membranes or part of a regulatory exocytosis kinase. Binding to these receptors promotes exocytosis by direct interaction with secretory machinery not involving closure of the plasma membrane K+ channels.40,47,48

FIGURE 53–1.Chemical structures of representative oral antidiabetics. The glucagonlike peptide (GLP-1) analogs and amylin analogs are large polypeptides. Their structures are not shown here.

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FIGURE 53–2.Under normal conditions, cells release insulin in response to elevation of intracellular ATP concentrations. Sulfonylureas potentiate the effects of ATP at its “sensor” on the ligand gated K+channels and prevent efflux of K+. The subsequent rise in intracellular potential opens voltage-gated Ca2+ channels, which increases intracellular calcium concentration through a series of phosphorylation reactions. The increase in intracellular calcium results in the release of insulin. Release of insulin is also caused by binding of sulfonylureas to postulated receptor sites on regulatory exocytosis kinase and insulin granular membranes. Octreotide inhibits calcium entry through Ca2+ channel thereby inhibiting insulin release. GLUT = membrane bound glucose transporter.

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The linkage of two guanidine molecules forms the biguanides. Metformin is an oral biguanide approved for treatment of type 2 diabetes mellitus. Its glucose-stabilizing effect is caused by several mechanisms, the most important of which appears to involve inhibition of gluconeogenesis and subsequent decreased hepatic glucose output. Enhanced peripheral glucose uptake also plays a significant role in maintaining euglycemia. The ability of metformin to lower blood glucose concentrations also results from decreased fatty acid oxidation and increased intestinal use of glucose.9,142 In skeletal muscle and adipose cells, metformin enhances activity and translocation of glucose transporters. Although the details are unclear, the mechanism by which this process occurs involves an interaction between metformin and tyrosine kinase on the intracellular portion of the insulin receptor. Figure 53–3 depicts the mechanism of action of metformin.

FIGURE 53–3.Under normal conditions, insulin binding to its receptor on myocytes and adipocytes activates tyrosine kinase, resulting in phosphorylation and activation of the membrane-bound glucose transporter GLUT. Non–insulin dependent diabetes mellitus is causally associated with an increased activity of PC-1, a glycoprotein that inhibits tyrosine kinase activity and thus reduces myocyte and adipocyte glucose uptake. Metformin reduces PC-1 activity in these cells, enhancing peripheral glucose utilization. In addition, gluconeogenesis in hepatic cells is reduced through interference with pyruvate carboxylase, the enzyme responsible for conversion of pyruvate to oxaloacetate.

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Acarbose and miglitol are oligosaccharides that inhibit α-glucosidase enzymes such as glucoamylase, sucrase, and maltase in the brush border of the small intestine. As a result, postprandial elevations in blood glucose concentrations are blunted.149 Delayed gastric emptying may be another mechanism for the antihyperglycemic effect of these oligosaccharides.120

Insulin resistance in patients with type 2 diabetes mellitus may occur because of secretion of biologically defective insulin molecules, circulating insulin antibodies, or target tissue defects in insulin action.103 The thiazolidinedione derivatives decrease insulin resistance by potentiating insulin sensitivity in the liver, adipose tissue, and skeletal muscle. Uptake of glucose into adipose tissue and skeletal muscle is enhanced, while hepatic glucose production is reduced.17,58

Repaglinide (Prandin) and nateglinide (Starlix) are oral representatives of the meglitinide class that also bind to K+ channels on pancreatic cells, resulting in increased insulin secretion.121 Compared to the sulfonylureas, the hypoglycemic effects of the meglitinides are shorter in duration.

Exenatide and liraglutide are structurally similar to glucagonlike peptide-1 (GLP-1), an incretin that is released in response to an oral glucose load. GLP-1 enhances the release of insulin, delays gastric emptying, and reduces food intake. GLP-1 is metabolized very rapidly, rendering it therapeutically ineffective. Exenatide and liraglutide have much longer half-lives, rendering them useful in the treatment of type 2 diabetes mellitus.146 Sitagliptin, saxagliptin, and linagliptin inhibit dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for the inactivation of GLP-1.1 Pramlintide is an amylin analog. Amylin is produced in the pancreatic β cell and acts in conjunction with insulin to inhibit gastric emptying, decrease postprandial glucagon secretion, and promote satiety.77

PHARMACOKINETICS AND TOXICOKINETICSPharmacokinetic parameters of the hypoglycemics are given in Tables 53–2 and 53–3. The onset and duration of action in therapeutic doses vary considerably among preparations. Insulin overdose usually occurs after administration by the subcutaneous or intramuscular route. As might be predicted based on slow onset and prolonged duration of action of some of the preparations, insulin overdose may result in delayed and prolonged hypoglycemia. However, hypoglycemia may also occur with short acting forms because of some unusual toxicokinetic features. Some of these unpredicted responses may be caused by a depot effect following intramuscular or subcutaneous administration, and poor absorption may be further potentiated by the poor perfusion that can occur during periods of hypoglycemia.95,139 Further complicating the prediction of the clinical course is the delayed release of insulin from adipose tissue at the injection site(s). Because there are a finite number of insulin receptors, insulin overdoses of varying amounts probably are equivalent in terms of the degree of resultant hypoglycemia once receptor saturation occurs, but not in terms of its duration. A comparison can be made with the current treatment of diabetic ketoacidosis, in which lower doses of insulin are as effective as the higher doses used in the past.66

TABLE 53–2.Characteristics of Noninsulin AntidiabeticsView Large|

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TABLE 53–3.Characteristics of Various Forms of InsulinView Large|

Favorite Table|Download (.pdf)Many of the sulfonylureas have long durations of action, which may explain the unusually long period of hypoglycemia that can occur in both therapeutic use and overdose. Second generation sulfonylureas (glimepiride, glipizide, glyburide) have half-lives that approach 24 hours and are characterized by substantial fecal excretion of the parent drug. These drugs frequently cause hypoglycemia (Table 53–2). Like insulin, the sulfonylureas may cause delayed onset of hypoglycemia following overdose.104,118 The reason for the potential delayed onset of effects with sulfonylureas cannot be simply explained by known kinetic principles but may be related to effective counterregulatory mechanisms that fail over time.

Metformin metabolism is negligible, and the majority of an absorbed dose is actively secreted in the urine unchanged. Plasma protein binding is also negligible.9 Repaglinide and nateglinide are prandial glucose regulators characterized by rapid onset and short duration of action. Overdose experience and toxicokinetic data for repaglinide are lacking. It is not clear whether hypoglycemia would be prolonged or delayed in onset following overdose. In one case of nateglinide overdose, hypoglycemia occurred early and was short lived.96 Exenatide and liraglutide are available only for parenteral (subcutaneous) injection. Sitagliptin, saxagliptin, and linagliptin have long half-lives and cause pronounced inhibition of DPP-4, resulting in a long duration of action (approximately 24 hours) after therapeutic doses.74 Pramlintide is available only for parenteral (subcutaneous) injection and has a half-life of approximately 40 minutes when used in therapeutic doses.26

PATHOPHYSIOLOGY OF HYPOGLYCEMIATo varying degrees, the antidiabetics may all produce a nearly identical clinical condition of hypoglycemia. The etiologies of hypoglycemia are divided into three general categories44: physiologic or pathophysiologic conditions (Table 53–1), direct effects of various hypoglycemics (Tables 53–2 and 53–3), and potentiation of hypoglycemics by interactions with other xenobiotics (Table 53–4).

TABLE 53–4.Xenobiotics Known to React with Hypoglycemics Resulting in HypoglycemiaView Large|

Favorite Table|Download (.pdf)Hypoglycemia usually results in decreased insulin secretion, with production of alternate fuels, particularly ketones. Ketone production occurs as a result of fatty acid metabolism.70 Nonketotic hypoglycemia can occur in a hyperinsulinemic state such as insulinoma.106

Central nervous system (CNS) symptoms predominate in hypoglycemia because the brain relies almost entirely on glucose as an energy source. However, during prolonged starvation, the brain can utilize ketones derived from free fatty acids. In contrast to the brain, other major organs such as the heart, liver, and skeletal muscle often function during hypoglycemia because they can use various fuel sources, particularly free fatty acids.132

Emphasis on tighter glucose control as a means of preventing microvascular effects carries with it an increased risk for hypoglycemia.32,33 Regulation of glucose control to near-normal glucose concentrations, the characteristics of each individual’s awareness of hypoglycemia, and the individual counterregulatory mechanisms define the frequency and intensity of hypoglycemia.131 The Diabetic Control and Complications Trial research group reported 62 episodes of blood glucose concentration less than 50 mg/dL with CNS manifestations requiring assistance for every 100 patient-years in patients undergoing an intensive insulin therapy regimen. This was in comparison to a conventional therapy group, which had 19 such episodes per 100 patient-years.32,33 The intensive therapy group received three or more insulin injections per day or used a pump in an effort to achieve a glucose concentration as close to normal as possible, whereas the conventional therapy group received one or two daily insulin injections.

There has also been a recent emphasis in tighter control of glucose in critically ill patients, even in the absence of known diabetes mellitus. Hyperglycemia occurs in critically ill patients due to several mechanisms and is associated with increased mortality in patients with a variety of medical and surgical diagnoses.68 In a study of critically ill surgical patients, tight control of glucose was associated with decreased morbidity and mortality.151 However, such benefits in other studies are not always clearly replicated, and significant hypoglycemia is reported.41,150

The autonomic nervous system regulates glucagon and insulin secretion, glycogenolysis, lipolysis, and gluconeogenesis. β-Adrenergic antagonists affect all of these mechanisms and can result in hypoglycemia. In the presence of kidney failure, β-adrenergic antagonist–induced hypoglycemia is a particular risk51 secondary to increased insulin half-life and reduced renal gluconeogenesis.107 In addition, the clinical presentation of hypoglycemia may be muted when β-adrenergic antagonists are present because the expected autonomic responses of tachycardia, diaphoresis, and anxiety may not occur. Although this is assumed to be true, an adverse effect on hypoglycemic awareness could not be demonstrated in healthy volunteers

given metoprolol, atenolol, and propranolol.64

The concept of hypoglycemia-associated autonomic failure in diabetes mellitus is well described.30 Recurrent episodes of hypoglycemia result in autonomic failure by causing defective glucose counterregulation and possibly hypoglycemic awareness. As glucose concentrations fall, normal sensing mechanisms result in decreased insulin secretion and increased glucagon and epinephrine secretion. These counterregulatory defenses against hypoglycemia are defective in most people with type 1 diabetes mellitus and in many with type II diabetes mellitus.

Although various nonantidiabetic xenobiotics can cause hypoglycemia (Table 53–1), salicylates and ethanol are particularly notable for their unintended hypoglycemic effects. The mechanism of ethanol-induced hypoglycemia is discussed in Chap. 80. Salicylate inhibition of prostaglandin synthesis in the β cell of the pancreas is postulated to result in enhanced insulin secretion.11 Salicylates may also cause hypoglycemia by poorly defined mechanisms that do not involve enhanced insulin secretion.

CLINICAL MANIFESTATIONSHypoglycemia and its secondary effects on the CNS (neuroglycopenia) are the most common adverse effects related to insulin and the sulfonylureas. It is essential to remember that hypoglycemia is primarily a clinical, not a numerical, disorder. Clinical hypoglycemia is the failure to maintain a plasma glucose concentration that prevents signs or symptoms of glucose deficiency. The clinical presentations of patients with hypoglycemia are extremely variable. Hypoglycemia must be considered to be the etiology of any neuropsychiatric abnormality, whether persistent or transient, focal or generalized. The cerebral cortex usually is most severely affected. These findings are categorized below115:

• Delirium with subdued, confused, or manic behavior.

• Coma with multifocal brainstem abnormalities, including decerebrate spasms and respiratory abnormalities, with preservation of the oculocephalic (doll’s eyes), oculovestibular (cold-caloric), and pupillary responses.

• Focal neurologic deficits simulating a cerebrovascular accident (CVA) with or without the presence of coma. During a 12-month study period, 3 of 125 (2.4%) hypoglycemic patients presented with hemiplegia.83 There are numerous reports4,135 and series128,148 of patients with focal neurologic deficits.

• Solitary or multiple seizures.

These neuropsychiatric symptoms are usually reversible if the hypoglycemia is corrected promptly. The morbidity resulting from undiagnosed hypoglycemia is related partly to the etiology and partly to the duration and severity of the hypoglycemia. Because the etiologies of hypoglycemia encompass both severe diseases such as fulminant hepatic failure and benign problems such as a missed meal by an insulin-requiring diabetic, the literature with regard to outcome is confusing. Although a study of 125 emergency department (ED) cases of symptomatic hypoglycemia reported an 11% mortality rate,83only one death (0.8%) was attributed directly to hypoglycemia. In that same study, nine patients (7.2%) presented with seizures (focal in one case), three patients (2.4%) presented with hemiparesis, and four survivors (3.2%) suffered residual neurologic deficits. In one tertiary care medical center, 1.2% of all admitted patients had hypoglycemia (defined as a glucose concentration less than 50 mg/dL). The overall mortality was 27% for this group of 94 patients.44 The longer and more profound the hypoglycemic episode, the more likely permanent CNS damage will occur.7

No absolute criteria available from the physical examination or history distinguish one form of metabolic coma from another. Moreover, the findings classically associated with hypoglycemia, such as tremor, sweating, tachycardia, confusion, coma, and seizures, frequently may not occur.56 The glycemic threshold is the glucose concentration below which clinical manifestations develop, a threshold that is host variable. In one study, the mean glycemic threshold for hypoglycemic symptoms was 78 mg/dL in patients with poorly controlled type 1 diabetes compared to 53 mg/dL in those without the disease.15

Patients with well-controlled type 1 diabetes may be unaware of hypoglycemia. It appears that even in the presence of numerical hypoglycemia, diabetics with near-normal glycosylated hemoglobin concentrations

maintain near-normal glucose uptake by the brain, thereby preserving cerebral metabolism and limiting the response of counterregulatory hormones. The result of this limited response is unawareness of hypoglycemia.14,15 A threshold is likely achieved below which the glucose concentration is inadequate, but this may be a concentration so close to that causing serious neuroglycopenia that patients have limited opportunity for corrective action.14Hypoglycemia unawareness is most likely in diabetics with chronic use of hypoglycemics because of hypoglycemia-associated autonomic failure.30 Acute ingestion of hypoglycemics in nondiabetic patients likely would cause more classic signs and symptoms.

Sinus tachycardia, atrial fibrillation, and ventricular premature contractions are the most common dysrhythmias associated with hypoglycemia.75,102 An outpouring of catecholamines, hypoglycemia itself, transient electrolyte abnormalities, and underlying heart disease appear to be the most likely etiologies. Based on their mechanisms of action, both insulin and the sulfonylureas are expected to promote the shift of potassium into cells, and hypokalemia after insulin overdose is well documented.6,139 Other cardiovascular manifestations include angina and ischemia, which rarely may be the sole manifestations of hypoglycemia.38 Both are directly related to hypoglycemia.12,112Increased release of catecholamines during hypoglycemia increases myocardial oxygen demand and may decrease supply by causing coronary vasoconstriction.

Hypothermia may occur in hypoglycemic patients.45,63,141 If present, hypothermia usually is mild (90°–95°F {32°–35°C}), unless coexisting conditions such as environmental exposure, infection, head injury, or hypothyroidism are present. In a study comparing two groups of patients with depressed mental status, hypothermia was almost exclusively limited to the hypoglycemic patients; of these patients, 53% with demonstrated hypoglycemia showed hypothermia.141 The central hypothalamic response to hypoglycemia stimulated by the sympathetic nervous system may actually “overshoot” normal temperatures, resulting in hyperthermia following recovery.27

Besides decreasing glucose concentrations, the hypoglycemics can produce a number of adverse effects, both in overdose and in therapeutic doses. Older sulfonylureas, predominantly chlorpropamide, cause a syndrome of inappropriate antidiuretic hormone secretion61 and disulfiram-ethanol reactions.113 These adverse effects are exceedingly uncommon with the newer second-generation sulfonylureas.

Hypoglycemia may not occur until 18 hours after lente insulin overdose,95 may persist for up to 53 hours after subcutaneous insulin glargine overdose,18 and may persist up to 6 days after ultralente insulin overdose.84 Death after insulin overdose cannot be correlated directly with either the dose or preparation. Some patients have died with doses estimated in the hundreds of units, whereas others have survived doses in the thousands of units.127Mortality and morbidity may correlate better with delay in recognition of the problem, duration of symptoms, onset of therapy, and type of complications, as opposed to the absolute degree of hypoglycemia or persistence of elevated insulin concentrations. A significant correlation exists between the amount of insulin injected and either the total amount of dextrose used for treatment or the duration of dextrose infusion.139 In a retrospective study of insulin overdose, 7 of 17 cases (41%) developed recurrent hypoglycemia between 5 and 39 hours after overdose despite oral feeding and intravenous dextrose infusion ranging from 5 to 17 g of dextrose per hour.

In a retrospective review of 40 patients with sulfonylurea overdoses, the time from ingestion to the onset of hypoglycemia, when known, was variable.105 The longest delay was 21 hours after ingestion of glyburide and 48 hours after ingestion of chlorpropamide. In a retrospective poison center review of 93 cases of sulfonylurea exposures in children, 25 patients (27%) developed hypoglycemia, with a time of onset ranging from 0.5 to 16 hours and a mean of 4.3 hours.118 In a prospective poison center study of sulfonylurea exposures in children, 56 of 185 (30%) patients developed hypoglycemia, with a time of onset ranging from 1 to 21 hours and a mean of 5.3 hours.136 Single-tablet ingestions of chlorpropamide 250 mg, glipizide 5 mg, and glyburide 2.5 mg can result in hypoglycemia in young children,118 and the hypoglycemia may be delayed.143 Hypoglycemia did not occur until 45 hours after ingestion of a 10 mg extended-release glipizide tablet in a 6 year-old child.108

Hypoglycemia is reported in at least two cases of metformin overdose.144 In both cases, metabolic acidosis with elevated lactate was evident on initial presentation. Hypoglycemia was present initially in one of the cases but did not develop until 7 hours later in the second case. Hypoglycemia and metabolic acidosis with hyperlactatemia are reported in a case of overdose with metformin, atenolol, and diclofenac.52 Hypoglycemia

is reported in a case of metformin-associated metabolic acidosis with hyperlactatemia related to therapeutic use.69 Insufficient evidence supports the concept that metformin-associated hypoglycemia can develop in a patient who is not critically ill without metabolic acidosis. Because many patients receiving metformin also take sulfonylureas, hypoglycemia should be anticipated after overdose. Phenformin is similar to metformin in that ingestion alone rarely causes hypoglycemia, in overdose or following therapeutic use.130

The α-glucosidase inhibitors, thiazolidinediones, meglitinides, GLP-1 analogs, gliptins, and amylin analogs are xenobiotics for which overdose data are limited. Acarbose and miglitol are not likely to cause hypoglycemia based on their mechanism of action of inhibiting α-glucosidase. The most common adverse effects associated with therapeutic use of these xenobiotics are gastrointestinal, including nausea, bloating, abdominal pain, flatulence, and diarrhea. Elevated aminotransferase concentrations were noted after use of acarbosein clinical trials.57 Most patients were asymptomatic, and the aminotransferase concentrations returned to normal after the drug was discontinued. The therapeutic use ofacarbose in some cases reportedly led to hepatotoxicity that resolved after the drug was discontinued.5,24

Hypoglycemia would not be expected after thiazolidinedione overdose. The most serious adverse effect of troglitazone is the development of liver toxicity with therapeutic doses, which in some cases was severe enough to require liver transplantation.49,99 Liver toxicity related to therapeutic use of rosiglitazone3,46 and pioglitazone is also reported.82,85Therapeutic use of pioglitazone and rosiglitazone may precipitate fluid retention in patients with underlying congestive heart failure.98 A meta-analysis concluded thatrosiglitazone therapy is associated with an increased risk of myocardial infarction and death from cardiovascular causes.101

Hypoglycemia should be anticipated after repaglinide and nateglinide ingestion. Hypoglycemia is reported after nateglinide overdose,96 and a case of intentionally self-induced hypoglycemia secondary to repaglinide is reported.55 Hypoglycemia did not occur in a recently published case of intentional overdose with a total of 90 µg exenatide.29“Severe hypoglycemia” was reported in a phase III clinical trial after inadvertent administration of 10 times the normal dose of exenatide. The specific glucose concentration is not noted in the report.22 Pramlintide is used therapeutically in conjunction with insulin, and hypoglycemia in this setting is more likely than with insulin use alone.77

DIAGNOSTIC TESTINGSuspicion of hypoglycemia, particularly neuroglycopenia, is important in any patient with an abnormal neurologic examination. The most frequent reasons for failure to diagnose hypoglycemia and mismanaging patients are the erroneous conclusions that the patient is not hypoglycemic but rather is psychotic, epileptic, experiencing a CVA, or intoxicated because of an “odor of alcohol” on the breath (Chap. 80). Compounding the problem of misdiagnosis is the erroneous assumption that a single bolus of 0.5 to 1 g/kg of hypertonicdextrose will always be sufficient.

Plasma glucose concentrations are accurate, but treatment cannot be delayed pending the results of laboratory testing. Glucose reagent strip testing can be performed at the bedside. The sensitivity of these tests for detecting hypoglycemia is excellent, but these tests are not perfect. Several interfering substances may cause false elevation of bedside glucose reagent strip concentrations, including maltodextrin, acetaminophen, bilirubin, triglyceride, and uric acid.39,65 Bedside glucose testing is discussed in more detail in Antidotes in Depth: A12.

Diagnostic studies other than determinations of glucose concentrations may be indicated, depending on the clinical situation. In some instances, determination of serum ethanol concentration may be helpful in confirming alcohol as a contributing or sole etiologic factor. Kidney function tests may indicate the presence of kidney impairment as a causative factor of hypoglycemia. This commonly occurs in diabetics taking insulin, who often develop kidney failure after they have had the disease for several years. Insulin half-life increases as kidney function declines. Measures of hepatic function may be a clue to liver disease as a cause of hypoglycemia, although liver disease may also be evident on physical examination. Seizures are commonly associated with hypoglycemia, but other studies, such as electrolytes, calcium, magnesium, and imaging of the brain, may be indicated if doubt about the etiology exists.

In the majority of overdose cases, laboratory testing for specific antidiabetics is not helpful. Exceptions might include malicious, surreptitious, or unintentional overdoses (discussed in the next section). Metformin concentrations vary and do not necessarily correlate with the clinical condition.2,71,72

For known diabetics in whom overdose is not suspected, the clinician must search diligently for the cause of hypoglycemia. Sometimes it is as simple as a missed meal in an insulin user or an unusually strenuous exercise routine, but in many cases the cause cannot be clearly defined. Numerous medical conditions, as well as a variety of medications, may be involved (Table 53–1), and diagnostic testing must be individualized for each episode depending on the clinical suspicion. Diagnosing the etiology as “idiopathic” is never acceptable.

EVALUATION OF MALICIOUS, SURREPTITIOUS, OR UNINTENTIONAL INSULIN OVERDOSEThe physical examination may provide helpful clues to the evaluation of a suspected malicious, surreptitious, or unintentional insulin overdose. A meticulous search may reveal a site that is erythematous, hemorrhagic, atypically boggy in nature, or even painful if the subcutaneous (or intramuscular) injection of insulin was particularly large. A simple unexplained needle puncture mark in the appropriate clinical setting may suggest insulin injection.

An understanding of how the β cells of the pancreas secrete insulin in response to glucose concentrations in the blood is essential to understanding the investigation of fasting hypoglycemia.31 When the plasma glucose concentration is less than 45 mg/dL, insulin secretion should be almost completely suppressed, so plasma insulin concentrations should be minimal or absent.114 Moreover, insulin is secreted as proinsulin, which is cleaved in vivo to form insulin (a double stranded peptide) and C-peptide, which are released into the blood in equimolar quantities. Insulin is biologically active, whereas proinsulin has limited activity, and C-peptide has no activity. Although insulin is normally cleared during hepatic transit, C-peptide is not. For this reason, C-peptide can be utilized as a quantitative marker of endogenous insulin secretion. In contrast, commercially available exogenous human insulin does not contain C-peptide fragments (Table 53–5). When plasma glucose concentration falls to hypoglycemic concentrations (usually less than 60 mg/dL), insulin concentration should fall to less than 6 µU/mL. If hypoglycemia is caused by exogenous insulin administration, plasma C-peptide concentrations should be less than 0.2 nmol/L in the presence of insulin concentrations that are substantially higher than insulin concentrations resulting from an insulinoma. With insulinoma, insulin concentrations generally are greater than 6 µU/mL in the presence of hypoglycemia. Insulinoma results in elevations of both C-peptide and insulin concentrations. Sulfonylurea overdose is expected to have similar effects, but concentrations in reported cases of sulfonylurea-induced hypoglycemia vary considerably.36 In the face of uncertainty, sulfonylurea concentrations are available from reference laboratories. Animal insulin can be distinguished from human insulin by high performance liquid chromatography.50 However, this technique has limited use because of the virtually exclusive use of human insulin at present.

TABLE 53–5.Laboratory Assessment of Fasting HypoglycemiaView Large|

Favorite Table|Download (.pdf)In summary, patients with exogenous insulin induced hypoglycemia will have high insulin concentrations, the presence of insulin-binding antibodies (if chronic insulin users),43 and low C-peptide concentrations. Those who have taken sulfonylureas will have high insulin concentrations, absent insulin-binding antibodies, high C-peptide concentrations, and presence of urinary sulfonylurea metabolites (Table 53–5). The issues of evidence collection that are appropriate to document malicious or surreptitious use of insulin successfully are described80 (Chap. 141).

MANAGEMENTTreatment centers on the correction of hypoglycemia and the anticipation that hypoglycemia may recur. Symptomatic patients with hypoglycemia require immediate treatment with 0.5 to 1 g/kg concentrated intravenous dextrose in the form of D50W in adults, D25W in children, and D10W in neonates. Occasionally, patients require a larger dose to achieve an initial response. If hypoglycemia is suspected but not confirmed, as

in the absence of rapid reagent strip availability or when such readings are “borderline,”dextrose should be administered. Theoretical risks are associated with use of concentrated dextrose in the setting of cerebral ischemia, but failure to rapidly correct hypoglycemia may lead to deleterious neurologic effects. Appropriate emergency and toxicologic uses of hypertonic dextrose are covered in detail in Antidotes in Depth: A12.

Glucagon should not be considered as an antihypoglycemic except in the uncommon situation where intravenous access cannot be obtained. Glucagon has a delay to onset of action and may be ineffective in patients with depleted glycogen stores, as in the elderly, cancer patients, or alcoholics. Glucagon also stimulates insulin release from the pancreas, which may lead to prolonged hypoglycemia in settings such as sulfonylurea ingestion and insulinoma.145

Numerous studies have evaluated approaches for treating insulin reactions with carbohydrates in tablet, solution, or gel forms in a well-defined diabetic population.133None of these forms is appropriate for the undifferentiated, possibly hypoglycemic patient if intravenous access is available.

A common occurrence involves symptomatic hypoglycemic patients who receive intravenous dextrose in the prehospital setting and subsequently refuse transport to the hospital. The authors of a retrospective review of 571 paramedic runs involving hypoglycemic patients concluded that out-of-hospital treatment of hypoglycemic diabetic patients is safe and effective even when transport is refused.134 However, of the 159 patients who agreed to hospital transport, 40% were admitted. The admitted group was older than those released from the ED. The admission rate for transported patients on oral hypoglycemics was higher than those on insulin. The reasons for admission are not otherwise detailed. The authors of a prospective study involving 132 hypoglycemic diabetic patients who refused transport after therapy concluded that most such patients have good short-term outcome, but they still encouraged transport because of the risk of recurrent hypoglycemia.91 One patient died in each of these two studies. A prospective study in 35 patients with 38 hypoglycemic events related to insulin use concluded that most patients were successfully treated in the prehospital setting without transport.78However, two patients developed recurrent hypoglycemia that they treated themselves, and one of these patients required placement in a long-term care facility for posthypoglycemic encephalopathy. We therefore recommend that all hypoglycemic patients should be transported to EDs.

Emesis, lavage, and catharsis are of limited benefit in the management of patients who overdose on hypoglycemics. The extensive affinity between chlorpropamide, tolazamide, tolbutamide, glyburide, glipizide, and activated charcoal is demonstrated in vitro.62 The affinities ranged from 0.45 to 0.52 g/g activated charcoal at pH 7.5 and were higher at pH 4.9. Single-dose activated charcoal should be beneficial in the management of these overdoses. Although affinity studies are lacking for the other oral hypoglycemics, their chemical characteristics are such that single-dose activated charcoal is expected to be beneficial for these overdoses as well. Multiple-dose activated charcoal and whole-bowel irrigation may be of benefit and should be considered after overdose of modified-release antidiabetics and hypoglycemics, but outcome studies are not available.

In patients who overdose on insulin, case reports describe the use of surgical excision of the injection site.23,79,87 However, this technique has not been studied in a systematic fashion, until then, it is expected that IV dextrose should be sufficient. Needle aspiration of a depot site is less invasive and should be considered.

Urinary alkalinization to a pH of 7 to 8 can reduce the half-life of chlorpropamide from 49 hours to approximately 13 hours. Urinary alkalinization is not useful for other hypoglycemics because of their limited renal excretion.100

MAINTAINING EUGLYCEMIA AFTER INITIAL CONTROLAfter the patient is awake and alert, further therapy depends on the xenobiotic involved and pancreatic islet cell function. Some patients, particularly those with prolonged hypoglycemia, may have persistent altered mental status despite euglycemia. Whether the event was unintentional or intentional with suicidal or homicidal intent must be determined. One problem associated with dextrose administration occurs in individuals who can produce insulin via glucose-stimulated insulin release (nondiabetics and those with type 2 diabetes mellitus), placing them at substantial risk for recurrent hypoglycemia. This complication can occur with insulin overdose but is particularly problematic with overdoses of sulfonylurea or meglitinide because these hypoglycemics stimulate insulin release. Treatment with hypertonic dextrose solutions can be expected to result in dramatic yet only transient increases in glucose concentrations, with a subsequent fall in plasma

glucose concentration, possibly back to hypoglycemic concentrations.

For diabetics who unintentionally inject an excessive amount of insulin and are not neuroglycopenic, feeding should be initiated and intravenous access maintained while avoiding routine dextrose infusion. In the event of recurrent symptomatic hypoglycemia, a concentrated dextrose bolus should be used. Overdose in the setting of suicidal or homicidal intent likely involves significant quantities of insulin. Nondiabetics may be particularly prone to significant hypoglycemia because they lack insulin resistance. Feeding should be initiated and glucose concentrations maintained in the 100 to 150 mg/dL range using a concentrated dextrose infusion (D10W or greater) as needed.

Central venous lines should be used when D20W infusion is instituted, because concentrated dextrose solutions are substantial venous irritants. The presence of glycosuria is not an adequate indicator of euglycemia; frequent serial blood or reagent strip glucose concentrations should be obtained. The appropriate timing of glucose monitoring varies depending on the clinical situation. Mental status must be observed. As a rough guide, glucose monitoring every 1 to 2 hours after initial control is reasonable, with subsequent spacing of the intervals to once every 4 to 6 hours. Phosphate concentrations should be monitored because glucose loading may lead to hypophosphatemia.92 Potassium concentrations should be monitored because glucose administration may lead to hypokalemia in nondiabetics and hyperkalemia in patients with impaired insulin secretion.28 The duration of sampling depends on the stability of the patient, the underlying metabolic disorders, the extent of overdose, and the rate of improvement. When the patient begins to eat an adequate diet and the initial hypoglycemia is controlled, the plasma glucose concentration will rise, and the concentration and rate of dextrose infusion can be tapered. Many patients may actually develop significant hyperglycemia.

The therapeutic approach differs for patients who overdose on sulfonylureas or meglitinides. After initial control of hypoglycemia with concentrated dextrose, the patient should be fed. Intravenous access is necessary, but routine dextrose infusion should be avoided. As with insulin overdose, frequent monitoring of glucose concentrations and mental status is critical. We recommend early use of octreotide in this setting because of the significant risk of glucose stimulated insulin release.

Octreotide, a semisynthetic long-acting analog of somatostatin with an intravenous half-life of 72 minutes, inhibits glucose-stimulated β cell insulin release via receptors coupled to G proteins on β islet cells.13 Somatostatin is present in diverse tissues such as the hypothalamus, pancreas, and gastrointestinal tract. It alters the secretion of growth hormone and thyroid-stimulating hormone, gastrointestinal secretions, and the endocrine pancreas (glucagon and insulin).122,123 Octreotide was compared to intravenous hypertonic dextrose and to diazoxide and concomitant dextrose in normal subjects brought to hypoglycemia using glipizide.13 Fewer episodes of recurrent hypoglycemia occurred after octreotide therapy, and overall dextrose requirements were lower than in the dextrose-alone and dextrose-plus-diazoxide groups. Several successful clinical experiences with octreotide are reported with quinine-induced hypoglycemia resulting from malaria therapy,111 insulinoma,54 nesidioblastosis of infancy,34 hypoglycemia related to therapeutic use of gliclazide,16 and tolbutamide overdose.13 In a retrospective study of nine patients with hypoglycemia resulting from either glyburide or glipizide, octreotideeffectively reduced the risk of recurrent hypoglycemia.88

Octreotide appears to be relatively free of serious side effects. The most likely adverse effects are injection-site discomfort if it is administered subcutaneously and gastrointestinal symptoms such as nausea, bloating, diarrhea, and constipation.81 The suggested adult octreotide dose is 50 µg subcutaneously every 6 hours (Antidotes in Depth: A13). The patient should be monitored for 12 to 24 hours after the last dose ofoctreotide. This observation will ensure that recurrence of hypoglycemia does not occur. Like octreotide, diazoxide may be effective in patients with refractory sulfonylurea-induced hypoglycemia.60,104 However, because of its potential to cause hypotension, diazoxide should be considered only if octreotide is unavailable.

ADMITTING PATIENTS TO THE HOSPITALThe decision to admit a patient may be complex, but several guidelines can be followed. Admission is required for hypoglycemia related to sulfonylureas, ethanol, starvation, hepatic failure, and kidney failure and for hypoglycemia of unknown etiology. The decision to admit a patient often depends on finding an etiology for hypoglycemia, particularly in the setting of insulin use. In most cases, if a diabetic patient on therapeutic doses

of insulin develops hypoglycemia after a missed meal, the patient can be discharged after a 4 to 6 hour observation period during which the individual eats a meal and remains asymptomatic with no evidence of hypoglycemia. Patients receiving therapeutic doses of insulin require inpatient evaluation of recurrent and unexplained hypoglycemic episodes. All patients with hypoglycemia after unintentional overdose with long-acting insulin should be admitted. Hospitalization is recommended after unintentional overdose with ultrashort-acting, short-acting, or intermediate-acting insulin if hypoglycemia is persistent or recurrent during a 4 to 6 hour observation period in the ED. Many factors may be responsible for unintentional insulin overdose, such as patient error because of impaired vision, syringe structure, and prescription error; hospital admission may be warranted. Admission is indicated for any patient, regardless of serum glucose concentration or presence or absence of symptoms, who intentionally overdoses on a sulfonylurea or any form of injected insulin, because delayed, profound, and protracted hypoglycemia may result. Although intravenous insulin overdose is expected to result in more immediate symptoms, experience with this scenario is limited. Admission in this setting is advised unless short-acting insulin is involved. Glargine is expected to act like regular insulin when administered intravenously. It is long-acting when administered subcutaneously due to the formation of microprecipitates which are absorbed slowly. Hypoglycemia related to sulfonylurea use in any setting requires hospitalization.20

Patients with possible intentionally self-induced hypoglycemia should be admitted. Intentionally self-induced hypoglycemia is most commonly recognized by members of the medical profession. Administration of insulin to a nondiabetic child is a form of child abuse or an attempt at homicide37 (Chap. 32). Children who have been given an inappropriate dose of insulin, as well as any patient who may be a victim of attempted homicide, should be admitted.

A 4 to 6 hour observation period is recommended after metformin overdose. Further observation or hospital admission is not required for patients who remain asymptomatic during this period with no evidence of metabolic acidosis or hypoglycemia. Patients who overdose on α-glucosidase inhibitors are not expected to have delayed or serious systemic toxicity, and routine medical admission is unnecessary. There are limited data regarding the risk of hypoglycemia and other adverse events after thiazolidinedione ingestion. Based on the mechanism of action and existing clinical experience, hypoglycemia is possible but uncommon after thiazolidinedione overdose. Delayed onset of hypoglycemia or other serious clinical manifestations is unlikely. A 4 to 6 hour observation period after thiazolidinedione overdose is recommended. Significant hypoglycemia is reported with nateglinide overdose,96 and with repaglinide used in a setting of intentionally self-induced hypoglycemia.55 Meglitinides are expected to behave pharmacologically like sulfonylureas. For this reason alone, hospital admission after meglitinide overdose is advisable, even when the patient is asymptomatic. Admission after exenatide, liraglutide, sitagliptin, saxagliptin, linagliptin, and pramlintide overdose is advised until more overdose data are obtained. Delays in onset of clinical manifestations, particularly hypoglycemia, are not expected, but there is currently limited clinical experience with regard to overdose.

Children who unintentionally ingest one or more sulfonylurea tablets should be hospitalized for 24 hours. Although this recommendation may be controversial and some authors suggest shorter observation periods21 or even home monitoring in some cases,124 we believe that delayed hypoglycemic effects of sulfonylurea ingestion in children are well documented118,136,143 and convincing enough to support admission in all cases. Asymptomatic children with single tablet exposures to sulfonylureas are best managed without prophylactic intravenous dextrose, which could contribute to delayed onset of hypoglycemia.21 Elevations in glucose concentrations stimulate insulin release by the pancreas. Such patients instead are best managed by early feeding, frequent checks of glucose concentrations, and observation of mental status.

METFORMIN-ASSOCIATED METABOLIC ACIDOSIS WITH HYPERLACTATEMIAThroughout this chapter, the term metabolic acidosis with hyperlactatemia is used rather than metformin-associated lactic acidosis. The biochemical and pathophysiologic processes involving lactate are complex, but a few points are worth summarizing. Hyperlactatemia occurs in various diseases and can be present in the absence of acidosis. The production of lactic acid does not result in a net increase in hydrogen ion concentration unless there is associated impairment of oxidative metabolism. Impaired oxidative metabolism leads to an increase in hydrogen ion production through the hydrolysis of ATP.93 In a pig overdose

model, metformin caused metabolic acidosis with hyperlactatemia, mitochondrial dysfunction, and inhibition of oxygen consumption. Infusion of lactic acid alone did not cause inhibition of oxygen consumption.117

The biguanides are uniquely associated with the occurrence of metabolic acidosis with hyperlactatemia. Phenformin causes lactic acid production by several mechanisms, including interference with cellular aerobic metabolism and subsequent enhanced anaerobic metabolism. Phenformin suppresses hepatic gluconeogenesis from pyruvate and causes a decrease in hepatocellular pH, resulting in decreased lactate consumption and hepatic lactate uptake. Metformin-associated metabolic acidosis with elevated lactate occurs 20 times less commonly than that occurring with phenformin. In isolated perfused rat liver, metformin inhibits both hepatic lactate uptake and conversion of lactate to glucose.119 Metabolic acidosis with hyperlactatemia related to metformin usually occurs in the presence of an underlying condition, particularly kidney impairment.25,69 In this setting, increased tissue burden of metformin, which is renally eliminated, probably occurs. Other risk factors include cardiorespiratory insufficiency, septicemia, liver disease, history of metabolic acidosis with hyperlactatemia, advanced age, alcohol abuse, and use of radiologic contrast media.9,25 Iodinated contrast material may induce acute kidney injury, leading to accumulation of metformin and subsequent risk of development of metabolic acidosis with hyperlactatemia. However, the risk of developing metabolic acidosis with hyperlactatemia after contrast administration is low in patients taking metformin who have normal kidney function and no other risk factors.86,97

Severe metabolic acidosis with hyperlactatemia occurs after acute metforminoverdose72,89,104,144 but appears to be uncommon. In one case,89 metabolic acidosis was not diagnosed until 14 hours after metformin overdose. The patient had early symptoms of repeated vomiting at 1 hour postingestion. Metabolic acidosis with hyperlactatemia occurred in two of 65 adult metformin overdose cases reported to a poison center137 and was not reported in a poison center series of 55 pediatric metformin exposures.138 In a retrospective review of 398 cases of acute metformin overdose from two poison centers, metabolic acidosis with hyperlactatemia occurred in 9.1% of single product overdose and in 0.7% of polypharmacy overdoses.152

A systematic review from the Cochrane Library concluded that therapeutic use ofmetformin is not associated with an increased risk of metabolic acidosis with hyperlactatemia compared with other antidiabetic treatments if no contraindications are present.125 This conclusion was based on a review of prospective comparative trials and observational cohort studies. However, the risk of metformin-associated metabolic acidosis with hyperlactatemia in the setting of overdose setting or kidney insufficiency was not assessed. Although metabolic acidosis with hyperlactatemia after overdose is not common, it does occur with sufficient frequency to require vigilance on the part of the treating physician. Case reports were not used in the Cochrane review, and a few cases of metformin-associated metabolic acidosis with hyperlactatemia in the setting of therapeutic use with no underlying risk factors are reported.25,109,147

It is difficult to predict outcome after metformin overdose. A retrospective literature review found no deaths in cases with a nadir serum pH greater than 6.9, a peak serum lactate concentration less than 25 mmol/L, or a peak serum metformin concentration less than 50 µg/mL.35 However, a retrospective review of intensive care unit patients with metabolic acidosis with hyperlactatemia found no association between metformin concentrations in survivors and nonsurvivors.129 There was an association between mortality and lactate concentrations and pH.

Metformin associated metabolic acidosis with hyperlactatemia is a potentially lethal condition. Recognition and awareness of this disorder are important. Symptoms may be nonspecific and include abdominal pain, nausea, vomiting, malaise, myalgia, and dizziness. However, gastrointestinal symptoms are common adverse effects associated with therapeutic use of metformin and do not necessarily require discontinuation of the drug. More severe clinical manifestations of metformin-associated metabolic acidosis with hyperlactatemia include confusion, blindness, mental status depression, hypothermia, respiratory insufficiency, and hypotension. Serum metformin concentrations can be obtained as a diagnostic aid, but these may not correlate with the clinical condition in both the acute overdose setting and in the setting of therapeutic metformin use.71,72

Aggressive airway management and vasopressor therapy may be required. Indications for use of intravenous sodium bicarbonate in critically ill patients with metabolic acidosis with hyperlactatemia of various etiologies are poorly defined and controversial. Rather than using an arterial pH cutoff, we recommend using sodium bicarbonate given evidence of impaired buffering capacity based on a serum bicarbonate

threshold concentration of less than 5 mEq/L. Based on case reports, hemodialysis may be effective in improving acid–base status and clinical outcome in patients with significant metabolic acidosis with hyperlactatemia.53,69,73 In some of these cases, metformin concentrations were measured and remained abnormally high after dialysis. Clinical improvement despite inadequate removal of metformin may be related to correction of acid–base status.

SUMMARY• Numerous xenobiotics and medical conditions may cause hypoglycemia.

• Hypoglycemia is the predominant adverse effect related to therapeutic use and overdose of many of the drugs used for treatment of diabetes mellitus.

• Various clinical manifestations, particularly neurologic, may occur and can be confused with conditions such as ethanol intoxication, psychosis, epilepsy, and cerebrovascular accidents.

• The potential for delayed and prolonged hypoglycemia must be recognized in overdose situations.

• Although several treatment options exist, rapid intravenous administration ofdextrose is the most important measure.

• Octreotide is useful for patients with recurrent hypoglycemia following sulfonylurea or meglitinide overdose.

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