R E V I E W
`
`Oral Agents for the Treatment of Type 2
`Diabetes Mellitus: Pharmacology, Toxicity,
`and Treatment
`
`Richard A. Harrigan, MD
`Michelle S. Nathan, MD
`Philip Beattie, MD
`
`From the Division of Emergency
`Medicine, Temple University Hospital,
`Philadelphia, PA.
`
`Received for publication
`December 9, 1999. Revisions received
`October 17, 2000, and
`December 15, 2000. Accepted for
`publication January 2, 2001.
`
`Reprints not available from the
`authors.
`
`Address for correspondence:
`Richard A. Harrigan, MD, Division of
`Emergency Medicine, Temple Univer-
`sity Hospital, Jones Hall, 10th Floor,
`Park Avenue and Ontario Street,
`Philadelphia, PA 19140;
`215-707-5034,
`fax 215-707-3494;
`E-mail rharriga@nimbus.temple.edu.
`
`Copyright © 2001 by the American
`College of Emergency Physicians.
`
`0196-0644/2001/$35.00 + 0
`47/1/114314
`doi:10.1067/mem.2001.114314
`
`Currently available oral agents for the treatment of type 2 dia-
`betes mellitus include a variety of compounds from 5 different
`pharmacologic classes with differing mechanisms of action,
`adverse effect profiles, and toxicities. The oral antidiabetic drugs
`can be classified as either hypoglycemic agents (sulfonylureas
`and benzoic acid derivatives) or antihyperglycemic agents (bi-
`guanides, α-glucosidase inhibitors, and thiazolidinediones). In
`this review, a brief discussion of the pharmacology of these
`agents is followed by an examination of the adverse effects,
`drug-drug interactions, and toxicities. Finally, treatment of
`sulfonylurea-induced hypoglycemia is described, including general
`supportive care and the management of pediatric sulfonylurea
`ingestions. The adjunctive roles of glucagon, diazoxide, and
`octreotide for refractory hypoglycemia are also discussed.
`
`[Harrigan RA, Nathan MS, Beattie P. Oral agents for the
`treatment of type 2 diabetes mellitus: pharmacology, toxicity,
`and treatment. Ann Emerg Med. July 2001;38:68-78.]
`
`I N T R O D U C T I O N
`
`The overproduction and underutilization of glucose
`characterizes type 2 diabetes mellitus (DM).1-3 Diet and
`exercise remain the cornerstones of treatment, although
`pharmacologic therapy is frequently necessary.3-5 Inade-
`quate glycemic control with a single agent should prompt
`the addition of a second oral agent or bedtime insulin.
`Persistent unsatisfactory control can lead to (1) continu-
`ation of the 2 oral agents with addition of bedtime insulin,
`(2) conversion to a mixed-split insulin regimen, or (3)
`addition of a third oral agent.6
`Current oral treatment options can be subdivided into
`the hypoglycemic drugs (sulfonylureas and benzoic acid
`derivatives) and antihyperglycemic drugs (biguanides,
`α-glucosidase inhibitors, and thiazolidinediones). This
`review of oral antidiabetic agents focuses on pharmacol-
`ogy, adverse effects, drug interactions, and toxicity. A dis-
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`O R A L A G E N T S F O R T Y P E 2 D I A B E T E S M E L L I T U S
`Harrigan, Nathan & Beattie
`
`cussion of the treatment of hypoglycemia resulting from
`oral antidiabetic agents follows.
`
`S U L F O N Y L U R E A S
`
`All sulfonylureas increase insulin secretion and enhance
`insulin activity. Second- and third-generation sulfonyl-
`ureas more readily penetrate cell membranes than do
`first-generation agents because of enhanced lipid solubil-
`ity; they also feature a greater selective binding capacity.7,8
`Sulfonylureas stimulate insulin release from the pancreatic
`β cells, displaying a more pronounced action in the pres-
`ence of glucose.9 They do so by inhibiting an adenosine
`triphosphate–dependent potassium channel, which re-
`sults in cell membrane depolarization and leads to calcium
`influx and release of stored insulin from secretory granules
`within the cell.3,10 They also decrease hepatic insulin
`clearance, resulting in increased serum insulin concen-
`trations.11-15 Increased circulating insulin levels then
`feed back to suppress hepatic glucose production.6 In
`vitro data suggest sulfonylureas indirectly decrease peri-
`pheral insulin resistance and enhance its action,11 although
`the clinical significance of these effects is questionable.15
`In those patients with type 2 DM who do respond to
`sulfonylureas, secondary treatment failure may ensue.
`The cause is multifactorial, including patient factors
`(noncompliance and weight gain), therapy issues (desen-
`sitized β cells caused by long-term therapy and other
`drug effects on insulin homeostasis), and features of the
`disease itself (escalating insulin resistance and increased
`insulin deficiency).6,16
`Pharmacokinetic data for the sulfonylureas are pre-
`sented in Table 1.6,17-21 The prolonged duration of action,
`
`hepatic metabolism, and renal excretion of active parent
`compound or metabolite (with selected agents) should be
`noted. All have implications with regard to sulfonylurea-
`related hypoglycemia.
`The principal toxicity associated with sulfonylureas is
`hypoglycemia. Overdoses generally occur as intentional
`attempts or accidental ingestions, and most accidental
`ingestions involve children. However, there have been
`several cases of drug-dispensing errors in which nondia-
`betic patients received sulfonylureas.22 In addition, drug
`interactions can cause profound hypoglycemia (Table
`2).23-33 Factors that increase the risk of having a hypo-
`glycemic episode include advanced age, poor nutrition,
`alcohol consumption, renal and hepatic disease, and
`polypharmacy.2,34
`Clinically, time to peak and duration of action are the
`most important considerations when anticipating hypo-
`glycemia after sulfonylurea overdose (Table 1). Adverse
`outcomes were rare in case series of pediatric accidental
`ingestions,35-37 and pediatric fatalities from accidental
`ingestions have not been reported.38 The most recent
`annual report from the American Association of Poison
`Control Centers Toxic Surveillance System listed 5,351
`reported exposures to oral hypoglycemic agents (not lim-
`ited to sulfonylureas), resulting in 3,349 cases of treatment
`in a health care facility and only 9 fatalities.39 However, in
`a study of 101 intentional ingestions of sulfonylureas in
`adults, 5 deaths and 5 cases of permanent neurologic
`deficit occurred.40
`Of the sulfonylureas, chlorpropamide, glyburide, and
`the long-acting glipizide (Glucatrol XL) are the most likely
`to cause prolonged hypoglycemia.16,41 The duration of
`action for all the sulfonylureas will be increased in the
`
`Table 1.
`Pharmacokinetics of the sulfonylureas.6,17-21
`
`Generation
`
`Generic
`Name
`
`Trade Name
`
`Time to Peak
`(h)
`
`Half-life
`(h)
`
`Duration of Action
`(h)
`
`Metabolism
`
`Renal Excretion of
`Active Metabolite
`
`Diabinase
`Chlorpropamide
`First
`Orinase
`Tolbutamide
`First
`Dymelor
`Acetohexamide
`First
`Tolinase
`Tolazamide
`First
`Glucatrol
`Glipizide
`Second
`Glucotrol XL
`Glipizide
`Second
`Micronase, DiaBeta, Glynase
`Glyburide
`Second
`Amaryl
`Glimepiride
`Third
`*Parent drug undergoes prolonged excretion.
`
`2–7
`3–4
`3
`4–6
`1–3
`6–12
`2–6
`2–3
`
`36
`3–28
`4–6
`4–8
`7
`7
`10
`5–9
`
`60
`6–12
`12–18
`12–24
`12–24
`24
`12–24
`16–24
`
`Hepatic
`Hepatic
`Hepatic
`Hepatic
`Hepatic
`Hepatic
`Hepatic
`Hepatic
`
`Yes*
`Insignificant
`Yes
`No
`No
`No
`Yes
`Yes (?)
`
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`O R A L A G E N T S F O R T Y P E 2 D I A B E T E S M E L L I T U S
`Harrigan, Nathan & Beattie
`
`presence of hepatic and, in some cases, renal disease and
`is especially a concern in the elderly.2,34,41 The frail elderly,
`those taking multiple medications, and those frequently
`hospitalized have been found to be at increased risk for
`sulfonylurea-related hypoglycemia.42 A recent prospec-
`tive study43 of well patients with type 2 DM subjected to a
`23-hour fast while taking glyburide or glipizide found
`that none of the 58 patients had hypoglycemia during the
`fast. Laboratory data suggested an enhanced counterreg-
`ulatory hormonal response was responsible for the pre-
`vention of hypoglycemia. It should be noted that severe
`concurrent medical problems (cardiovascular, gastroin-
`testinal, renal, or hepatic problems), substance abuse,
`and concurrent medications that interfere with glucose
`homeostasis were criteria for exclusion, and many of the
`patients had poorly controlled blood glucose levels at the
`time of the study.43 Thus, generalization to the emergency
`department population is limited. A recent retrospective
`study looking at only patients with end-stage renal disease
`found glyburide to be the culprit sulfonylurea in all
`patients who had prolonged sulfonylurea-induced hypo-
`glycemia.44 Excretion of active metabolite in the urine
`makes glyburide a less desirable therapeutic option in
`patients with severe renal insufficiency. Recently, pro-
`longed hypoglycemia after chlorpropamide ingestion (27
`days after suicidal ingestion of 5 to 10 g) was reported,45
`again illustrating the toxic potential of long-acting sul-
`fonylureas with active metabolites.
`Beyond hypoglycemia, several other toxicologic issues
`should be mentioned with regard to the sulfonylureas.
`
`Chlorpropamide deserves special attention because of its
`association with symptomatic hyponatremia, regardless
`of dosage. It has been shown to induce inappropriate
`antidiuretic hormone secretion, featuring serum hypona-
`tremia and hypo-osmolality with an elevated excretion of
`urinary sodium.46 The incidence of chlorpropamide-
`induced hyponatremia is increased in elderly patients
`and in those receiving thiazide diuretics.47 There have
`also been a few reports of hyponatremia associated with
`tolbutamide.16 Chlorpropamide can also induce choles-
`tatic jaundice, which can occur at higher doses (>500
`mg/d) but resolves rapidly with drug discontinuation.
`Agranulocytosis, thrombocytopenia, and anemia have all
`been associated with chlorpropamide use.48,49
`Glipizide undergoes some enterohepatic circulation,
`possibly leading to a prolonged duration of action in
`patients with liver failure, yet it appears safer than gly-
`buride in renal insufficiency.44 Adverse effects include
`gastrointestinal discomfort and abnormal liver function
`test results.3 Glyburide has the highest incidence of hypo-
`glycemia of the second- and third-generation sulfonyl-
`ureas, possibly because of the presence of its active
`metabolite.16,30,41 Hepatic breakdown results in multi-
`ple metabolites, one of which is active. All metabolites are
`renally excreted, leading to potentiation of hypoglycemic
`effects in patients with kidney dysfunction.3,15,44,48,49
`Glimepiride, the newest sulfonylurea, has few clinical
`differences when compared with earlier sulfonylureas. It
`is completely metabolized by the liver, and one of its
`metabolites is active, although the clinical relevance of
`
`Table 2.
`Drug-drug interactions: first- and second-generation sulfonylureas.
`
`Sulfonylurea
`
`Chlorpropamide
`
`Tolbutamide
`
`Glipizide
`
`Glyburide
`
`Drug
`
`Mechanism
`
`Effect
`
`Reference No.
`
`Warfarin, chloramphenicol
`Probenicid, allopurinol
`Rifampin
`Digoxin
`Warfarin, chloramphenicol, sulfonamides
`Rifampin
`Salicylates, clofibrate
`Trimethoprim-sulfamethoxazole, miconazole
`Cholestyramine
`Rifampin
`H2 blockers
`H2 blockers
`Trimethoprim-sulfamethoxazole
`Ciprofloxacin
`Rifampin
`
`↓ Hepatic metabolism
`↓ Renal tubular secretion
`↑ Hepatic metabolism
`↓ Hepatic metabolism
`↑ Hepatic metabolism
`Displace from proteins
`Inconsistent/unclear
`↓ Absorption
`↑ Hepatic metabolism
`↓ Hepatic metabolism
`↓ Hepatic metabolism
`Inconsistent/unclear
`↓ Hepatic metabolism
`↑ Hepatic metabolism
`
`↑ Hypoglycemia
`↑ Hypoglycemia
`↓ Hypoglycemia
`↑ Digoxin level
`↑ Hypoglycemia
`↓ Hypoglycemia
`↑ Hypoglycemia
`↑ Hypoglycemia
`↓ Hypoglycemia
`↓ Hypoglycemia
`↑ Hypoglycemia
`↑ Hypoglycemia
`↑ Hypoglycemia
`↑ Hypoglycemia
`↓ Hypoglycemia
`
`23, 24
`25
`26
`27
`24, 28, 29
`26
`30, 31
`30, 31
`30, 31
`30, 31
`30, 31
`31
`31
`32
`31, 33
`
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`
`this is unknown. Metabolites are eliminated in the feces
`and urine.8 Although there are conflicting data, hypo-
`glycemia is either similar to or less than that which is seen
`with the second-generation agents.8 The most common
`adverse effects are headache and dizziness. Hyponatremia
`is a rare complication, as are leukopenia, thrombocytope-
`nia, and anemia. Thrombocytopenic purpura associated
`with glimepiride was recently reported.50 Drug interac-
`tions are similar to those of the second-generation sul-
`fonylureas; however, cimetidine and ranitidine do not
`alter the effect of glimepiride. There is evidence that pro-
`pranolol increases glimepiride concentrations by about
`20%.8
`Other drugs may enhance or attenuate the hypo-
`glycemic effect of the sulfonylureas (Table 2). Enhance-
`ment of effect may result from competition for binding
`sites on plasma proteins, hepatic metabolic inhibition, or
`impairment of renal excretion.30,31 On the other hand,
`attenuation of the hypoglycemic effect of sulfonylureas
`may result from drug interactions, leading to a decrease in
`digestive absorption or induction of liver metabolism.30,31
`
`B I G U A N I D E S
`
`Three biguanides—metformin, phenformin, and
`buformin—have historically been used for the treatment
`of type 2 DM, but only metformin remains in wide use
`today.17 Phenformin was taken off the market in the
`United States and Europe in 1976 because of its associa-
`tion with lactic acidosis51-53; however, it is still rarely
`encountered in this country today because patients from
`overseas may still be using this agent.53 Metformin is
`
`indicated either as monotherapy or in combination with a
`sulfonylurea.17,54 Sulfonylureas and metformin cause a
`similar decrease in fasting blood glucose levels in diabetic
`subjects, but whereas the sulfonylureas generally cause
`weight gain, metformin does not.54,55
`Metformin decreases hepatic production and intestinal
`absorption of glucose in addition to decreasing the oxida-
`tion of fatty acids. Moreover, it increases insulin sensitivity,
`thereby decreasing the insulin resistance that is often a
`problem in patients with type 2 DM.17,54,56 It decreases
`the blood glucose level of diabetic patients but not that of
`nondiabetic patients.57 As such, it is an antihyperglycemic
`agent and not a hypoglycemic agent, as are the sulfonyl-
`ureas.17,54 Metformin undergoes virtually no hepatic
`metabolism and is 90% to 100% excreted by the kidneys.
`The pharmacokinetics (Table 3)6,17,54,55,58-65 differ from
`those of phenformin, which undergoes metabolism by
`the liver, is excreted in the bile and urine, and features
`some degree of protein binding and a larger volume of
`distribution.17,51,53,54,56-58
`Lactic acidosis is the most serious adverse effect linked
`to the biguanides, although the link is much stronger with
`phenformin than with metformin.17,34,51,52,54,56,66,67
`Phenformin was found to be associated with lactic acido-
`sis at a rate of approximately 66 cases per 100,000 patient-
`years, whereas the incidence with metformin is only about
`3 per 100,000 patient-years.54 The lactic acidosis is char-
`acterized as type B (aerobic lactic acidosis), which is
`attributable to enhanced metabolic production of lactate;
`this is in contradistinction to type A, which is caused by
`tissue hypoxia and thus termed anaerobic lactic acido-
`sis.51,53 Signs and symptoms are nonspecific, including
`
`Table 3.
`Pharmacokinetics of nonsulfonylurea antidiabetic agents: biguanides, α-glucosidase inhibitors, thiazolidinediones, and benzoic acid deriva-
`tives.
`
`Generic Name
`
`Trade
`Name
`
`Time to Peak
`(h)
`
`Half-life
`(h)
`
`Duration of
`Action
`
`Glucophage
`Metformin
`Precose
`Acarbose
`Glyset
`Miglitol
`Avandia
`Rosiglitazone
`Actos
`Pioglitazone
`Prandin
`Repaglinide
`*Parent drug excreted >90% unchanged in the urine.
`†Pharmacologic effect not dependent on systemic absorption.
`‡Fraction (2%) of drug absorbed is excreted unchanged in the urine.
`
`2–3
`1–2†
`2–3†
`1–2
`1–2
`1
`
`1–5
`2
`2
`3–4
`3–7
`1
`
`>3–4 wk
`4 h
`4 h
`>3–4 wk
`>3–4 wk
`4–6 h
`
`Metabolism
`
`Insignificant hepatic
`Intestinal
`Intestinal
`Hepatic
`Hepatic
`Hepatic
`
`Renal Excretion of
`Active Metabolite
`
`Reference
`No.
`
`Yes*
`Yes‡
`Yes
`No
`No
`No
`
`6, 54, 55
`6, 17, 58–61
`17, 61
`6, 62
`6, 63
`6, 64, 65
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`nausea, vomiting, diarrhea, somnolence, epigastric pain,
`anorexia, tachypnea, and lethargy. The pathogenesis of
`metformin-associated lactic acidosis is incompletely
`understood. It seems to occur only in certain settings:
`renal insufficiency, hepatic dysfunction, cardiovascular
`disease, severe infection, or alcoholism.17,54 This has led
`to the development of certain exclusion criteria for the
`use of metformin in the management of DM, which in-
`clude the following: (1) renal insufficiency (plasma crea-
`tinine level ≥1.5 mg/dL in male subjects or ≥1.4 mg/dL in
`female subjects); (2) cardiac or pulmonary insufficiency
`likely to result in decreased tissue perfusion or hypoxia;
`(3) history of lactic acidosis; (4) profound infection that
`might cause impaired tissue perfusion; (5) liver disease,
`including alcohol-related liver disease (as evidenced by
`abnormal liver-function tests); (6) alcohol abuse with
`binge pattern capable of causing acute liver toxicity; and
`(7) use of intravenous contrast agents.54 A report67 of a
`patient receiving metformin with normal renal function
`and no other exclusion criteria who had lactic acidosis
`revealed that, at the time of presentation with the syn-
`drome, he no longer had a creatinine level of less than 1.5
`mg/dL. Thus, physicians must be aware that although
`patients may meet criteria initially, conditions may develop
`that preclude the safe use of the drug.17,67 A recent report
`has shown that the rate of lactic acidosis in diabetic sub-
`jects not taking metformin is equivalent to that of diabetic
`subjects taking metformin, suggesting the conditions
`underlying lactic acidosis may be operative in diabetic
`subjects independent of metformin therapy.57 Lactic aci-
`dosis in patients taking metformin who have been given
`radiocontrast media seems to occur principally in those
`with underlying renal insufficiency, and thus the previ-
`ously recommended blanket exclusion of intravenous
`contrast administration to patients taking metformin has
`been questioned.68,69 A recent case series of patients with
`metformin-associated lactic acidosis demonstrated that
`arterial lactate levels and plasma metformin levels did not
`have prognostic significance with regard to mortality; fatal
`outcome instead seemed to be linked to other concomitant
`conditions (eg, hypoxia), resulting in elevated lactate lev-
`els.70
`Other adverse effects associated with metformin are
`largely gastrointestinal. Nausea, vomiting, diarrhea, ano-
`rexia, and abdominal discomfort are all well described;
`they are usually mild, dose related, and transiently seen at
`the initiation of therapy.34,54 Hypoglycemia is said to
`occur rarely with metformin monotherapy but may be
`seen with concomitant ethanol abuse.53,54,56,66 Malab-
`sorption of vitamin B12 and folate occurs with long-term
`
`treatment, although it usually does not lead to ane-
`mia.34,54,56 Recently, a case of metformin-induced
`hemolysis with jaundice was described, which occurred
`on rechallenge with the drug.71 No clinically important
`drug interactions are known to occur,56 although cimeti-
`dine reduces its renal clearance.72 Some authors have
`cautioned about the concomitant use of nonsteroidal
`anti-inflammatory drugs in diabetic subjects taking met-
`formin because of the propensity for nonsteroidal anti-
`inflammatory drugs to reduce the glomerular filtration
`rate and possibly cause deterioration of renal function,
`with resultant decreased clearance of metformin.73
`More cases of toxicity have been described with the
`therapeutic use of biguanides than in overdose. The clinical
`course is generally mild in cases of small ingestions.17,74
`Gastrointestinal symptoms, as described above, predomi-
`nate; hypoglycemia may rarely occur in the milieu of pro-
`longed fasting.17,53,74 Lactic acidosis may also occur in
`overdose. The onset may take several hours, and there-
`fore, in cases of serious ingestion, the patient should be
`observed for approximately 6 to 8 hours.17 Treatment is
`supportive and should include standard gastrointestinal
`decontamination. Metabolic acidosis, should it develop,
`should be treated with bicarbonate, although this should
`be done with caution because of the incumbent high
`sodium load (and issues of volume overload).75 The nearly
`nonexistent protein binding of the drug makes hemodial-
`ysis a possible treatment option in cases of massive inges-
`tion, especially if lactic acidosis occurs.54 Three cases of
`metformin overdose have been described recently, 2 of
`which were fatal.75 All 3 featured profound metabolic aci-
`dosis caused by lactate; the 2 fatal cases were refractory to
`treatment with sodium bicarbonate and ultimately veno-
`venous hemofiltration, whereas the other patient re-
`sponded. In both fatalities, refractory hypotension with
`low systemic vascular resistance precluded hemodialysis
`treatment. Both patients were hypothermic and hypo-
`glycemic, the latter condition being without any known
`coingestion of hypoglycemic agents. Two of the cases fea-
`tured large ingestions (ie, 50 g [nonfatal] and 35 g [fatal]),
`and the other fatality involved an indeterminate amount,
`suggesting that profound acidosis may be associated with
`massive ingestions.
`
`α - G L U C O S I D A S E I N H I B I T O R S
`There are 3 α-glucosidase inhibitors: acarbose was re-
`leased first, miglitol has just recently been marketed in the
`United States, and voglibose is not yet widely available.17
`Although they can be used as monotherapy for type 2 DM,
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`
`these antihyperglycemic drugs are frequently used in
`combination with the sulfonylureas or insulin.17,58-60
`These agents competitively and reversibly inhibit α-
`glucosidase, an intestinal brush border hydrolase enzyme.
`This leads to a postprandial decrease in carbohydrate
`absorption because complex dietary polysaccharides are
`not broken down into absorbable monosaccharides. As a
`result, there is a decrease in hyperinsulinism and in he-
`patic triglyceride synthesis. Lactose absorption is not
`affected because lactase is a β-galactosidase.17,58-60 The
`pills should be taken with the first bite of each meal.60
`The mechanism of action of the α-glucosidase inhibitors
`has implications for the treatment of hypoglycemia;
`should it develop, simple sucrose (table sugar) will not be
`effective. Glucose should be administered, if oral therapy
`is used, to raise the serum blood glucose.60
`Acarbose is poorly absorbed; its mechanism of action is
`dependent on its local effects, as is its side effect pro-
`file.17,58,60 Miglitol is rapidly and fully absorbed at low
`doses. Its antihyperglycemic mechanism of action is similar
`to that of acarbose; the implications of its systemic absorp-
`tion are unknown.17,61 Hypothetically, because miglitol is
`cleared by the kidney, its use in patients with significant
`renal impairment may lead to toxicity (Table 3).60,61
`As might be expected, the side effect profile of the α-
`glucosidase inhibitors is predominantly gastrointestinal
`because of their limited absorption. The undigested sug-
`ars may lead to bloating, flatulence, diarrhea, and abdom-
`inal pain. Side effects may decrease in 1 to 2 months, and
`gradual escalation from low to higher doses may attenu-
`ate the adverse effects.17,58-60 The gastrointestinal side
`effects may be additive with those of metformin. General
`contraindications to α-glucosidase inhibitor therapy
`include cirrhosis, inflammatory bowel disease, predispo-
`sition to bowel obstruction, and malabsorption syn-
`dromes.60 The α-glucosidase inhibitors are not known to
`cause hypoglycemia when used as monotherapy.17,60
`Acarbose appears to inhibit iron absorption, and
`although the clinical relevance appears to be negligible,
`mild anemia may occur.58,60
`Significant hepatic injury has been reported with
`chronic acarbose therapy.60,76-80 Not detected in clinical
`trials, the incidence appears to be low, unpredictable, and
`idiosyncratic, although real because it has occurred with
`rechallenge.59,78,79 Laboratory and histologic data do not
`reflect a hypersensitivity mechanism.78,79 It is recom-
`mended that transaminase levels be checked regularly in
`patients taking acarbose,78 and the emergency physician
`should be aware of the potential for hepatic toxicity in
`patients taking this agent.
`
`There are no published reports of overdose or severe
`toxicity with the α-glucosidase inhibitors.17,58 Their
`localized mechanism of action makes systemic toxicity
`unlikely; it seems reasonable that the abdominal side
`effects seen in therapeutic use could be expected in over-
`dose. It may be prudent to perform liver function tests in
`cases of massive acarbose overdose.17
`
`T H I A Z O L I D I N E D I O N E S
`
`There are 2 drugs from this class currently on the market
`in the United States: rosiglitazone and pioglitazone.
`Troglitazone, the first of the thiazolidinediones on the
`market, received much recent public and professional
`scrutiny because of a link with serious, and at times fatal,
`hepatic dysfunction.81-89 It was withdrawn from the mar-
`ket in the United States early in 2000.
`The thiazolidinediones enhance the effect of insulin in
`skeletal muscle, adipose, and hepatic tissues without
`increasing pancreatic secretion of insulin. They seem to
`bind to peroxisomal proliferator-activated receptors,
`changing insulin-dependent gene expression in the liver;
`the exact mechanism remains elusive. The thiazolidine-
`diones decrease blood glucose levels in diabetic subjects,
`variably lower triglycerides, and have a mild, clinically
`insignificant, antihypertensive effect caused by decreasing
`insulin levels.81
`Rosiglitazone and pioglitazone are rapidly absorbed.
`Both agents are greater than 99% protein bound. They
`undergo extensive hepatic metabolism, with metabolites
`being excreted in the urine and feces (Table 3). They are
`not recommended for use in patients with hepatic disease
`but require no dosage adjustment in individuals with renal
`impairment. Both drugs can be taken without regard to
`meals.62,63
`The thiazolidinediones are generally very well toler-
`ated.62,63,81 Both rosiglitazone and pioglitazone may
`reinstate ovulation in premenopausal women who have
`not been ovulating. They also should be used with cau-
`tion in patients with congestive heart failure because of a
`propensity to increase the circulating plasma volume,
`which may lead to edema.62,63 Ethinyl estradiol/
`norethindrone plasma levels are reportedly decreased by
`pioglitazone, leading to a loss of contraceptive effect.
`Ketoconazole may inhibit the metabolism of pioglitazone,
`thereby increasing the effect of the latter.63
`The withdrawal of troglitazone as a result of hepatic
`toxicity is concerning because of the structural similarity
`among the thiazolidinediones. To date, although there are
`no reports of serious hepatotoxicity with pioglitazone,
`
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`O R A L A G E N T S F O R T Y P E 2 D I A B E T E S M E L L I T U S
`Harrigan, Nathan & Beattie
`
`there have been 2 reported cases of hepatotoxicity
`attributed to rosiglitazone.90,91 One case involved hepa-
`tocellular injury that rapidly reversed on cessation of the
`drug,90 whereas the other patient manifested liver failure
`with a period of profound metabolic acidosis and coma,
`which gradually resolved.91 Neither patient underwent a
`liver biopsy. The manufacturers of rosiglitazone vehe-
`mently disagreed with the attribution of liver failure to
`the drug in the latter case, stating that their review of the
`case suggested ischemic hepatitis to be the culprit.92 The
`manufacturers of both pioglitazone and rosiglitazone rec-
`ommend monitoring of alanine aminotransferase levels
`in patients taking these agents, including baseline levels,
`followed by levels at 2-month intervals for the first year
`and periodic checks thereafter.62,63
`
`B E N Z O I C A C I D D E R I V A T I V E S
`
`Repaglinide is the first nonsulfonylurea oral hypoglycemic
`agent on the market in the United States.17,64 It is indicated
`either as monotherapy or in combination with metformin;
`clinical and toxicologic experience with this agent is lim-
`ited to date.64,65
`Repaglinide binds to the adenosine triphosphate–
`sensitive potassium channels on pancreatic β cells at a re-
`ceptor different from that of the sulfonylureas. However, it
`decreases insulin levels, whereas the sulfonylureas do not,
`and an extrapancreatic effect leading to increased insulin
`sensitivity has been postulated.64,65 It is rapidly absorbed
`(within 1 hour) and quickly metabolized by the liver, with
`an apparent half-life of approximately 1 hour, and then
`excreted primarily in the bile, with only 6% being excreted
`by the kidneys (Table 3). Protein binding is greater than
`98%. Absorption is not affected by food. Its pharmacoki-
`netics require dosing to be synchronized with meals
`(within 30 minutes of the meal is optimal), leading to a
`profound decrease in postprandial hyperglycemia.64,65,93
`Comparative clinical trials have shown that mild-to-
`moderate hypoglycemia occurred in approximately 16%
`of patients taking repaglinide, as opposed to 20% of those
`taking glyburide and 19% of those taking glipizide. The
`pharmacokinetics of the drug should decrease the fre-
`quency, severity, and duration of the hypoglycemia, how-
`ever. Downregulation of the β cells in the pancreas, which
`leads to secondary drug failure, is also expected to be less
`of a problem with repaglinide than with the sulfonyl-
`ureas. Drug interactions have not yet been reported; it is
`anticipated that CYP3A4 inhibitors (eg, erythromycin)
`and CYP3A4 inducers (eg, rifampin) may increase and
`decrease the effects of the drug, respectively. It should be
`
`used cautiously in patients with liver dysfunction but
`appears to be safe in patients with renal insufficiency on
`the basis of limited data.64,65
`There have been no reports of repaglinide overdose
`and toxicity. It is expected that hypoglycemia would
`occur in cases of overdose, as with the sulfonylureas.17
`
`T R E A T M E N T O F H Y P O G L Y C E M I A R E S U L T I N G
`F R O M O R A L A N T I D I A B E T I C A G E N T S
`
`Hypoglycemia is a well-known occurrence after both
`accidental and intentional ingestion of sulfonylureas, as
`well as in patients taking these drugs as prescribed for
`type 2 DM. It also may arise in patients with DM because
`of impaired hepatic metabolism or renal excretion,
`depending on the degree of impairment and the clearance
`characteristics of the drug (Table 1). Hypoglycemia is not
`expected to be encountered in patients treated solely with
`metformin or a thiazolidinedione, but the addition of
`these antihyperglycemic agents to a regimen that includes
`sulfonylureas may precipitate hypoglycemia. Repaglinide
`has the capacity to induce hypoglycemia, yet taken thera-
`peutically, it should not cause prolonged hypoglycemia
`because of its pharmacokinetics, and hypoglycemia
`should be avoided altogether if the dose corresponding to
`a missed meal is omitted.93
`Thus, a discussion of the treatment of hypoglycemia
`caused by oral antidiabetic agents should focus on the
`treatment of hypoglycemia as a result of sulfonylureas.
`Several issues will be highlighted below: (1) general sup-
`portive treatment; (2) recommendations for periods of
`observation after sulfonylurea ingestion in the pediatric
`population; and (3) pharmacotherapeutic adjuncts to the
`administration of glucose in cases of refractory hypo-
`glycemia.
`In all cases (eg, overdose, unexpected hypoglycemia in
`adults with DM, and symptomatic pediatric ingestions),
`the airway should be secured and hemodynamic stability
`verified while a rapid bedside estimate of serum glucose is
`obtained. If the patient is hypoglycemic, glucose should
`be administered. Activated charcoal is expected to bind
`sulfonylureas and can be reasonably administered in sus-
`pected cases of toxicity, although the efficacy of this ther-
`apy specific to sulfonylurea overdose is unclear. Random-
`ized controlled trials exist that demonstrate substantial
`reduction in the absorption of chlorpropamide and glip-
`izide by activated charcoal administered to human volun-
`teers.94 A dose of 1 to 2 g/k