CHA PTE R 3 8

Drugs that Alter

Glucose Regulation
Vivek K. Moitra

Diabetes Mellitus and cardiac muscle. Production of ketones can lead to

­ketoacidosis; urinary excretion of ketones contributes to
According to recent recommendations by the American the depletion of electrolytes, especially potassium. Hypo-
Diabetes Association and the World Health Organization, kalemia, however, may not be apparent, because intracel-
diabetes mellitus is classified by the underlying disease lular potassium ions are exchanged for extracellular ions
etiology (i.e., type 1 vs. type 2) rather than by age-of-onset to compensate for the acidosis.
(i.e., juvenile-onset vs. adult-onset diabetes) or treatment Low plasma concentrations of insulin, although inad-
modality (i.e., insulin-dependent vs. non–insulin-depen- equate to prevent hyperglycemia, may block lipolysis. This
dent diabetes).1 The insulin deficiency in type 1 diabetes differential effect of insulin explains why hyperglycemia
is the result of autoimmune-mediated destruction of pan- can exist without the presence of ketone bodies. Ketosis
creatic b cells. Patients depend on exogenous insulin to can be reliably prevented by continuously providing all
regulate metabolism. Onset of type 1 diabetes is at a youn- diabetic patients with glucose and insulin.3 Prevention is
ger age than onset of type 2 d iabetes, and sensitivity to uniquely important in the perioperative period when nu-
insulin is normal. Lack of insulin may precipitate diabetic tritional intake is altered.
ketoacidosis, a c omplex and potentially life-threatening Hyperglycemia impairs vasodilation and induces a
metabolic derangement. In contrast, the peripheral insulin chronic proinflammatory, prothrombotic, and proathero-
resistance of type 2 diabetes is often coupled with a failure genic state leading to vascular complications.4 Although
to secrete insulin because of pancreatic b cell dysfunction. all tissues are affected, of greatest relevance for anesthesia
Oral hypoglycemic drugs are alternatives to exogenous are atherosclerotic vascular, renal, and nervous system ef-
administration of insulin to patients with type 2 diabetes. fects with peripheral vascular disease, renal insufficiency,
The vast majority of cases of diabetes are either type 1 or and cerebrovascular disease.
type 2 in an approximate ratio of 1:9. Gestation, exocrine The goals of therapy for patients with diabetes mellitus
pancreas disease, medications, endocrinopathies, genetic include preventing the adverse consequences of hypoglyce-
defects in insulin action and b cell function, infections, mia and hyperglycemia, avoiding weight gain, and reducing
and uncommon immune-mediated disorders also cause microvascular and macrovascular complications. Symp-
diabetes2 (Table 38-1). toms often resolve when blood glucose levels are less than
Without sufficient insulin, transport of glucose across 200 mg/dL. Long-term metabolic control of diabetes is best
certain cell membranes slows markedly to cause hyper- monitored by measurement of glycosylated hemoglobin
glycemia. The formation of glucose from protein accounts (HbA1c), which reflects glucose control over the previous
for the discovery that glucose in urine may exceed oral 2 to 3 months. In general, HbA1c values less than 6.0% to
intake. Much of the protein used for glucose formation 7.0% are associated with fewer microvascular complica-
comes from skeletal muscles; glucose loss may manifest tions. Therapy choices consider compliance, age, comorbid-
in extreme cases as skeletal muscle wasting. Elevations in ities, and impact on organ function (heart, kidney, liver).5
blood glucose levels and hypoinsulinemia cause diabetic
myopathy via muscle proteolysis. Increased free fatty acid
concentrations in the plasma of diabetic patients show in- Insulin
hibition of the lipase enzyme system so that mobilization
of fatty acids proceeds unopposed. The insulin-­deficient Because patients with type 1 diabetes mellitus do not pro-
liver is likely to use fatty acids to produce ketones, duce insulin, they require insulin therapy to survive. Insu-
which can serve as an energy source for skeletal muscles lin is prescribed for patients with type 2 diabetes mellitus

748

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 Chapter 38  •  Drugs that Alter Glucose Regulation 749

can bind and inactivate insulin, but this effect is of minor

Table 38-1 quantitative significance. Despite rapid clearance from
Etiologic Classification of Diabetes plasma after IV i njection of insulin, the pharmacologic
Mellitus effect lasts for 30 to 60 minutes because insulin is tightly
bound to tissue receptors. Insulin administered subcuta-
Type 1 diabetes mellitus (absolute insulin deficiency neously releases slowly into the circulation to produce a
from pancreatic b cell destruction) sustained biologic effect.
Type 2 diabetes mellitus (insulin resistance vs. insulin Insulin is secreted into the portal venous system in the
defi iency) basal state at a rate of approximately 1 unit per hour. After
Gestational diabetes mellitus food intake, the rate of insulin secretion increases to 5-
Exocrine pancreas disease (pancreatitis, pancreatectomy, to 10-fold. The total daily secretion of insulin is approxi-
cystic fibrosis, hemochromatosis) mately 40 u nits. The sympathetic and parasympathetic
Drug-induced (glucocorticoids, thiazides, thyroid hor- nervous systems innervate the insulin-producing islet
mone, b-adrenergic agonists) cells to influence the basal rate of hormone secretion as
Endocrinopathies (acromegaly, Cushing syndrome, well as the response to stress. For example, a-­adrenergic
glucagonoma) stimulation decreases and b-adrenergic or parasympa-
Genetic defects in pancreatic b cell function thetic nervous system stimulation increases the basal
Genetic defects in insulin action (resistance) secretion of insulin. The insulin response to glucose is
Infections (congenital rubella, cytomegalovirus) greater after oral ingestion than after IV infusion because
Uncommon immune-mediated diabetes (“stiff man” glucose-dependent insulinotropic polypeptide is released
syndrome, anti-insulin receptor antibodies) after oral ingestion of glucose and the pancreatic b cell
response is augmented. To gain adequate glycemic control
in type 1 diabetes, at least two daily subcutaneous injec-
if treatment with oral glucose regulators fails. In these tions of intermediate- or long-acting insulin combined
patients, pancreatic b cells have been destroyed or auto- with rapid-acting insulin are nearly always required.
antibodies have developed (see Chapter 37 f or insulin’s
mechanism of action). Insulin therapy mirrors the nor-
mal pattern of insulin secretion (pulsatile secretion that Insulin Preparations and Delivery
occurs under basal conditions and in response to meals) Human insulin manufactured using recombinant DNA
with basal supplementation and by short-acting insulin technology has replaced insulin extracted from beef and
taken before food absorption. Insulin receptors become pork pancreas. Allergy or immunoresistance to animal
fully saturated with low concentrations of insulin. For insulins is no longer a serious problem. In rare instances
example, continuous infusion of insulin, 1 to 2 units per of local allergy to human insulin, pure porcine insulin or
hour, has the same or even greater pharmacologic effect lispro insulin is substituted. The basic principle of replace-
than a single larger intravenous (IV) dose that is cleared ment is to provide a slow, long-acting, continuous supply
rapidly from the circulation. Large doses of insulin, how- of insulin (neutral protamine Hagedorn [NPH] insulin,
ever, will last longer and exert a g reater net effect than insulin glargine, insulin detemir, or insulin degludec)
small doses. The number of insulin receptors seems to be that mimics the nocturnal and interprandial basal secre-
inversely related to the plasma concentration of insulin, tion of normal pancreatic b cells.6 A rapid and relatively
which reflect the ability of insulin to regulate the popula- short-acting form of insulin (insulin aspart, lispro, or glu-
tion of its receptors. Obesity and type 1 diabetes mellitus lisine) delivered before meals mimics the normal meal-­
appear to be associated with fewer insulin receptors. stimulated (prandial) release of insulin.
A number of insulin preparations for subcutaneous
administration are available (Table 38-2).7 The pharma-
Pharmacokinetics cokinetics of these insulins vary from individual to indi-
The elimination half-time of IV i nsulin is 5 t o 10 m in- vidual and even within the same individual from day to
utes in both healthy and diabetic patients. Insulin is me- day. Rates of insulin absorption from subcutaneous sites
tabolized in the kidneys and liver by a proteolytic enzyme. differ with the injection site (absorption from abdominal
Approximately 50% o f the insulin that reaches the liver sites is least variable), depth and angle of injection, ambi-
through its portal vein is metabolized in a single passage. ent temperature, and exercise of an injected extremity.
Nevertheless, renal dysfunction alters the disappearance Commercially prepared insulin is bioassayed, and its
rate of circulating insulin to a g reater extent than does physiologic activity (potency), based on the ability to de-
hepatic disease. Indeed, unexpected prolonged effects of crease blood glucose concentration, is expressed in units.
insulin are found in patients with renal disease, reflecting The potency of insulin is 22 t o 26 U/mg. Insulin U-100
impairment of both its metabolism and excretion by the (100  U/mL) is the most commonly used commercial
kidneys. Peripheral tissues such as skeletal muscles and fat preparation. The total daily exogenous dose of insulin

Shafer_Ch38.indd 749 10/24/14 11:24 PM

 750 Part VII  •  Endocrine System

Table 38-2
Classification of Insulin Preparations
Hours after Subcutaneous Administration
Insulin Preparation Onset Peak Duration (h)
Very rapid–acting
Lispro 5–15 min 45–75 min 2–4
Insulin aspart 5–15 min 45–75 min 2–4
Glulisine 5–15 min 45–75 min 2–4
Rapid-acting
Regular 30 min 2–4 h 6–8
Intermediate-acting
NPH 2h 4–12 h 18–28
Long-acting
Detemir 2h 3–9 h 6–24
Glargine 1.5 h None 20–.24
Ultra long-acting
Degludec 2h None .40
NPH, neutral protamine Hagedorn.

for treatment of type 1 diabetes mellitus is usually in the i­ njected just before eating provides a postprandial plasma
range of 0.5 to 1 U/kg/day. This insulin requirement, how- insulin concentration profile similar to that of normal insu-
ever, may be increased dramatically by stress associated lin secretion. An important benefit of lispro is a decrease in
with sepsis or trauma. postprandial hyperglycemia and less risk of hypoglycemia,
Continuous subcutaneous insulin infusion (CSII) which may follow injection of regular insulin. Loss of the
through an external pump delivers basal insulin (0.01 to late action of regular insulin, however, may result in recur-
0.015 U/kg/hour) and bolus doses before meals. With this rent hyperglycemia before the next meal. In patients treated
system, nocturnal versus daytime basal requirements can with lispro, HbA1c may not decrease unless the doses of
be accommodated, infusions can be altered during exer- basal insulin (NPH, detemir, or glargine) are increased.
cise, and doses can be calculated via algorithms of pre-
vious glucose values and insulin delivery. Short-acting Insulin Aspart and Glulisine
insulin (regular) and ultra rapid–acting insulins (lispro, Insulin aspart and glulisine are synthetic rapid-acting an-
aspart, and glulisine) are the only preparations used for alogues with a profile of action and therapeutic benefits
CSII delivery pumps. similar to those of lispro.

Lispro Regular Insulin (Crystalline Zinc

Lispro is a short-acting insulin analogue that more closely Insulin)
parallels physiologic insulin secretion and needs. A feature Regular insulin is a fast-acting preparation and is the only
of natural or synthetic human insulin is that six molecules form of insulin that can be administered IV as well as sub-
associate with a zinc molecule to form hexamers. Insulin cutaneously. This form can be mixed in the same syringe
hexamers must dissociate to monomers before absorp- with other insulin preparations if the pH of the solutions
tion from subcutaneous injection sites. This feature is the is similar.
reason that crystalline zinc insulin (regular insulin) has a Administration of regular insulin is preferred for treat-
peak action 2 to 4 hours after its subcutaneous injection. ing the abrupt onset of hyperglycemia or the appearance
It must be administered 30 to 60 minutes before eating to of ketoacidosis. In the perioperative period, regular insu-
eff ctively limit postprandial hyperglycemia. By exchang- lin is administered as a single IV injection (1 to 5 units) or
ing lysine and proline at positions 28 and 29 of the insulin as a continuous infusion (0.5 to 2.0 units per hour) to treat
B chain, hexamer formation is prevented and the mono- metabolic derangements associated with diabetes mellitus.
mer is rapidly absorbed from the injection site. Therefore,
lispro insulin injected subcutaneously begins to act within Neutral Protamine Hagedorn
15 minutes, the peak effect is reached in 45 to 75 minutes, NPH is an intermediate-acting preparation whose ab-
and the duration of action is only 2 t o 4 h ours. Lispro sorption from its subcutaneous injection site is delayed

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 Chapter 38  •  Drugs that Alter Glucose Regulation 751

because the insulin is conjugated with protamine. The ac- Allergic Reactions
ronym NPH designates a neutral solution (N), protamine Use of human insulin preparations has eliminated the
(P), and origin in Hagedorn’s (H) laboratory.8 This insulin problem of systemic allergic reactions that could result
preparation contains 0.005 mg protamine/U of insulin. from administration of animal-derived insulins. Local
Glargine, Detemir, Degludec allergic reactions to insulin are approximately 10 t imes
more frequent than systemic allergic reactions. Local al-
Glargine, detemir, and degludec are long-acting insu- lergic reactions are characterized by an erythematous
lin analogues for basal insulin replacement. Compared indurated area that develops at the site of insulin injec-
to NPH insulin, these long-acting insulins have a l ater tion. The cause of local allergic reactions is likely to be
onset of action and less pronounced peaks. Glargine or noninsulin materials in the insulin preparation. Chronic
detemir can be administered as a single bedtime injection exposure to low doses of protamine in NPH insulin may
to provide basal insulin for 24 hours with less nocturnal stimulate the production of antibodies against protamine.
hypoglycemia.9 Unlike glargine and detemir, degludec can Patients remain asymptomatic until a large dose of prot-
be mixed with rapid-acting insulins. Degludec is not ap- amine is administered IV to antagonize the anticoagulant
proved for use in the United States. effects of heparin. Indeed, patients with diabetes who are
treated with NPH insulin have had allergic reactions to
Side Effects protamine.11 Yet allergic reactions to protamine are not
found more in patients treated with NPH insulin than in
Side effects of treatment with insulin may manifest as nondiabetics.12
(a) hypoglycemia, (b) allergic reactions, (c) lipodystrophy,
(d) insulin resistance, or (e) drug interactions. Lipodystrophy
Hypoglycemia Lipodystrophy results when fat atrophies at the site of
subcutaneous injection of insulin. This side effect is min-
The most serious side effect of insulin therapy is hypo- imized by frequently changing the site used for injection
glycemia. Patients are vulnerable to hypoglycemia if they of insulin.
receive exogenous insulin in the absence of carbohy-
drate intake, as during a p erioperative period, especially Insulin Resistance
before surgery. The fi st symptoms of hypoglycemia are Patients requiring greater than 100 units of exogenous in-
the compensatory effects of increased epinephrine secre- sulin daily are in a s tate of insulin resistance. Even this
tion: diaphoresis, tachycardia, and hypertension. Rebound value is high, because insulin requirements for pancre-
hyperglycemia caused by sympathetic nervous system ac- atectomized adults are often as low as 30 u nits. The use
tivity in response to hypoglycemia (Somogyi effect) may of human insulins has eliminated the problem of im-
mask the correct diagnosis. Symptoms of hypoglycemia munoresistance that could accompany administration of
involving the central nervous system (CNS) include men- animal insulins. Acute insulin resistance is associated with
tal confusion progressing to seizures and coma. The CNS trauma from infection or surgery.
effects are intense because the brain depends on glucose
as a s elective substrate for oxidative metabolism. A pro- Drug Interactions
longed period of hypoglycemia may result in irreversible There are hormones administered as drugs that counter
brain damage. the hypoglycemic effect of insulin: adrenocorticotrophic
The diagnosis of hypoglycemia during general anes- hormone, estrogens, and glucagon. Epinephrine inhibits
thesia is difficult because anesthetic drugs mask the clas- the secretion of insulin and stimulates glycogenolysis.
sic signs of sympathetic nervous system stimulation. The Certain antibiotics (tetracycline or chloramphenicol), sa-
signs of sympathetic nervous system stimulation are likely licylates, and phenylbutazone increase the duration of ac-
to be confused with responses evoked by painful surgi- tion of insulin and may have a direct hypoglycemic effect.
cal stimulation in an anesthetized patient. The anesthesi- The hypoglycemic effect of insulin may be potentiated by
ologist may then decide to increase the dose of anesthetic monoamine oxidase inhibitors.
drugs. Changes in heart rate and systemic blood pressure
may be caused by hypoglycemia.10 Nonselective b-adren-
ergic antagonists also may mask the symptoms of hypo- Oral Glucose Regulators
glycemia.
Severe hypoglycemia is treated with 50 to 100 mL o f Oral drugs with different mechanisms of action are avail-
50% glucose solution administered IV. Alternatively, glu- able for controlling plasma glucose concentrations in pa-
cagon, 0.5 to 1.0 mg IV or administered subcutaneously, tients with type 2 diabetes mellitus (Table 38-3). None of
is given. Nausea and vomiting are frequent side effects of these drugs will adequately control hyperglycemia indefi-
glucagon treatment. In the absence of CNS d epression, nitely. Therefore, use of combinations of oral drugs from
carbohydrates may be administered orally. the onset of treatment may be indicated.13 Insulin itself

Shafer_Ch38.indd 751 10/24/14 11:24 PM

 752 Part VII  •  Endocrine System

Metformin also has been used in patients with polycystic

Table 38-3 ovarian disease, nonalcoholic fatty liver disease, and pre-
Oral Drugs for Treatment of Type 2 mature puberty.
Diabetes Mellitus
Pharmacokinetics
Sulfonylureas (stimulate insulin secretion; hypoglycemia In contrast to sulfonylureas, metformin is not bound to
a risk) plasma proteins and does not undergo metabolism. It is
Glyburide eliminated by the kidneys, with 90% of an oral dose ex-
Glipizide creted in approximately 12 hours. Peak plasma concentra-
Glimepiride tions of metformin occur approximately 2 hours after oral
Gliclazide administration. The drug has an elimination half-time of
Tolbutamide 2 to 4 hours, which means that it is taken up to three times
Tolazamide a day (500 to 1,000 mg with meals). In view of its depen-
Chlorpropamide dence on renal clearance, metformin is prescribed with
Acetohexamide caution, if at all, to patients with renal dysfunction.
Meglitinides (stimulate insulin secretion; hypoglycemia
a risk) Mechanism of Action
Repaglinide The blood glucose–lowering effect of metformin is not
Nateglinide mediated through stimulation of endogenous insulin
Biguanides (inhibit glucose production by the liver; secretion.15 Metformin activates adenosine monophos-
hypoglycemia not a risk) phate–activated protein kinase to suppress hepatic glucose
Metformin production by decreasing gluconeogenesis and glycoge-
Thiazolidinediones (increase sensitivity to insulin for nolysis and to enhance postprandial insulin suppression
glucose uptake by skeletal muscles and adipose tissues; of hepatic glucose production. Metformin also regulates
hypoglycemia not a risk) glucose levels by decreasing gastrointestinal glucose ab-
Rosiglitazone sorption, increasing insulin sensitivity in peripheral tis-
Pioglitazone sues, and enhancing synthesis of glucagon-like peptide-1
a-Glucosidase inhibitors (slow digestion and absorption (GLP-1) in the ileum.14
of carbohydrates from the diet; hypoglycemia not a risk)
Acarbose Side Effects
Miglitol
The most common side effects of metformin are anorexia,
nausea, and diarrhea, which are dose related. Up to 15%
of patients experience side effects sufficient to warrant
may be administered with sulfonylureas and meglitinides. withdrawal of the drug.5 In contrast to sulfonylureas,
The effect on HbA1c is similar for these drugs. ­metformin does not cause hypoglycemia. Metformin is
associated with vitamin B12 defi iency.5 The most serious,
although rare, side effect of metformin therapy is lactic
Metformin acidosis.
Metformin is an oral biguanide that is often prescribed as
the initial agent to prevent hyperglycemia in patients with Lactic Acidosis
type 2 d iabetes (Fig. 38-1). Metformin decreases blood Lactic acidosis is a possible side effect associated with met-
glucose concentrations in both the fasting and postpran- formin that has been described during the intraoperative
dial state and rarely causes hypoglycemia. It can be used period.15–17 For this reason, some have recommended dis-
in combination with other medications such as insulin continuing metformin 48 hours or longer before elective
and sulfonylureas. Metformin should not be prescribed operations.16 If metformin cannot be discontinued before
for patients with lactic acidosis, acute kidney injury, gas- surgery, the patient is monitored for the development of
trointestinal intolerance, or acute hepatic disease. Metfor- lactic acidosis (arterial blood gases and pH, serum lactate
min has pleiotropic effects. It improves lipid profiles and concentrations, renal function) in the perioperative period.
fibrinolysis and promotes mild to moderate weight loss.14 Metformin binds to mitochondrial membranes to de-
crease intracellular adenosine triphosphate and increase
adenosine monophosphate concentrations. Glucose is
CH3 NH metabolized anaerobically. The resulting pyruvate is re-
duced to lactate, which is usually metabolized quickly in
NCNHCNH2
the liver. For this reason, metformin should be adminis-
CH3 NH
tered with caution, if at all, to patients with a history of
FIGURE 38-1  Metformin. hepatic ­dysfunction, renal insufficiency (creatinine level

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 Chapter 38  •  Drugs that Alter Glucose Regulation 753

.1.5 mg/dL), IV administration of radiographic iodinated Mechanism of Action

contrast media, acute myocardial infarction, congestive Sulfonylurea receptors are found on pancreatic and car-
heart failure, arterial hypoxemia, or sepsis. Hemodialysis diac cells. These drugs inhibit adenosine triphosphate–­
along with bicarbonate administration can be effective sensitive potassium ion channels (now known as the
therapy for metformin-induced lactic acidosis. Manage- sulfonylurea receptor-1) on pancreatic b cells.5 As a result,
ment of biguanide-induced lactic acidosis is supportive there is an influx of calcium and stimulation of exocytosis
because the underlying pathologic change (blockade of (release) of insulin storage granules. Although sulfonyl-
the mitochondrial respiratory chain) cannot be treated. ureas decrease insulin resistance, this effect is minor, if at
all, in decreasing blood glucose concentrations.
Sulfonylureas Pharmacokinetics
Sulfonylurea compounds are drugs capable of lowering Oral hypoglycemics are readily absorbed from the gastro-
blood glucose concentrations even to hypoglycemic levels intestinal tract, with the most important distinguishing
(Fig. 38-2).15,18 The drug-induced improvement in blood features being differences in duration of action and elim-
glucose control is associated with decreased ­hepatic pro- ination half-time (Table 38-4).18 The biological effects of
duction of very-low-density lipoproteins as well as ame- sulfonylureas such as glyburide may be longer than plasma
lioration of hypertriglyceridemia. Yet as many as 20% of half-lives because of the formation of active metabolites.19
patients with type 2 d iabetes mellitus who begin sulfo- Weakly acidic, sulfonylureas circulate bound to protein
nylurea therapy do not have an adequate hypoglycemic (90% to 98%), principally to albumin. Metabolism in the
response to maximal doses (primary failures), and each liver is extensive, and the active and inactive metabolites
year, an additional 10% to 15% of patients who responded are eliminated by renal tubular secretion. ­Approximately
initially fail to respond to sulfonylurea therapy (secondary 50% of glyburide is excreted in feces.
failure). Successful management of glucose control with
sulfonylureas requires some b cell function. The sulfonyl- Side Effects
ureas have no effect on and no role in the treatment of Sulfonylureas are generally well tolerated; the most com-
patients with type 1 diabetes mellitus. Although sulfonyl- mon severe complication of these drugs is hypoglyce-
ureas are derivatives of sulfonamides, they have no anti- mia. The greatest risk of hypoglycemia occurs with drugs
bacterial actions. These drugs should not be administered with the longest elimination half-times, glyburide and
to patients with known allergy to sulfa drugs. chlorpropamide; sulfonylureas may act for up to 7 days.

CI
O O O
O SNHCNH H3C N O SNHCNH
CNHCH2CH2 O N CNHCH2CH2 O

Glyburide Glipizide

O
H3C O CH3C O
SO2NHCNHCH2CH2CH2CH3 SO2NHCNH

Tolbutamide Acetohexamide

CI O
SO2NHCNHCH2CH2CH3

Chlorpropamide

H3C O H CH3
N C O
NH CH2 CH2 SO2 NH C NH H
H3C CH2
O

Glimepiride

FIGURE 38-2  Oral hypoglycemics derived from sulfonylurea.

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 754 Part VII  •  Endocrine System

Table 38-4
Classification and Pharmacokinetics of Sulfonylurea Oral Hypoglycemics
Equivalent Daily Dose Duration of Elimination
Daily Dose (mg) Range (mg) Doses/Day Action (h) Half-Time (h)a
Glyburide 2.5–5 2.5–20 1–2 18–24 4.6–12
Glipizide 5–10 5–40 1–2 12–24 4–7
Glimepiride 2 2–4 1 241 5–8
Tolbutamide 1,000 500–1,000 2–3 6–12 4–8
Tolazamide 250 200–1,000 1–2 16–24 7
Acetohexamide 500 250–1,500 2 12–18 1.3–6
Chlorpropamide 100–250 100–750 1 36 30–36
a
Approximate.

Although hypoglycemia from sulfonylureas may be in- sulfonylureas, especially in patients who have had a prior
frequent, it is often more prolonged and more dangerous myocardial infarction.21,22 Gliclazide, a newer sulfonylurea
than hypoglycemia from insulin (Table 38-5). selective for pancreatic b cells may not be associated with
Hypoglycemia caused by sulfonylureas is treated with the same cardiac morbidity.23,24 For this reason, sulfonyl-
prolonged infusion of glucose-containing solutions. Risk ureas may be discontinued 24 to 48 hours before elective
factors for sulfonylurea-induced hypoglycemia include surgery in high-risk patients. Approximately 1% t o 3%
(a) impaired nutrition, as in the perioperative period; (b) of patients treated with oral hypoglycemics experience
age older than 60 years; (c) impaired renal function; and gastrointestinal disturbances including nausea, vomit-
(d)  concomitant drug therapy that potentiates sulfonyl- ing, abnormal liver function tests, and cholestasis. Sulfo-
ureas (phenylbutazone, sulfonamide antibiotics, warfarin) nylureas are not recommended for patients with hepatic
or itself produces hypoglycemia (alcohol or salicylates). dysfunction as liver disease prolongs their elimination
Renal disease decreases elimination of sulfonylureas and half-time and enhances their hypoglycemic action, with
their active metabolites, thus increasing the likelihood of the exception of acetohexamide. Disulfiram-like reactions
hypoglycemia. In this regard, only small amounts of tol- and inappropriate secretion of arginine vasopressin hor-
butamide and glipizide are excreted unchanged in urine, mone that results in hyponatremia are unique side effects
making these drugs preferable for patients with renal dis- of chlorpropamide.
ease. Sulfonylureas cross the placenta and may produce
fetal hypoglycemia. Glyburide
Sulfonylureas close KATP channels and inhibit isch- Glyburide stimulates insulin secretion over a 24-hour pe-
emic preconditioning, a cardioprotective mechanism.20 riod after a morning oral dose.25 Peak plasma levels occur
Cardiovascular mortality has been associated with some approximately 3 h ours after an oral dose. Glyburide in-
creases sensitivity to insulin and inhibits the production
of glucose by the liver. Metabolism is in the liver, with me-
tabolites excreted equally in urine and feces. One of the
Table 38-5 hepatic metabolites of glyburide has approximately 15%
Comparison of Sulfonylurea Therapy of the activity of the parent compound. A mild diuretic
with Insulin Therapy effect accompanies use of this drug. When administration
is discontinued, the drug is cleared from plasma in about
Sulfonylurea Insulin 36 hours.
Failed initial response in 10% to No maximum dose Glipizide
15% of patients
Secondary failure rate each year Glipizide stimulates insulin secretion over a 12-hour pe-
among treated patients is riod after a morning oral dose. Peak plasma levels occur
about 10% approximately 1 hour after oral administration. Glipizide
Hypoglycemia may be more Hypoglycemia may increases glucose uptake and suppresses glucose output
severe be more frequent by the liver.26 These effects persist for prolonged periods
Associated cardiac ­complications Lipid levels lowered (at least 3 y ears) without evidence of tolerance. Unlike
Patients may prefer oral Patients may resist glyburide, metabolism of glipizide in the liver produces
­medication ­injections inactive substances that are excreted in urine. A mild di-
uretic effect accompanies use of this drug. Relatively rapid

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 Chapter 38  •  Drugs that Alter Glucose Regulation 755

clearance from the plasma minimizes the potential for similar to those of sulfonylurea drugs, their peak effect is
long-lasting hypoglycemia. about 1 hour and duration of action is about 4 hours. b
cell stimulants lower HbA1c about 1%. Repaglinide and
Glimepiride nateglinide must be administered 15 to 30 minutes before
Glimepiride decreases blood glucose concentrations by a meal and should never be ingested while fasting. The
stimulating release of insulin from the pancreas and may short duration of action and activity only in the presence
decrease hepatic glucose production. It is combined with of glucose should decrease the risk of prolonged hypo-
insulin therapy when oral sulfonylureas are not effective. glycemic episodes.27 Nateglinide is metabolized by the
liver, and its metabolites are excreted by the kidney. The
Tolbutamide accumulation of active metabolites may cause hypoglyce-
Tolbutamide is the shortest acting and least potent sulfo- mia. Excretion of repaglinide by the kidneys is minimal so
nylurea (see Table 38-4).18 It is extensively metabolized in adjustment is not necessary for patients with renal insuf-
the liver to much less potent compounds before excretion fi iency.
in urine. Of all the sulfonylureas, tolbutamide probably
causes the fewest side effects, although it can produce hy-
poglycemia and hyponatremia. a-Glucosidase Inhibitors
Acarbose and miglitol are a-glucosidase inhibitors (AGI)
Acetohexamide that decrease carbohydrate digestion and absorption of
Acetohexamide differs from other sulfonylureas in that disaccharides by interfering with intestinal glucosidase
most of its hypoglycemic action comes from its principal activity.18 As a r esult, both release of glucose from food
metabolite hydroxyhexamide, which is 2.5 times as potent and absorption from the gastrointestinal tract are slow.
as the parent compound. After oral ingestion, peak plasma HbA1c generally decreases 0.5% t o 0.8%. These drugs
concentrations of acetohexamide and its active metabolite are useful only as monotherapy when postprandial hy-
occur after 1.5 hours and 3.5 hours, respectively. This drug perglycemia is the main problem. Flatulence, abdominal
is not recommended for patients with renal disease be- cramping, and diarrhea are side effects that frequently
cause the kidneys excrete the active metabolite. Acetohex- result from undigested carbohydrates that reach bacteria
amide is the only sulfonylurea with uricosuric properties in the lower colon. With the exception of occasional in-
(urocosuric drugs increase the excretion of uric acid in creases in liver transaminases, these drugs are considered
the urine), making it an appropriate drug for the diabetic nontoxic.15 Although hypoglycemia does not occur with
patient with gout. monotherapy, it can occur when AGI are added to sulfo-
nylureas or insulin.
Chlorpropamide
Chlorpropamide is the longest acting sulfonylurea, with
a duration of action that may approach 72 h ours (see Thiazolidinediones
Table 38-4).18 The maximal effect of chlorpropamide may Thiazolidinediones (TZDs), such as rosiglitazone and
not be apparent for 7 t o 14 d ays, and several weeks are pioglitazone, act principally at skeletal muscle, liver,
needed for complete elimination of the drug. Because 20% and adipose tissue via peroxisome proliferator activator
of a dose is excreted unchanged, impaired renal function ­receptor-g (PPAR-g) to decrease insulin resistance and
can lead to accumulation and an enhanced hypoglyce- hepatic glucose production and to increase use of glucose
mic effect. Chlorpropamide is associated with reactions by the liver.5 Like metformin, TZDs act in the presence
similar to those produced by disulfiram (facial flushing of insulin and are especially effective in obese patients.
after ingestion of alcohol) and can cause severe hypona- As monotherapy, these drugs decrease HbA1c 1% to 1.5%.
tremia. Approximately 5% of patients treated with chlor- The clinical effect takes 4 to 12 weeks. TZDs can cause
propamide have serum sodium concentrations of less weight gain, which is partly extracellular fluid. The accu-
than 129 mEq/L, but they are usually asymptomatic. Risk mulation of extracellular fluid as edema is undesirable in
factors for the development of hyponatremia include age patients with congestive heart failure. These drugs also are
older than 60 years, female gender, and the concomitant contraindicated in patients with liver failure. The possibil-
administration of thiazide diuretics. If all these risk fac- ity of drug-induced liver dysfunction is the reason that
tors are present, the frequency of hyponatremia increases plasma concentrations of hepatic transaminases must
­threefold. be measured periodically. TZDs tend to decrease plasma
concentrations of triglycerides and increase high-density
lipoprotein and low-density lipoprotein cholesterol levels.
Meglitinides Although rosiglitazone has been associated with cardio-
Repaglinide and the phenylalanine derivative, nateglinide, vascular risk, particularly heart failure, this risk may be
differ in structure and timing of action from sulfonyl- similar to the cardiovascular risks observed with other
urea drugs. Although these drugs exert effects on b cells standard diabetes medications.28

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 756 Part VII  •  Endocrine System

Glucagon-Like Peptide-1 References

Receptor Agonists
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lin dose are a secondary benefit. sion sulfonylureas on mortality and cardiovascular outcomes in

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 Chapter 38  •  Drugs that Alter Glucose Regulation 757

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