1205

SECTION 8
ENDOCRINOLOGIC DISORDERS

77
C HAP T E R

Diabetes Mellitus

CURTIS L. TRIPLITT, CHARLES A. REASNER, AND WILLIAM L. ISLEY

(DCCT) in type 1 DM and the UKPDS in type 2 DM. The UKPDS

KEY CONCEPTS also reported that control of hypertension in patients with diabe-
tes will not only reduce the risk of retinopathy and nephropathy
 Diabetes mellitus is a group of metabolic disorders of fat, car- but also reduce cardiovascular risk.
bohydrate, and protein metabolism that results from defects in
insulin secretion, insulin action (sensitivity), or both.  Knowledge of the patient’s quantitative and qualitative meal
patterns, activity levels, pharmacokinetics of insulin prepara-
 The incidence of type 2 diabetes mellitus (DM) is increasing. This tions, and pharmacology of oral and injected antihyperglycemic
has been attributed in part to a Western style diet, increasing obe- agents are essential to individualize the treatment plan and op-
sity, sedentary lifestyle, and an increasing minority population. timize blood glucose control while minimizing risks for hypogly-
 The two major classifications of DM are type 1 (insulin defi- cemia and other adverse effects of pharmacologic therapies.
cient) and type 2 (combined insulin resistance and relative de- Type 1 treatment necessitates insulin therapy. Currently, the bas-
ficiency in insulin secretion). They differ in clinical presentation, al-bolus insulin therapy or pump therapy in motivated individuals
onset, etiology, and progression of disease. Both are associated often leads to successful glycemic outcomes. Basal-bolus thera-
with microvascular and macrovascular disease complications. py includes a basal insulin for fasting and postabsorptive control,
Diagnosis of diabetes is made by three criteria: fasting plasma and rapid-acting bolus insulin for mealtime coverage. Addition of
glucose ≥126 mg/dL, a 2-hour value from a 75-g oral glucose pramlintide in patients with uncontrolled or erratic postprandial
tolerance test ≥200 mg/dL, or a casual plasma glucose level of glycemia can be warranted, if the patient is willing to inject addi-
≥200 mg/dL with symptoms of diabetes; with results con- tional times before each meal.
firmed by any of the three criteria on a separate day. Treatment of type 2 DM often necessitates use of multiple ther-
 Goals of therapy in diabetes mellitus are directed toward attain- apeutic agents (combination therapy), including oral and/or in-
ing normoglycemia, reducing the onset and progression of ret- jected antihyperglycemics and insulin to obtain glycemic goals.
inopathy, nephropathy, and neuropathy complications, Aggressive management of cardiovascular disease risk factors
intensive therapy for associated cardiovascular risk factors, and in type 2 DM is necessary to reduce the risk for adverse cardio-
improving quality and quantity of life. vascular events or death. Smoking cessation, use of antiplatelet
 Metformin should be included in the therapy for all type 2 DM therapy as a primary prevention strategy, aggressive manage-
patients, if tolerated and not contraindicated, as it is the only oral ment of dyslipidemia minimally toward a goal of low-density li-
antihyperglycemic medication proven to reduce the risk of total poprotein-cholesterol (LDLC) at <100 mg/dL and secondarily
mortality, according to the United Kingdom Prospective Diabe- to increase high-density lipoprotein-cholesterol (HDLC) to ≥40
tes Study (UKPDS). mg/dL, and treatment of hypertension (again often requiring
multiple drugs) minimally to attain a blood pressure of <130/
 Intensive glycemic control is paramount for reduction of microvas- 80 mm Hg are vital.
cular complications (neuropathy, retinopathy, and nephropathy)
as evidenced by the Diabetes Control and Complications Trial Prevention strategies for type 1 DM have been unsuccessful.
Prevention strategies for type 2 DM are established. Lifestyle
changes, dietary restriction of fat, aerobic exercise for 30 min-
utes five times a week, and weight loss, form the backbone of
Learning objectives, review questions, successful prevention. No medication is currently FDA ap-
and other resources can be found at proved for prevention of diabetes, although several, including
www.pharmacotherapyonline.com. metformin and rosiglitazone, have evidence of potential delay
of the onset of diabetes.

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
1206
 Patient education and ability to demonstrate self-care and ad- 20
herence to therapeutic lifestyle and pharmacologic interven- 18
SECTION 8

tions are crucial to successful outcomes. Multidisciplinary teams 16 1988–1994

of healthcare professionals including physicians (primary care,

Percent with diabetes

14
1999–2002
endocrinologists, ophthalmologists, and vascular surgeons), po- 12
diatrists, dietitians, nurses, pharmacists, social workers, behav- 10
ioral health specialists, and certified diabetes educators are 8
needed to optimize these outcomes in persons with diabetes 6
mellitus. 4
2
Endocrinologic Disorders

0
 DM is a group of metabolic disorders characterized by hypergly- Mexican Black White
cemia. It is associated with abnormalities in carbohydrate, fat, and American
protein metabolism and results in chronic complications including
FIGURE 77-1. National Health and Nutrition Evaluation Survey (NHANES)
microvascular, macrovascular, and neuropathic disorders. Nearly prevalence of diabetes by race among adults ≥20 years of age: United
20.8 million Americans have DM, yet only approximately two- States, 1988–1994 and 1999–2002. (Adapted from Cowie et al.9)
thirds of them have been diagnosed.1 The economic burden of DM
approximated $132 billion in 2002, including direct medical and
 The prevalence of type 2 DM is increasing. Type 2 DM
treatment costs as well as indirect costs attributed to disability and
accounts for as much as 90% of all cases of DM, and the overall the
mortality.1 DM is the leading cause of blindness in adults aged 20 to
prevalence of type 2 DM in the United States is approximately 9.6%
74 years, and the leading contributor to development of end-stage
in persons age 20 years or older. However, there is likely one person
renal disease. It also accounts for approximately 82,000 lower
undiagnosed for every three persons currently diagnosed with the
extremity amputations annually.1 Finally, a cardiovascular event is
disease.1 Multiple risk factors for the development of type 2 DM have
responsible for two-thirds of deaths in individuals with type 2 DM.1
been identified, including family history (i.e., parents or siblings with
Although efforts to control hyperglycemia and associated symp-
diabetes); obesity (i.e., ≥20% over ideal body weight, or body mass
toms are important, the major challenges in optimally managing the
index [BMI] ≥25 kg/m2); habitual physical inactivity; race or ethnic-
patient with DM are targeted at reducing or preventing complica-
ity; previously identified impaired glucose tolerance or impaired
tions, and improving life expectancy and quality of life. Research
fasting glucose (see Diagnosis of Diabetes section); hypertension
and drug development efforts over the past several decades have
(≥140/90 mm Hg in adults); high-density lipoprotein (HDL) choles-
provided valuable information that applies directly to improving
terol ≤35 mg/dL and/or a triglyceride level ≥250 mg/dL; history of
outcomes in patients with DM and have expanded the therapeutic
gestational DM (see Classification of Diabetes section) or delivery
armamentarium. Additionally, interventions in an attempt to pre-
of a baby weighing >4 kg (9 lb); history of vascular disease; presence
vent disease in high-risk populations have been reported for type 1
of acanthosis nigricans; and polycystic ovary disease.8 The preva-
and 2 DM.
lence of type 2 DM increases with age, it is more common in women
than in men in the United States, and varies widely among various
EPIDEMIOLOGY racial and ethnic populations, being especially increased in some
groups of Native Americans, Hispanic American, Asian American,
Typical type 1 DM is an autoimmune disorder developing in African American, and Pacific Island people9 (Fig. 77–1). Although
childhood or early adulthood, although some latent forms do occur. the prevalence of type 2 DM increases with age (Fig. 77–2),9 the
Type 1 DM accounts for 5% to 10% of all cases of DM and is likely disorder is increasingly being recognized in adolescence. Much of the
initiated by the exposure of a genetically susceptible individual to an increase in adolescent type 2 DM is related to an increase in adiposity
environmental agent.2 Candidate genes and environmental factors and sedentary lifestyle, in addition to an inheritable predisposition.10
are reportedly prevalent in the general population, but development Most cases of type 2 DM do not have a well-known cause; therefore
of β-cell autoimmunity occurs in less than 10% of the genetically it is uncertain whether it represents a few or many independent
susceptible population and progresses to type 1 DM in less than 1% disorders manifesting as hyperglycemia.11
of the population.3 Gestational diabetes mellitus (GDM) complicates roughly 7% of
The prevalence of β-cell autoimmunity appears proportional to all pregnancies in the United States.12 Most women will return to
the incidence of type 1 DM in various populations. For instance, the
countries of Sweden, Sardinia, and Finland have the highest preva- 24 1988–1994
lence of islet cell antibody (3% to 4.5%) and are associated with the 22
highest incidence of type 1 DM, 22 to 35 per 100,000.4 20 1999–2002
Markers of autoimmunity have been detected in 14% to 33% of 18
Percent with diabetes

persons with type 2 DM in some populations and manifest with early 16

14
failure of oral agents and insulin dependence. This type of DM has also 12
been referred to as latent autoimmune diabetes of adults (LADA).4 10
Type 1 DM idiopathic is a nonimmune form of diabetes fre- 8
quently seen in minorities with intermittent insulin requirements.5 6
4
The prevalence of type 1 DM has been increasing over the last 100
2
years.6 Maturity-onset diabetes of youth (MODY), which can be 0
caused by one of at least six genetic defects, and endocrine disorders
such as acromegaly and Cushing syndrome, can be secondary causes 20–39 40–59 ≥ 60 ≥ 65
of DM.7 These unusual etiologies, however, only account for 1% to FIGURE 77-2. National Health and Nutrition Evaluation Survey (NHANES)
2% of the total cases of type 2 DM. See the section on Other Specific prevalence of diabetes mellitus in United States by age (≥20 years of age)
Types of Diabetes later in this chapter for further discussion. 1988–1994 and 1999–2002. (Adapted from Cowie et al.9)
 1207
normoglycemia postpartum, but 30% to 50% will develop type 2 cell are present at the time of diagnosis in 90% of individuals and
DM or glucose intolerance later in life. include islet cell antibodies, antibodies to glutamic acid decarboxy-

CHAPTER 77
lase, and antibodies to insulin. Although this form of diabetes
usually occurs in children and adolescents, it can occur at any age.
PATHOGENESIS, DIAGNOSIS, Younger individuals typically have a rapid rate of β-cell destruction
AND CLASSIFICATION and present with ketoacidosis, whereas adults often maintain suffi-
cient insulin secretion to prevent ketoacidosis for many years, which
CLASSIFICATION OF DIABETES is often referred to as LADA.4

Diabetes is a metabolic disorder characterized by resistance to the Type 2 Diabetes

Diabetes Mellitus
action of insulin, insufficient insulin secretion, or both.13 The clinical
 This form of diabetes is characterized by insulin resistance and a
manifestation of these disorders is hyperglycemia. The vast majority
relative lack of insulin secretion, with progressively lower insulin
of diabetic patients are classified into one of two broad categories:
secretion over time. Most individuals with type 2 diabetes exhibit
type 1 diabetes caused by an absolute deficiency of insulin, or type 2
abdominal obesity, which itself causes insulin resistance. In addi-
diabetes defined by the presence of insulin resistance with an inade-
tion, hypertension, dyslipidemia (high triglyceride levels and low
quate compensatory increase in insulin secretion. Women who
HDL-cholesterol levels), and elevated plasminogen activator inhib-
develop diabetes because of the stress of pregnancy are classified as
itor type 1 (PAI-1) levels are often present in these individuals. This
having gestational diabetes. Finally, uncommon types of diabetes
clustering of abnormalities is referred to as the insulin resistance
caused by infections, drugs, endocrinopathies, pancreatic destruction,
syndrome or the metabolic syndrome. Because of these abnormalities,
and known genetic defects are classified separately (Table 77–1).
patients with type 2 diabetes are at increased risk of developing
macrovascular complications. Type 2 diabetes has a strong genetic
Type 1 Diabetes predisposition and is more common in all ethnic groups other than
 This form of diabetes results from autoimmune destruction of those of European ancestry. At this point the genetic cause of most
the β cells of the pancreas. Markers of immune destruction of the β cases of type 2 diabetes is not well defined.14

TABLE 77-1 Etiologic Classification of Diabetes Mellitus

1.Type 1 diabetesa (β-cell destruction, usually leading to absolute insulin deficiency) Drug- or chemical-induced
Immune mediated Vacor (pyriminil)
Idiopathic Pentamidine
2.Type 2 diabetesa (can range from predominantly insulin resistance with relative insulin Nicotinic acid
deficiency to a predominantly insulin secretory defect with insulin resistance) Glucocorticoids
3.Other specific types Thyroid hormone
Genetic defects of β-cell function Diazoxide
Chromosome 20q, HNF-4α (MODY1) β-Adrenergic agonists
Chromosome 7p, glucokinase (MODY2) Thiazides
Chromosome 12q, HNF-1β (MODY3) Phenytoin
Chromosome 13q, insulin promoter factor (MODY4) Interferon alpha
Chromosome 17q, HNF-1β (MODY5) Others
Chromosome 2q, neurogenic differentiation 1/b-cell e-box transactivator 2 (MODY6) Infections
Mitochondrial DNA Congenital rubella
Others Cytomegalovirus
Genetic defects in insulin action Others
Type 1 insulin resistance Uncommon forms of immune-mediated diabetes
Leprechaunism “Stiff-man” syndrome
Rabson-Mendenhall syndrome Anti-insulin receptor antibodies
Lipoatrophic diabetes Others
Others Other genetic syndromes sometimes associated with diabetes
Diseases of the exocrine pancreas Down’s syndrome
Pancreatitis Klinefelter’s syndrome
Trauma/pancreatectomy Turner’s syndrome
Neoplasia Wolfram’s syndrome
Cystic fibrosis Friedreich’s ataxia
Hemochromatosis Huntington’s chorea
Fibrocalculous pancreatopathy Laurence-Moon-Biedel syndrome
Others Myotonic dystrophy
Endocrinopathies Porphyria
Acromegaly Prader-Willi syndrome
Cushing’s syndrome Others
Glucagonoma 4. Gestational diabetes mellitus (GDM)
Pheochromocytoma
Hyperthyroidism
Somatostatinoma
Aldosteronoma
Others
a
Patients with any form of diabetes can require insulin treatment at some stage of their disease. Such use of
insulin does not in itself classify the patient.
Adapted with permission from Report of the Expert Committee.13
1208
Gestational Diabetes Mellitus TABLE 77-2 Diagnosis of Gestational Diabetes Mellitus with a
GDM is defined as glucose intolerance that is first recognized during 100-g or 75-g Glucose Load
SECTION 8

pregnancy. Gestational diabetes complicates approximately 7% of Time Plasma Glucose

all pregnancies. Clinical detection is important, as therapy will
100-g Glucose load
reduce perinatal morbidity and mortality.
Fasting ≥95 mg/dL (5.3 mmol/L)
1 hour ≥180 mg/dL (10.0 mmol/L)
Other Specific Types of Diabetes
2 hours ≥155 mg/dL (8.6 mmol/L)
Genetic Defects MODY is characterized by impaired insulin 3 hours ≥140 mg/dL (7.8 mmol/L)
secretion with minimal or no insulin resistance. Patients typically 75-g Glucose load
Fasting ≥95 mg/dL (5.3 mmol/L)
Endocrinologic Disorders

exhibit mild hyperglycemia at an early age. The disease is inherited

in an autosomal dominant pattern with at least six different loci 1 hour ≥180 mg/dL (10.0 mmol/L)
2 hours ≥155 mg/dL (8.6 mmol/L)
identified to date. Genetic inability to convert proinsulin to insulin
results in mild hyperglycemia and is inherited in an autosomal Two or more values must be met or exceeded for a diagnosis of diabetes to be made. The test should
dominant pattern. Similarly, the production of mutant insulin be done in the morning after an 8- to 14-hour fast.
molecules has been identified in a few families and results in mild
glucose intolerance. marked obesity, or member of a high-risk ethnic group) should be
Several genetic mutations have been described in the insulin screened as soon as feasible. If the initial screening is negative, they
receptor and are associated with insulin resistance. Type A insulin should undergo retesting at 24 to 28 weeks of gestation, as should all
resistance refers to the clinical syndrome of acanthosis nigricans, other pregnant women with the possible exception of low-risk
virilization in women, polycystic ovaries, and hyperinsulinemia. In primigravidas. Evaluation for GDM can be done in one of two ways.
contrast, type B insulin resistance is caused by autoantibodies to the The one-step approach involves a 3-hour, 100 gram-OGTT and can
insulin receptor. Leprechaunism is a pediatric syndrome with spe- be cost-effective in high-risk patient populations. The two-step
cific facial features and severe insulin resistance because of a defect approach uses a screening test to measure plasma or serum glucose
in the insulin receptor gene. Lipoatrophic diabetes probably results concentration 1 hour after a 50 gram oral glucose load (glucose
from postreceptor defects in insulin signaling. challenge test), followed by a diagnostic 3-hour OGTT on the subset
of women exceeding a glucose threshold of either ≥140 mg/dL (80%
SCREENING sensitive) or ≥130 mg/dL (90% sensitive). The diagnosis of GDM is
based on a 75-gram (not as well validated) or 100-gram OGTT.
Type 1 Diabetes Mellitus Criteria for diagnosis of GDM based on the OGTT are summarized
There is still a low prevalence of type 1 DM in the general in Table 77–2.
population and because of the acuteness of symptoms, screening for
type 1 DM is not recommended.8 DIAGNOSIS OF DIABETES
Type 2 Diabetes Mellitus The diagnosis of diabetes requires the identification of a glycemic
cut point, which discriminates normal persons from diabetic
Based on expert opinion, and not uniformly accepted by all guidance patients (Table 77–3). The present cut points reflect the level of
organizations, the American Diabetes Association (ADA) recom- glucose above which microvascular complications have been shown
mends screening for type 2 DM every 3 years in all adults beginning to increase. Cross-sectional studies from Egypt, in Pima Indians,
at age 45 years.8 Testing should be considered at an earlier age and and in a representative sample from the United States have shown a
more frequently in individuals with risk factors. The recommended consistent increase in the risk of developing retinopathy at a fasting
screening test is the fasting plasma glucose (FPG). An oral glucose glucose level above 99 to 116 mg/dL (5.5 to 6.4 mmol/L), at a 2-hour
tolerance test (OGTT) (more costly, less convenient, less reproduc- postprandial level above 125 to 185 mg/dL (6.9 to 10.3 mmol/L),
ible) can be performed alternatively or in addition to FPG when a and a hemoglobin A1c (HbA1c) above 5.9 to 6.0% (Fig. 77–3).13,15,16
high index of suspicion for the disease is present.5 The ADA recommends using the fasting glucose test as the
principal tool for the diagnosis of DM in nonpregnant adults. In
Children and Adolescents addition, as shown in Table 77–4, they defined a new category of
Despite a lack of clinical evidence to support widespread testing of glycemia, impaired fasting glucose (IFG). IFG is a plasma glucose of
children for type 2 DM, it is clear that more children and adolescents at least 100 mg/dL (5.6 mmol/L) but less than 126 mg/dL (7.0
are developing type 2 DM. The ADA, by expert opinion, recommends
that overweight (defined as BMI >85th percentile for age and sex, TABLE 77-3 Criteria for the Diagnosis of Diabetes Mellitusa
weight for height >85th percentile, or weight >120% of ideal [50th
percentile] for height) youths with at least two of the following risk Symptoms of diabetes plus casualb plasma glucose concentration ≥200 mg/dL
factors: a family history of type 2 diabetes in first- and second-degree (11.1 mmol/L)
or
relatives; Native Americans, African Americans, Hispanic Americans,
Fasting c plasma glucose ≥126 mg/dL (7.0 mmol/L)
and Asians/South Pacific Islanders; and those with signs of insulin
or
resistance or conditions associated with insulin resistance (acanthosis 2-hour postload glucose ≥200 mg/dL (11.1 mmol/L) during an OGTTd
nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome)
be screened. Testing should be done every 2 years starting at 10 years OGTT, oral glucose tolerance test.
a
In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing
of age or at the onset of puberty if it occurs at a younger age.8 on a different day. The third measure is not recommended for routine clinical use.
b
Casual is defined as any time of day without regard to time since last meal. The classic symptoms
Gestational Diabetes of diabetes include polyuria, polydipsia, and unexplained weight loss.
c
Fasting is defined as no caloric intake for at least 8 hours.
Risk assessment for GDM should occur at the first prenatal visit. d
The test should be performed as described by the World Health Organization, using a glucose load
Women at high risk (positive family history, history of GDM, containing the equivalent of 75 g anhydrous glucose dissolved in water.
 1209

FPG

CHAPTER 77
15 2hPG

Retinopathy (%)
HbA1c
10

Diabetes Mellitus
FPG (mg/dL) 70- 89- 93- 97- 100- 105- 109- 116- 136- 226-
2hPG (mg/dL) 38- 94- 106- 116- 126- 138- 156- 185- 244- 364-
HbA1c(%) 3.4- 4.8- 5.0- 5.2- 5.3- 5.5- 5.7- 6.0- 6.7- 9.5-
A

FPG
50
2hPG
40
Retinopathy (%)

HbA1c

30

20

10

0
FPG (mg/dL) 57- 79- 84- 89- 93- 99- 108- 130- 178- 258-
2hPG (mg/dL) 39- 80- 90- 99- 110- 125- 155- 218- 304- 386-
HbA1c(%) 2.2- 4.7- 4.9- 5.1- 5.4- 5.6- 6.0- 6.9- 8.5- 10.3-
B

FIGURE 77-3. Prevalence of retinopathy by deciles of

FPG the distribution of fasting plasma glucose (FPG), 2-hour
15 2hPG postprandial glucose (2-h PG), and hemoglobin Alc
(HbAlc ) in (A) Pima Indians,12 (B) Egyptians,11 and (C) in
Retinopathy (%)

HbA1c
40- to 74-year old participants in National Health and
10
Nutrition Examination Survey (NHANES) III.13 The X-axis
labels indicate the lower limit of each decile group. Note
5 that these deciles and the prevalence rates of retinopathy
differ considerably among the studies, especially the
Egyptian study, in which diabetic subjects were oversam-
0 pled. Retinopathy was ascertained by different methods in
FPG (mg/dL) 42- 87- 90- 93- 96- 98- 101- 104- 109- 120- each study; therefore the absolute prevalence rates are
2hPG (mg/dL) 34- 75- 86- 94- 102- 112- 120- 133- 154- 195- not comparable between studies, but their relationships
HbA1c(%) 3.3- 4.9- 5.1- 5.2- 5.4- 5.5- 5.6- 5.7- 5.9- 6.2- with FPG, 2-h PG, and HbAlc are very similar within each
C population.

mmol/L). Impaired glucose tolerance (IGT), is defined as a 2-hour The fasting and postprandial glucose levels do not measure the
glucose value ≥140 mg/dL (7.8 mmol/L), but less than 200 mg/dL same physiologic processes and do not identify the same individuals
(11.0 mmol/L) during an OGTT. Patients with either IFG or IGT as having diabetes. The fasting glucose reflects hepatic glucose
are now commonly referred to as having “prediabetes” because of a production, which depends on insulin secretory capacity of the
higher risk of developing diabetes in the future. pancreas. The postprandial glucose reflects uptake of glucose in
peripheral tissues (muscle and fat) and depends on insulin sensitiv-
ity of these tissues.
TABLE 77-4 Categorization of Glucose Status The ADA recommends use of HbA1c determinations to monitor
Fasting plasma glucose (FPG) glycemic control in known diabetic patients. Because there is no
Normal gold standard assay and several countries do not have ready access
• FPG <100 mg/dL (5.6 mmol/L) to the test, a HbA1c determination is not recommended to diagnose
Impaired fasting glucose (IFG) diabetes at the present time.
• 100–125 mg/dL (5.6–6.9 mmol/L)
Diabetes mellitusa
• FPG ≥126 mg/dL (7.0 mmol/L)
PATHOGENESIS
2-Hour postload plasma glucose (oral glucose tolerance test)
Type 1 Diabetes Mellitus
Normal
• Postload glucose <140 mg/dL (7.8 mmol/L) Type 1 DM is characterized by an absolute deficiency of pancreatic
Impaired glucose tolerance (IGT) β-cell function. Most often this is the result of an immune-mediated
• 2-hour postload glucose 140–199 mg/dL (7.8–11.1 mmol/L) destruction of pancreatic β cells, but rare unknown or idiopathic
Diabetes mellitusa processes can contribute. What is evident are four main features:
• 2-hour postload glucose ≥200 mg/dL (11.1 mmol/L) (1) a long preclinical period marked by the presence of immune
a
Provisional diagnosis of diabetes (diagnosis to be confirmed; see Table 77–3). markers when β-cell destruction is thought to occur; (2) hypergly-
1210
Type 2 Diabetes Mellitus
Genetic predisposition
Immunologic abnormalities Normal Insulin Action In the fasting state 75% of total body
SECTION 8

ß-cell mass (% of max)

Normal insulin
glucose disposal takes place in non–insulin-dependent tissues: the
release brain and splanchnic tissues (liver and gastrointestinal [GI] tis-
Progressive impairment
100 in insulin release sues).22 In fact, brain glucose uptake occurs at the same rate during
Overt fed and fasting periods and is not altered in type 2 diabetes.
diabetes The remaining 25% of glucose metabolism takes place in muscle,
"Honeymoon which is dependent on insulin.23 In the fasting state approximately 85%
50
period" of glucose production is derived from the liver, and the remaining
amount is produced by the kidney.22–24 Glucagon, produced by
Endocrinologic Disorders

pancreatic α cells, is secreted in the fasting state to oppose the action

0 of insulin and stimulate hepatic glucose production. Thus, glucagon
0 prevents hypoglycemia or restores normoglycemia if hypoglycemia has
Birth Time (yr)
occurred.25 In the fed state, carbohydrate ingestion increases the plasma
FIGURE 77-4. Scheme of the natural history of the β-cell defect in type glucose concentration and stimulates insulin release from the pancre-
1 diabetes mellitus. (From ADA Medical Management of Type 1 Diabe- atic β cells. The resultant hyperinsulinemia (1) suppresses hepatic
tes, 3rd ed. American Diabetes Association, Alexandria, VA, 1998.) glucose production and (2) stimulates glucose uptake by peripheral
tissues.22,26 The majority (~80%–85%) of glucose that is taken up by
cemia when 80% to 90% of β cells are destroyed; (3) transient peripheral tissues is disposed of in muscle,22,26 with only a small
remission (the so-called honeymoon phase); and (4) established amount (~4%–5%) being metabolized by adipocytes. In the fed state,
disease with associated risks for complications and death. Unknown glucagon is suppressed.25
is whether there is one or more inciting factors (e.g., cow’s milk, or Although fat tissue is responsible for only a small amount of total
viral, dietary, or other environmental exposure) that initiate the body glucose disposal, it plays a very important role in the maintenance
autoimmune process (Fig. 77–4).2 of total body glucose homeostasis. Small increments in the plasma
The autoimmune process is mediated by macrophages and T insulin concentration exert a potent antilipolytic effect, leading to a
lymphocytes with circulating autoantibodies to various β-cell anti- marked reduction in the plasma free fatty acid (FFA) level. The decline
gens. The most commonly detected antibody associated with type 1 in plasma FFA concentration results in increased glucose uptake in
DM is the islet cell antibody. The test for islet cell antibody, however, muscle27 and reduces hepatic glucose production.28 Thus a decrease in
is difficult to standardize across laboratories. Other more readily the plasma FFA concentration lowers plasma glucose by both decreas-
measured circulating antibodies include insulin autoantibodies, ing its production and enhancing the uptake in muscle.20,29
antibodies directed against glutamic acid decarboxylase, insulin Type 2 diabetic individuals are characterized by (1) defects in
antibodies against islet tyrosine phosphatase, and several others. insulin secretion; and (2) insulin resistance involving muscle, liver,
More than 90% of newly diagnosed persons with type 1 DM have and the adipocyte. Insulin resistance is present even in lean type 2
one or another of these antibodies, as will 3.5% to 4% of unaffected diabetic individuals (Fig. 77–5).
first-degree relatives. Preclinical β-cell autoimmunity precedes the
diagnosis of type 1 DM by up to 9 to 13 years. Autoimmunity can Impaired Insulin Secretion The pancreas in people with a nor-
remit in some perhaps less-susceptible persons, or can progress to β- mal-functioning β cell is able to adjust its secretion of insulin to
cell failure in others. These antibodies are generally considered maintain normal glucose tolerance. Thus in nondiabetic individu-
markers of disease rather than mediators of β-cell destruction. They als, insulin is increased in proportion to the severity of the insulin
have been used to identify individuals at risk for type 1 DM in resistance, and glucose tolerance remains normal. Impaired insulin
evaluating disease-prevention strategies. Other nonpancreatic secretion is a uniform finding in type 2 diabetic patients and the
autoimmune disorders are associated with type 1 DM, most com- evolution of β-cell dysfunction has been well characterized in
monly Hashimoto thyroiditis, but the extent of organ involvement diverse ethnic populations.
can range from no other organs to polyglandular failure.17
There are strong genetic linkages to the DQA and B genes, and 250
certain human leukocyte antigens (HLAs) can be predisposing (DR3
and DR4) or protective (DRB1*04008-DQB1*0302 and DRB1*0411-
Glucose disposal (mg/m2•min)

DQB1*0302) on chromosome 6.17 Other candidate gene regions have 200

been identified on several other chromosomes as well. Because twin

studies do not show 100% concordance, environmental factors such 150
as infectious agents, chemical agents, and dietary agents are likely
contributing factors in the expression of the disease.
Destruction of pancreatic β-cell function causes hyperglycemia 100
because of an absolute deficiency of both insulin and amylin.18
Insulin lowers blood glucose by a variety of mechanisms including: 50
stimulation of tissue glucose uptake, suppression of glucose produc-
tion by the liver, and suppression of free fatty acid release from fat
cells.19 The suppression of free fatty acids plays an important role in 0
Lean Obese Lean Obese
glucose homeostasis. Increased levels of free fatty acids inhibit the T2DM T2DM
uptake of glucose by muscle and stimulate hepatic gluconeogene-
FIGURE 77-5. Whole body glucose disposal, a measure of insulin resis-
sis.20 Amylin, a glucoregulatory peptide hormone cosecreted with tance, is reduced 40% to 50% in obese nondiabetic and lean type 2 diabetic
insulin, plays a role in lowering blood glucose by slowing gastric individuals. Obese diabetic individuals are slightly more resistant than lean
emptying, suppressing glucagon output from pancreatic α cells, and diabetic patients. (T2DM, type 2 diabetes mellitus.) (Copyright © 1988
increasing satiety.21 In type 1 DM amylin production, caused by β- American Diabetes Association. From Diabetes, Vol. 37, 1988;667–687.
cell destruction, is very low. Reprinted with permission from The American Diabetes Association.)
 1211
that gut derived hormones when stimulated by glucose lead to an
increase in pancreatic insulin secretion. In type 2 diabetic patients this

CHAPTER 77
25
incretin effect is blunted, with the increase in insulin secretion to
only 50% of that seen in nondiabetic control individuals (Fig. 77–7).31
20
Fasting plasma insulin

It is now known that two hormones, glucagon-like peptide-1 (GLP-1)

and glucose-dependent insulin-releasing peptide (GIP), are responsi-
(μU/mL)

15 ble for more than 90% of the increased insulin secretion seen in
response to an oral glucose load. In patients with type 2 diabetes GLP-
10
1 levels are reduced whereas GIP levels are increased.32
GLP-1 is secreted from the L-cells in the distal intestinal mucosa

Diabetes Mellitus
in response to mixed meals. Because GLP-1 levels increase within
5 minutes of food ingestion, neural signals initiated by food entry in
the proximal gastrointestinal tract must simulate GLP-1 secretion.33
0 The insulinotropic action of GLP-1 is glucose-dependent, and for
60 140 220 300 GLP-1 to enhance insulin secretion, glucose concentrations must be
Fasting plasma glucose (mg/dL) higher than 90 mg/dL.32 In addition to stimulating insulin secretion,
FIGURE 77-6. The relationship between fasting plasma insulin and
GLP-1 suppresses glucagon secretion, slows gastric emptying and
fasting plasma glucose in 177 normal weight individuals. Plasma insulin reduces food intake by increasing satiety. These effects of GLP-1
and glucose increase together up to a fasting glucose of 140 mg/dL. combine to limit postprandial glucose excursions. GIP is secreted by
When the fasting glucose exceeds 140 mg/dL, the β cell makes K-cells in the intestine and like GLP, increase insulin secretion.34
progressively less insulin, which leads to an overproduction of glucose by However, GIP has no effect on glucagon secretion, gastric motility,
the liver and results in a progressive increase in fasting glucose. (Adapted or satiety.35 The half-life of GLP-1 and GIP are short (<10 minutes).
from DeFronzo,30 with permission.) Both hormones are rapidly inactivated by removal of two N-terminal
amino acids by the enzyme, dipeptidyl peptidase IV (DPP-IV).36
DeFronzo and colleagues30 measured the fasting plasma insulin
concentration and performed OGTTs in 77 normal-weight type 2 Site of Insulin Resistance in Type 2 Diabetes
diabetic patients and more than 100 lean subjects with normal or
Liver In type 2 diabetic subjects with mild to moderate fasting
impaired glucose tolerance (Fig. 77–6). The relationship between
hyperglycemia (140 to 200 mg/dL, 7.8 to 11.1 mmol/L), basal
the FPG concentration and the fasting plasma insulin concentration
hepatic glucose production is increased by ~0.5 mg/kg per minute.
resembles an inverted U or horseshoe. As the FPG concentration
Consequently, during the overnight sleeping hours the liver of an
increases from 80 to 140 mg/dL, the fasting plasma insulin concen-
80-kg diabetic individual with modest fasting hyperglycemia adds
tration increases progressively, peaking at a value that is 2- to 2.5-
an additional 35 g of glucose to the systemic circulation. This
fold greater than in normal weight nondiabetic controls. When the
increase in fasting hepatic glucose production is the cause of fasting
FPG concentration exceeds 140 mg/dL, the β cell is unable to
hyperglycemia.22
maintain its elevated rate of insulin secretion, and the fasting insulin
Following glucose ingestion, insulin is secreted into the portal
concentration declines precipitously. This decrease in fasting insulin
vein and carried to the liver, where it suppresses glucagon secretion
leads to an increase in hepatic glucose production overnight, which
and reduces hepatic glucose output. Type 2 diabetic patients fail to
results in an elevated FPG concentration.30
suppress glucagon in response to a meal and can even have a
In the type 2 diabetic patient, decreased postprandial insulin
paradoxical rise in glucagon levels.36,37 Thus, hepatic insulin resis-
secretion is caused by both impaired pancreatic β-cell function and a
tance and hyperglucagonemia result in continued production of
reduced stimulus for insulin secretion from gut hormones. The role
glucose by the liver. Therefore, type 2 diabetic patients have two
gut hormones play in insulin secretion is best shown by comparing
sources of glucose in the postprandial state, one from the diet and
the insulin response to an oral glucose load versus an isoglycemic
one from continued glucose production from the liver. These
intravenous glucose infusion.31 In nondiabetic control individuals
sources of glucose in combination with a shortened gastric empty-
73% more insulin is released in response to an oral glucose load
ing time can result in marked hyperglycemia.
compared to the same amount of glucose given intravenously (Fig.
77–7, left panel). This increased insulin secretion in response to an Peripheral (Muscle) Muscle is the major site of glucose disposal
oral glucose stimulus is referred to as the incretin effect and suggests in man, and approximately 80% of total body glucose uptake occurs

Insulin Secretion in Response to Nutrient Intravenous glucose

Control Subjects Type 2 Diabetic Subjects Oral glucose
80 80

60 60
IR-Insulin

IR-Insulin
(U/l)

(U/l)

40 40
20 * * * * * * 20 *
* **
0 0
0 60 120 180 0 60 120 180
Time (min) Time (min)

FIGURE 77-7. The loss of the incretin effect in type 2 diabetes mellitus. The plasma insulin responses to oral
and intravenous glucose in nondiabetic subjects (left figure), compared to patients with diabetes (right figure).
(Adapted from Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 [non-insulin
dependent] diabetes. Diabetologia 1986;29:46–52.)
1212
in skeletal muscle.22 In response to a physiologic increase in plasma resistance. These factors drain into the portal circulation and reduce
insulin concentration, muscle glucose uptake increases linearly, insulin sensitivity in peripheral tissues.50
SECTION 8

reaching a plateau value of 10 mg/kg per minute. In contrast, in lean The fat cell also has the capability of producing at least one
type 2 diabetic subjects, the onset of insulin action is delayed for ~40 hormone that improves insulin sensitivity: adiponectin. This factor
minutes, and the ability of insulin to stimulate leg glucose uptake is is made in decreasing amounts as an individual becomes more
reduced by 50%. Therefore the primary site of insulin resistance in obese.51,52 In animal models, adiponectin decreases hepatic glucose
type 2 diabetic subjects resides in muscle tissue. production and increases fatty acid oxidation in muscle.53,54
Peripheral (Adipocyte) In obese nondiabetic and diabetic humans, The Metabolic Syndrome The association of insulin resistance
basal plasma FFA levels are increased and fail to suppress normally with a clustering of cardiovascular risk factors including hyperinsuline-
after glucose ingestion. FFAs are stored as triglycerides in adipocytes mia, hypertension, abdominal obesity, dyslipidemia, and coagulation
Endocrinologic Disorders

and serve as an important energy source during conditions of abnormalities has been referred to by a variety of names including “the
fasting. Insulin is a potent inhibitor of lipolysis, and restrains the insulin resistance syndrome,” “the metabolic syndrome,” “the dysmet-
release of FFAs from the adipocyte by inhibiting the hormone-sensitive abolic syndrome,” and “the deadly quartet,” to name a few. Since the
lipase enzyme. It is now recognized that chronically elevated plasma FFA description of the “insulin resistance syndrome” by Reaven in 1988,55
concentrations can lead to insulin resistance in muscle and liver,20,22,27,38 the number of associated factors has continued to grow.
and impair insulin secretion.29,39,40 In addition to FFAs that circulate The most recent definition of the metabolic syndrome was
in plasma in increased amounts, type 2 diabetic and obese nondia- adopted by the International Diabetes Federation (IDF) in 2005
betic individuals have increased stores of triglycerides in muscle41,42 (Table 77–5).56
and liver,43,44 and the increased fat content correlates closely with In the IDF definition of the metabolic syndrome, central obesity
the presence of insulin resistance in these tissues. is recognized as an important causative factor and is a prerequisite
In summary, insulin resistance involving both muscle and liver component for the diagnosis. Central obesity can be easily assessed
are characteristic features of the glucose intolerance in type 2
diabetic individuals. In the basal state, the liver represents a major
site of insulin resistance, and this is reflected by overproduction of TABLE 77-5 NCEP ATP III: Five Components of the Metabolic
glucose. This accelerated rate of hepatic glucose output is the Syndrome (Individuals Having at Least Three
primary determinant of the elevated FPG concentration in type 2 Components Meet the Criteria for Diagnosis)
diabetic individuals. In the fed state, both decreased muscle glucose Risk Factor Defining Level
uptake and impaired suppression of hepatic glucose production
Abdominal obesity Waist circumference
contribute to the insulin resistance. In obese individuals and in the Men >102 cm (>40 in)
majority (>80%) of type 2 diabetic subjects, there is an expanded fat Women >88 cm (>35 in)
cell mass, and the adipocytes are resistant to the antilipolytic effects Triglycerides ≥150 mg/dL
of insulin. Most obese and diabetic individuals are characterized by High-density–lipoprotein C
expanded visceral adiposity, discussed in detail later in the chapter, Men <40 mg/dL
which is especially refractory to insulin effects and results in a high Women <50 mg/dL
lipolytic rate. Not surprisingly, both type 2 diabetes and obesity are Blood pressure ≥130/≥85 mm Hg
characterized by an elevation in the mean 24-hour plasma FFA Fasting glucose ≥110 mg/dL
concentration. Elevated plasma FFA levels, as well as increased The 2005 IDF definition of metabolic syndrome
For a person to be defined as having the metabolic syndrome they must have:
triglyceride/fatty acyl coenzyme A (CoA) content in muscle, liver,
Central obesity (defined as waist circumference >94 cm for Europid men and >80
and β cells, lead to the development of muscle/hepatic insulin
cm for Europid women, with ethnicity specific values for other groups)
resistance and impaired insulin secretion. Plus any two of the following four factors:
1. Raised TG level: >150 mg/dL (1.7 mmol/L), or specific treatment for this lipid
Cellular Mechanisms of Insulin Resistance abnormality
2. Reduced HDL cholesterol: <40 mg/dL (1.03 mmol/L) in males and <50 mg/
Insulin resistance and the components of the insulin resistance
dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality
syndrome are described below. 3. Raised blood pressure: systolic BP >130 or diastolic BP >85 mm Hg, or
Obesity and Insulin Resistance Weight gain leads to insulin treatment of previously diagnosed hypertension
resistance, and obese nondiabetic individuals have the same degree 4. Raised FPG >100 mg/dL (5.6 mmol/L), or previously diagnosed type 2
of insulin resistance as lean type 2 diabetic patients.45 In 1,146 diabetes
If above 5.6 mmol/L or 100 mg/dL, OGTT is strongly recommended but is not
nondiabetic, normotensive individuals, Ferrannini and associates
necessary to define the presence of the syndrome.
showed a progressive loss of insulin sensitivity when the BMI Ethnic specific values for waist circumference
increased from 18 kg/m2 to 38 kg/m2.46 The increase in insulin Country/Ethnic Group Waist Circumference
resistance with weight gain is directly related to the amount of Europids
visceral adipose tissue.47,48 Men >94 cm
The term visceral adipose tissue (VAT) refers to fat cells located Women >80 cm
within the abdominal cavity and includes omental, mesenteric, retro- South Asians, Chinese
peritoneal, and perinephric adipose tissue. VAT has been shown to Men >90 cm
correlate with insulin resistance and explain much of the variation in Women >80 cm
insulin resistance seen in a population of African Americans.49 Vis- Japanese
ceral adipose tissue represents 20% of fat in men and 6% of fat in Men >85 cm
Women >90 cm
women. This fat tissue has been shown to have a higher rate of
lipolysis than subcutaneous fat, resulting in an increase in FFA ASP III, Adult Treatment Panel III; BP, blood pressure; FPG, fasting plasma glucose; HDL, high-density
production. These fatty acids are released into the portal circulation lipoprotein; OGTT, oral glucose tolerance test; TG, triglyceride.
In the United States, the ATP III values (102 cm male, 88 cm female) are still being used. European
and drain into the liver, where they stimulate the production of very-
cut points are recommended for sub-Saharan Africans and Eastern Mediterranean and Middle East
low-density lipoproteins and decrease insulin sensitivity in peripheral (Arab) populations. South Asian values are recommended for South and Central Americans.
tissues.47 VAT also produces a number of cytokines that cause insulin Reproduced from Expert Panel on Detection.159
 1213
using waist circumference. The IDF has made a “first attempt” to TABLE 77-6 Clinical Presentation of Diabetes Mellitus a
provide ethnic group specific cut points for waist circumference. At

CHAPTER 77
the present time these are pragmatic estimates taken from various Characteristic Type 1 DM Type 2 DM
data sources. As more complete data becomes available these values Age <30 yearsb >30 yearsb
can be modified. Table 77–5 lists the ethnic specific values for waist Onset Abrupt Gradual
circumference. Body habitus Lean Obese or history of
The evolution of definitions of the metabolic syndrome is a result obesity
Insulin resistance Absent Present
of accumulating data correlating degree of risk and specific meta-
Autoantibodies Often present Rarely present
bolic abnormalities in various populations. As more robust data sets
Symptoms Symptomaticc Often asymptomatic
become available, future changes in the component cut points will Ketones at diagnosis Present Absentd

Diabetes Mellitus
be warranted. Need for insulin therapy Immediate Years after diagnosis
Prevalence. Regardless of the definition used, large numbers of Acute complications Diabetic Hyperosmolar hyper-
ketoacidosis glycemic state
U.S. adults have the metabolic syndrome. The National Health and
Microvascular complications at diagnosis No Common
Nutrition Examination Survey (NHANES) 1999 to 2002 is the most
Macrovascular complications at or Rare Common
scientifically rigorous sample of the U.S. population.57 A total of before diagnosis
3,601 men and women aged >20 years were included in the survey.
Using the National Cholesterol Education Program (NCEP) defini- DM, diabetes mellitus.
a
Clinical presentation can vary widely.
tion, the prevalence of metabolic syndrome was 33.7% of men and b
Age of onset for type 1 DM is generally < 20 years of age but can present at any age. The prevalence
35.4% of women. In comparison the prevalence using the IDF of type 2 DM in children, adolescents, and young adults is increasing. This is especially true in ethnic
definition was 39.9% of men and 38.1% of women. The largest and minority children.
c
difference in prevalence was found in Mexican American men Type 1 can present acutely with symptoms of polyuria, nocturia, polydipsia, polyphagia, and weight
loss.
among whom the age-adjusted prevalence was 40.3% using the d
Type 2 children and adolescents are more likely to present with ketones but after the acute phase
NCEP definition and 50.6% using the IDF definition. The percent can be treated with oral agents. Prolonged fasting can also produce ketones in individuals.
agreement between the two definitions was 89.8% among men and
96% among women.
withheld, or under conditions of severe stress with an excess of
In a sample of 4,060 predominantly European adults from South
counterregulatory hormones.2 Twenty to forty percent of patients
Australia, the metabolic syndrome was present in 19.4% of men and
with type 1 DM present with diabetic ketoacidosis after several days
14.4% of women using the Adult Treatment Panel III (ATP III)
of polyuria, polydipsia, polyphagia, and weight loss. Occasionally,
definition.58 Using the IDF definition, the metabolic syndrome was
patients are diagnosed as short of “metabolic bankruptcy” when
identified in 26.4% of men and 15.7% of women. In this population
they have blood tests drawn for other reasons or for early symp-
the IDF, using a smaller waist circumference, categorized 15 to 20%
toms. Because newly diagnosed patients with type 1 DM often have
more individuals as having the metabolic syndrome. Although the
a small amount of residual pancreatic β-cell function, they can enter
prevalence of the metabolic syndrome in these surveys is staggering,
a “honeymoon” phase, when their blood glucose concentrations are
these data are now more than 8 years old, and the prevalence has
relatively easy to control and small amounts of insulin are needed.
almost certainly increased as these populations age and become
Once this residual insulin secretion wanes, the patients are com-
more obese.
pletely insulin deficient and tend to have more labile glycemia.
The impact of treating the clinical components of the metabolic
Patients with type 2 DM often present without symptoms, even
syndrome was demonstrated in the Steno-2 Study.59 In this prospec-
though complications tell us that they may have had type 2 DM for
tive study, 63 patients with diabetes and microalbuminuria were
several years.10 Often these patients are diagnosed secondary to
randomized to the usual therapy group, and 67 patients were
unrelated blood testing. Lethargy, polyuria, nocturia, and polydip-
treated intensively. Intensive therapy consisted of diet and exercise
sia can be seen at diagnosis in type 2 diabetes, but significant weight
and pharmacologic intervention aimed at hyperglycemia, hyperten-
loss at diagnosis is less common.
sion, dyslipidemia, microalbuminuria, and increased coagulopathy
(aspirin therapy). Treatment goals for intensive therapy included a
blood pressure <130/80 mm Hg, HbA1c <6.5%, total cholesterol TREATMENT
<175 mg/dL, and triglycerides <150 mg/dL. All patients in the
intensive treatment group were given an aspirin and treated with an
angiotensin-converting enzyme (ACE) inhibitor. Patients in the
DM
intensively treated group showed a 53% relative risk reduction in ■ DESIRED OUTCOME
cardiovascular disease and a 61% relative risk reduction in nephrop-
athy. In this small study, the magnitude of this reduction is greater  The primary goals of DM management are to reduce the risk for
than has been demonstrated with individual interventions, stressing microvascular and macrovascular disease complications, to amelio-
the importance of targeting all the components of the metabolic rate symptoms, to reduce mortality, and to improve quality of life.8
syndrome. The study design did not allow conclusions regarding Near-normal glycemia will reduce the risk for development of
which interventions had the most impact. microvascular disease complications, but aggressive management of
traditional cardiovascular risk factors (i.e., smoking cessation, treat-
ment of dyslipidemia, intensive blood pressure control, and antiplate-
CLINICAL PRESENTATION let therapy) are needed to reduce the likelihood of development of
macrovascular disease. Evidence-based guidelines, as published by the
The clinical presentations of type 1 DM and type 2 DM are very ADA, can help in the attainment of these goals (Table 77–7).
different (Table 77–6). Autoimmune type 1 DM can occur at any Hyperglycemia not only increases the risk for microvascular
age. Approximately 75% will develop the disorder before age 20 disease, but contributes to poor wound healing, compromises white
years, but the remaining 25%, including relatives of index patients, blood cell function, and leads to classic symptoms of DM. Diabetic
develop the disease as adults. Individuals with type 1 DM are often ketoacidosis and hyperosmolar hyperglycemic state are severe man-
thin and are prone to develop diabetic ketoacidosis if insulin is ifestations of poor diabetes control, invariably requiring hospitaliza-
1214

TABLE 77-7 Selected American Diabetes Association Evidence-Based Recommendationsa

SECTION 8

Recommendation Area Specific Recommendation Evidence Levela

Screening for diabetes Screen overweight at 45 years old, repeat at 3-year intervals E
Screen with fasting plasma glucose or 2-hour 75-g OGTT B
Monitoring Home blood-glucose monitoring is needed if on insulin A
Subjects on other therapeutic interventions, including oral agents may need home blood glucose monitoring E
Quarterly HbA1c in individuals not meeting glycemic goals, twice yearly in individuals meeting glycemic goals should be E
performed
Glycemic goals HbA1c goal for patients in general is <7% B
HbA1c goal for individuals is as close to normal (<6%) as possible without significant hypoglycemia E
Endocrinologic Disorders

Treatment
Medical nutrition therapy Weight loss is recommended for all insulin-resistant/overweight or obese individuals A
Saturated fat should be <7% of total calories A
Monitoring carbohydrate intake by carbohydrate counting or exchanges is recommended. A
Glycemic index can give modest benefits over total carbohydrate intake. B
Low-carbohydrate diets (<130 g of carbohydrate) are not currently recommended as long-term effects are unknown B
Physical activity 150 min/wk of moderate intensity exercise is recommended or 90 minutes of vigorous exercise per week A
Resistance-train large muscle groups 3 times per week A
Blood pressure Systolic blood pressure should be treated to <130 mm Hg C
Diastolic blood pressure should be treated to <80 mm Hg B
Initial drug therapy should be with an ACE inhibitor, angiotensin receptor blocker, diuretic, β-blocker, or calcium channel A
blocker
Nephropathy Type 1 DM with any degree of albuminuria—ACE inhibitor A
Type 2 DM with microalbuminuria—ACE inhibitor or angiotensin receptor blocker A
Type 2 DM with macroalbuminuria—angiotensin receptor blocker A
Dyslipidemia The primary goal is an LDL<100 mg/dL A
If 40 years of age or older, statin therapy to reduce LDL 30–40%, regardless of baseline LDL, is recommended A
LDL<70 mg/dL is an optional goal in individuals with overt cardiovascular (CV) disease C
Triglycerides should be lowered to <150 mg/dL C
Increase HDL to >40 mg/dL in men and >50 mg/dL in women C
Antiplatelet Use aspirin (75–162 mg daily) for secondary cardioprotection A
Use aspirin (75–162 mg) for primary prevention in type 2 DM if the subject is >40 years old or has additional CV risks A
Use aspirin (75–162 mg) for primary prevention in type 1 DM if the subject is >40 years old or has additional CV risks C
ACE, angiotensin-converting enzyme; DM, diabetes mellitus; HbA1c, glycosylated hemogloblin; HDL, hight-density lipoprotein; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test.
a
Evidence levels: A, Clear evidence from well-conducted, generalizable, randomized controlled trials that are adequately powered; B, supportive evidence from well-conducted cohort studies or well-conducted
case-control study; C, supportive evidence from poorly controlled or uncontrolled studies or conflicting evidence with weight of evidence supporting intervention; and E, expert consensus or clinical experience.
Based on American Diabetes Association Practice Recommendations.8

tion. Reducing the potential for microvascular complications is lower values should be targeted if significant hypoglycemia and/or
targeted at adherence to therapeutic lifestyle intervention (i.e., diet weight gain can be avoided.8
and exercise programs) and drug-therapy regimens, as well as at
maintaining blood pressure as near normal as possible. ■ MONITORING COMPLICATIONS
The ADA recommends initiation of complications monitoring at the
■ GENERAL APPROACH TO TREATMENT time of diagnosis of DM.8 Current recommendations continue to
Appropriate care requires goal setting for glycemia, blood pressure, advocate yearly dilated eye examinations in type 2 DM, and an initial
and lipid levels, regular monitoring for complications, dietary and eye examination in the first 3 to 5 years in type 1 DM, then yearly
exercise modifications, medications, appropriate self-monitored thereafter. Less frequent testing (every 2 to 3 years) can be implemented
blood glucose (SMBG), and laboratory assessment of the aforemen- on the advice of an eye care specialist. The feet should be examined and
tioned parameters.8 Glucose control alone does not sufficiently the blood pressure assessed at each visit. A urine test for microalbumin
reduce the risk of macrovascular complications in persons with DM. once yearly is appropriate. Yearly testing for lipid abnormalities, and
more frequently if needed to achieve lipid goals, is recommended.
■ GLYCEMIC GOAL SETTING AND THE
HEMOGLOBIN A1C TABLE 77-8 Glycemic Goals of Therapy

Controlled clinical trials provide ample evidence that glycemic Biochemical Index ADA ACE and AACE
control is paramount in reducing microvascular complications in Hemoglobin A1c <7%a ≤6.5%
both type 1 DM60 and type 2 DM.61 HbA1c measurements are the Preprandial plasma glucose 90–130 mg/dL <110 mg/dL
gold standard for following long-term glycemic control for the (5.0–7.2 mmol/L)
previous 2 to 3 months.62 Hemoglobinopathies, anemia, and red cell Postprandial plasma glucose <180 mg/dLb <140 mg/dL
membrane defects can affect HbA1c measurements. Other strategies (<10 mmol/L)
such as measurement of fructosamine, which measures glycated ADA, American Diabetes Association; ACE, American College of Endocrinology; AACE, American
plasma proteins and correlates to glucose control over the last 2 to Association of Clinical Endocrinologists; DCCT, Diabetes Control and Complications Trial.
a
3 weeks, can be necessary to assess diabetes control in these patients. Referenced to a nondiabetic range of 4.0–6.0% using a DCCT-based assay. More stringent glycemic
goals (i.e., a normal HbA1c, <6%) can further reduce complications at the cost of increased risk of
Unless the risk outweighs the benefit (as in elderly patients, patients hypoglycemia (particularly in those with type 1 diabetes).
with advanced complications, and patients with other advanced b
Postprandial glucose measurements should be made 1–2 hours after the beginning of the meal,
disease), a HbA1c target of <7% is appropriate (Table 77–8), and generally the time of peak levels in patients with diabetes.
 1215

■ SELF-MONITORING OF BLOOD GLUCOSE

fat percentage and decrease the carbohydrate percentage in a

CHAPTER 77
The advent of SMBG in the early 1980s revolutionized the treatment patient’s diet to accomplish improved glycemic control. Recent
of DM, enabling patients to know their blood glucose concentration studies have documented short-term success for weight loss on
at any moment easily and relatively inexpensively. Frequent SMBG low-carbohydrate diets (~6 months), without deleterious effects
is necessary to achieve near-normal blood glucose concentrations on the lipid panel. Weight loss can reduce cardiovascular risk
and to assess for hypoglycemia, particularly in patients with type 1 factors in type 2 DM.
DM.62 The more intense the pharmacologic regimen is, the more
intense the SMBG needs to be (four or more times daily in patients
on multiple insulin injections or pump therapy). The optimal Activity
frequency of SMBG for patients with type 2 DM is unresolved.

Diabetes Mellitus
In general, most patients with DM can benefit from increased
Frequency of monitoring in type 2 DM should be sufficient to activity.65 Aerobic exercise improves insulin resistance and glycemic
facilitate reaching glucose goals. The role of SMBG in improving control in the majority of individuals, and reduces cardiovascular
glycemic control in type 2 DM patients is controversial but has risk factors, contributes to weight loss or maintenance, and
shown to reduce the HbA1c ~0.4%.63 What is clear is that patients improves well-being. The patient should choose an activity that she
must be empowered to change their therapeutic regimen (lifestyle or he is likely to continue. Start exercise slowly in previously
and medications) in response to test results, or no meaningful sedentary patients. Older patients, patients with long-standing dis-
glycemic improvement is likely to be effected. ease (age >35 years, or >25 years with DM ≥10 years), patients with
multiple cardiovascular risk factors, presence of microvascular dis-
ease, and patients with previous evidence of atherosclerotic disease
CLINICAL CONTROVERSY should have a cardiovascular evaluation, probably including an
SMBG improves glycemic control when insulin is used, but few electrocardiogram and graded exercise test with imaging, prior to
well-conducted studies have shown significant glycemic reduc- beginning a moderate to intense exercise regimen. In addition,
tions with increasing use of home blood-glucose testing for type several complications (autonomic neuropathy, insensate feet, and
2 DM patients not on insulin. In a recent review, the average retinopathy) can require restrictions on the activities recom-
HbA1c reduction with use of SMBG in type 2 DM patients not on mended. Physical activity goals include at least 150 minutes/week of
insulin was 0.4%, although others have reported no glycemic moderate (50%–70% maximal hear rate) intensity exercise. In
improvement.63 Patients must be empowered to change their addition, resistance training, in patients without retinal contraindi-
therapeutic regimen (lifestyle and medications) in response to cations, is recommended for 30 minutes three times per week.
test results, or no meaningful glycemic improvement is likely to
be effected, and thus the money spent on the strip is wasted. ■ PHARMACOLOGIC THERAPY
Until 1995, only two options for pharmacologic treatment were
■ NONPHARMACOLOGIC THERAPY available for patients with diabetes; sulfonylureas (for type 2 DM
only) and insulin (for type 1 or 2). Since 1995, a number of new oral
Diet agents, injectables, and insulins have been introduced in the United
Medical nutrition therapy is recommended for all persons with States.
DM.64 Paramount for all medical nutrition therapy is the attain- Currently, six classes of oral agents are approved for the treat-
ment of optimal metabolic outcomes and the prevention and ment of type 2 diabetes: α-glucosidase inhibitors, biguanides,
treatment of complications. For individuals with type 1 DM, the meglitinides, peroxisome proliferator-activated receptor γ-agonists
focus is on regulating insulin administration with a balanced diet to (which are also commonly identified as thiazolidinediones [TZDs]
achieve and maintain a healthy body weight. A meal plan that is or glitazones), DPP-IV inhibitors, and sulfonylureas. Oral antidia-
moderate in carbohydrates and low in saturated fat (<7% of total betic agents are often grouped according to their glucose-lowering
calories), with a focus on balanced meals is recommended. The mechanism of action. Biguanides and TZDs are often categorized
amount (grams) and type (via the glycemic index, although contro- as insulin sensitizers because of their ability to reduce insulin
versial) of carbohydrates, whether accounted for by exchanges or resistance. Sulfonylureas and meglitinides are often categorized as
carbohydrate counting, should be considered.64 It is imperative that insulin secretagogues because they enhance endogenous insulin
patients understand the connection between carbohydrate intake release.
and glucose control. In addition, patients with type 2 DM often New options for implementation of insulin therapy are now
require caloric restriction to promote weight loss. Rather than a set available. Detemir has given an additional option for choice of basal
diabetic diet, advocate a diet using foods that are within the insulin for type 1 and 2 DM patients. Exubera, the first inhaled
financial reach and cultural milieu of the patient. As most patients prandial insulin, was FDA approved, but has been withdrawn from
with type 2 DM are overweight or obese, bedtime and between-meal the market due to poor sales. The subsequent sections describe the
snacks are not needed if pharmacologic management is appropriate. current antidiabetic medications that are available to treat type 1
and type 2 DM.

CLINICAL CONTROVERSY Drug Class Information

The recommended daily carbohydrate intake for type 2 DM, and Insulin Pharmacology. Insulin is an anabolic and anticatabolic
even type 1 DM, has become controversial since low-carbohy- hormone. It plays major roles in protein, carbohydrate, and fat
drate diets such as the Atkins, South Beach, and Carbohydrate metabolism. For a complete review of insulin action, the reader is
Addict’s Diets have become exceptionally popular. Currently, referred to a diabetes physiology text.66 Endogenously produced
the ADA recommends that approximately 45% to 65% of daily
insulin is cleaved from the larger proinsulin peptide in the β cell to
caloric intake should come from carbohydrates and does not
the active peptide of insulin and C-peptide, which can be used as a
recommend restricting diets to <130 grams of carbohydrate a
marker for endogenous insulin production. All commercially avail-
day. Many clinicians are trying to increase the monounsaturated
able insulin preparations contain only the active insulin peptide.
1216

TABLE 77-9 Available Injectable and Insulin Preparations

SECTION 8

Trade/Generic Name Manufacturer Analoga Administration Options Room Temperatureb Expiration

Rapid-acting insulins
Humalog (insulin lispro) Lilly Yes Insulin pen 3-mL, vial, and 3-mL pen cartridge 28 days
NovoLog (insulin aspart) Novo-Nordisk Yes Insulin pen 3-mL, vial, or 3-mL pen cartridge 28 days
Apidra (insulin glulisine) Sanofi-Aventis Yes 3-mL, pen cartridge or Opticlick pen system 28 days
Exubera (inhaled human insulin) Pfizer No 1 and 3-mg blister packs 3 months once foil overwrap opened
Short-acting insulins
Humulin R (regular; human insulin rDNA) Lilly No 100 units, 10-mL vial 28 days
500 units, 20-mL vial
Endocrinologic Disorders

Novolin R (regular; human insulin rDNA) Novo-Nordisk No Insulin pen, vial, or 3-mL pen cartridge, and Vial: 30 days; others: 28 days
InnoLetd
Intermediate-acting insulins
NPH
Humulin N Lilly No Vial, prefilled pen Vial: 28 days; pen: 14 days
Novolin N Novo-Nordisk No Vial, prefilled pen, and InnoLetd Vial: 30 days; others: 14 days
Long-acting insulins
Lantus (insulin glargine) Sanofi-Aventis Yes Vial, 3-mL Opticlick pen cartridge 28 days
Levemir (insulin detemir) Novo-Nordisk Yes Vial, 3-mL pen cartridge and pen, InnoLetd 42 days
Pre-mixed insulins
Premixed insulin analogs
Humalog Mix 75/25 (75% neutral protamine Lilly Yes Vial, prefilled pen Vial: 28 days; pen: 10 days
lispro, 25% lispro)
NovoLog Mix 70/30 (70% aspart protamine Novo-Nordisk Yes Vial, prefilled pen, 3-mL pen cartridge Vial: 28 days; others: 14 days
suspension, 30% aspart)
Humalog Mix 50/50 (50% neutral protamine Lilly Yes 3-mL pen 10 days
lispro/ 50% lispro)
NPH-regular combinations
Humulin 70/30 Lilly No Vial, prefilled pen Vial: 28 days; pen: 10 days
Novolin 70/30 Novo-Nordisk No Vial, pen cartridge, InnoLetc Vial: 30 days; others: 10 days
Humulin 50/50 Lilly No Vial 28 days
Other injectables
Byetta (exenatide) Amylin/Lilly No 5 mcg and 10 mcg pen, ~60 injections (doses)/ Pen in use can be used at room
pen temperature
(< 25°C [< 77° F ])
Symlin (pramlintide) Amylin Yes 5-mL vial 28 days
NPH, neutral protamine Hagedern.
a
All insulins available in the United States are now made by human recombinant DNA technology. An insulin analog is a modified human insulin molecule that imparts particular pharmacokinetic advantages.
b
Room temperature defined as 15–30°C (59–86°F).
c
InnoLet: A prefilled insulin pen with a “kitchen timer” type of dial for determining the number of insulin units. Can be useful in patients with impaired eyesight or dexterity.
Adapted from the Texas Diabetes Council.

Characteristics. Characteristics that are commonly used to cate- Purity of insulin refers to the amount of proinsulin and other
gorize insulins include source, strength, onset, and duration of action. impurities present in a given insulin product. Prior to 1980, most
Additionally, insulins can be characterized as analogs, defined as insulin contained enough impurities (300 to 10,000 ppm) to cause
insulins that have had amino acids within the insulin molecule local reactions on injection, as well as systemic adverse effects from
modified to impart particular physiochemical and pharmacokinetic antibody production. Modern technology has provided less expensive
advantages. Table 77–9 summarizes available insulin preparations. techniques to purify insulin. As a result, all insulin products contain
The strengths of injectable insulin currently available in the ≤10 ppm of proinsulin, with purified preparations (all rDNA human
United States are 100 units/mL (U-100) and 500 units/mL (U-500). insulin and insulin analogs) containing <1 ppm of proinsulin.
For individuals who require large doses of insulin to control their Regular crystalline insulin naturally self-associates into a hexameric
diabetes, 500 units/mL regular insulin is available. In the United (six insulin molecules) structure when injected subcutaneously.
States, all other insulins are available only in 100 units/mL strength. Before absorption through a blood capillary can occur, the hexamer
For some type 1 diabetes patients who require extremely low doses must dissociate first to dimers, and then to monomers. This principle
of insulin, dilution of 100 units/mL insulin to obtain accurate is the premise for additives such as protamine and zinc described
insulin doses can be necessary. Diluents and empty bottles can be below, and modification of amino acids for insulin analogs. Lispro,
obtained from the manufacturers for dilution. aspart, and glulisine insulins dissociate rapidly to monomers, thus
Historically, insulin came from either beef or pork sources. Beef absorption is rapid. Lispro (B-28 lysine and B-29 proline human
insulin differs by three amino acids and pork by one amino acid insulin; monomeric) insulin with two amino acids transposed, aspart
when compared to human insulin. Manufacturers in the United (B-28 aspartic acid human insulin; mono- and dimeric) insulin with
States have discontinued production of beef and pork source replacement of one amino acid, and glulisine (B-3 lysine and B-29
insulins as of December 2003, and now exclusively use recombinant glutamic acid) are rapidly absorbed, peak faster, and have shorter
DNA (rDNA) technology to manufacture insulin. Eli Lilly, Pfizer, durations of action when compared to regular insulin. In comparison
and Sanofi-Aventis currently use a non–disease-producing strain of to human insulin, with an isoelectric point of 5.4, the analog glargine
Escherichia coli for synthesis of insulin, whereas Novo Nordisk uses insulin (A-21 glycine, B-30a-arginine, B-30a L-arginine, and B-30b L-
Saccharomyces cerevisiae, or bakers’ yeast, for synthesis. arginine human insulin) has an isoelectric point of 6.8. In the bottle,
 1217
glargine is buffered to a pH of 4, a level at which it is completely As detemir has a unique mechanism to prolong absorption, it
soluble, resulting in a clear colorless solution. When injected into the should not be surprising that its pharmacokinetics are unique. The

CHAPTER 77
neutral pH of the body, it rapidly forms microprecipitates that slowly onset of detemir is consistent across doses, but the peak is delayed
dissolve into monomers and dimers which are then subsequently slightly with higher dosing. Also, at low dose (0.2 units/kg) the
absorbed. The result is a long-acting, peakless, 24-hour duration duration of action is approximately 14 hours, whereas at higher
insulin analog. Detemir, in contrast, attaches a C14 fatty acid (a 14 doses it is close to 24 hours.
carbon fatty acid) at the B-29 position and removes the B-30 amino The half-life of an intravenous (IV) injection of regular insulin is
acid. This allows the fatty acid side chain to bind to interstitial approximately 9 minutes. Thus the effective duration of action of a
albumin at the subcutaneous injection site. Also, the formulation single IV injection is short, and changes in IV insulin rates will reach
allows stronger hexamer (six molecules of insulin associated together) steady state in approximately 45 minutes. Intravenous pharmacok-

Diabetes Mellitus
associations, which prolong absorption. Once detemir dissociates inetics of other soluble insulins (lispro, aspart, glulisine, and even
from the interstitial albumin, it is free to enter a capillary, where it is glargine) appear similar to IV regular insulin, but they have no
again bound to albumin. It then travels to a site of action and advantages over IV regular insulin and are more expensive.
interacts, after dissociation from albumin, with insulin receptors. Insulin is degraded in the liver, muscle, and kidney. Liver deacti-
Insulin analogs are modified human insulin molecules, and safety vation is 20% to 50% in a single passage. Approximately 15% to
is paramount for FDA approval. Key factors that should be consid- 20% of insulin metabolism occurs in the kidney. This can partially
ered in the approval process include local injection reactions, explain the lower insulin dosage requirements in patients with end-
antigenicity, efficacy compared to human insulin, insulin receptor stage renal disease.
binding affinity, and insulin-like growth factor 1–receptor affinity
Human Insulin (rDNA Origin) Inhalation Powder (Exubera)
(which is compared to that of human insulin to determine mitoge-
Due to poor sales, Exubera was recently discontinued, and subjects
nic potential).
were asked to be switched to alternative treatments. Exubera was the
Pharmacokinetics. Subcutaneous injection kinetics are depen- first inhaled insulin, and was formulated to easily reach the alveolar
dent on onset, peak, and duration of action, and are summarized in space. Bronchial tubes are impermeable to insulin, but it is easily
Table 77–10. The pharmacokinetic considerations for Exubera will absorbed across the alveoli. The onset and peak of Exubera insulin
be discussed later in the section. Absorption of insulin from a after inhalation is similar to rapid-acting insulin analogs, but the
subcutaneous depot is dependent on several factors, including: duration of action is similar to regular insulin (see Table 77–10).
source of insulin, concentration of insulin, additives to the insulin Exubera consists of blister packets labeled as 1 mg or 3 mg of human
preparations (e.g., zinc, protamine, etc.), blood flow to the area insulin inhalation powder, which are administered using the Exubera
(rubbing of injection area, increased skin temperature, and exercise inhaler. After an Exubera blister is inserted into the inhaler, the
in muscles near the injection site can enhance absorption), and patient pumps the handle of the inhaler. When the patient presses a
injection site. Regular or neutral protamine Hagedorn (NPH) “fire” button, the insulin blister is pierced and the insulin inhalation
insulin is commonly injected in (from most rapid to slowest powder is dispersed into the chamber, allowing inhalation. Normally,
absorption): abdominal fat, posterior upper arms, lateral thigh area, up to 45% of the 1 mg blister contents and up to 25% of the 3 mg
and superior buttocks area. Insulin analogs, unlike regular or NPH blister contents can be retained in the blister. The 1 mg blister packet
insulin, appear to retain their kinetic profile at all sites of injection. is equal to ~3 units of subcutaneously injected insulin and the 3 mg
When compared to 100 units/mL insulin, 500 units/mL regular blister packet is equal to ~8 units. One puff of a 3 mg blister is not
insulin has a delayed onset, peak, and a longer duration of action. equivalent to three 1 mg blisters, which will deliver a higher dose of
Addition of protamine (NPH, insulin lispro protamine [NPL], and insulin than the one 3 mg blister. Human insulin inhalation powder
aspart protamine suspension) or excess zinc (historically lente or should be given as prandial insulin, and the efficacy is equivalent to
ultralente insulin) will delay onset, peak, and duration of the rapid-acting injected insulin analogs. Human insulin inhalation pow-
insulin’s effect. Variability in absorption, inconsistent suspension of der can be used in type 1 or type 2 DM, though the smallest increment
the insulin by the patient or healthcare provider when drawing up a between inhaled doses is equivalent to 2 to 3 units injected subcuta-
dose, and inherent insulin action based on the pharmacokinetics of neously. This can restrict the usefulness in many patients with type 1
the products can all contribute to a labile glucose response. NPH DM, who may have large reductions in glucose with a single unit of
should be inverted or rolled gently at least 10 times to fully insulin. The following patient populations have relative contraindica-
resuspend the insulin prior to each use. tions to Exubera: chronic smoking in last 6 months, which increases

TABLE 77-10 Pharmacokinetics of Various Insulins Administered Subcutaneously or Inhaled

Type of Insulin Onset (Hours) Peak (Hours) Duration (Hours) Maximum Duration (Hours) Appearance
Rapid-acting
Aspart 15–30 min 1–2 3–5 5–6 Clear
Lispro 15–30 min 1–2 3–4 4–6 Clear
Glulisine 15–30 min 1–2 3–4 5–6 Clear
Inhaled human insulin 15–30 min 1–2 6 8 Powder
Short-acting
Regular 0.5–1.0 2–3 3–6 6–8 Clear
Intermediate-actinga
NPH 2–4 4–6 8–12 14–18 Cloudy
Long-acting
Detemir 2 hours 6–9 14–24b 24 Clear
Glargine 4–5 — 22–24 24 Clear
NPH, neutral protamine Hagedorn.
a
Lente and ultralente insulin has been discontinued.
b
See text for further discussion.
Adapted from the Texas Diabetes Council.
1218
absorption two- to fivefold when compared to nonsmokers; chronic approximately 3 years. This was most evident in subjects who were
passive smoke, which reduces absorption of insulin inhalation; insulin-naïve or had a low cardiovascular risk prior to the acute
SECTION 8

asthma, which decreases Exubera absorption, but bronchodilator use myocardial infarction.72 The importance of glycemic control in
prior to insulin inhalation can increase absorption; chronic obstruc- hospitalized patients is covered later in the chapter.
tive pulmonary disease (COPD), which increases the absorption of
insulin inhalation; and other chronic lung diseases. A dry cough near Adverse Effects. The most common adverse effects reported
inhalation, increased sputum, and dyspnea are the three most com- with insulin are hypoglycemia and weight gain. Hypoglycemia is
mon drug-related side effects. Hypoglycemia rates are similar to more common in patients on intensive insulin therapy regimens
regular insulin. There was a small, but statistically significant decrease versus those on less-intensive regimens. Also, patients with type 1
in forced expiratory volume in the first second of expiration (FEV1) DM tend to have more hypoglycemic events compared to type 2
DM patients. In the UKPDS, performed over 10 years, the percent-
Endocrinologic Disorders

and diffusing capacity of the lung for carbon monoxide (DLCO) in

type 1 DM (T1DM) patients treated with Exubera. Two-year safety age of diabetic patients who needed assistance (third-party or
data indicate that in both T1DM and type 2 DM (T2DM) changes in hospitalization) because of a hypoglycemic reaction was 2.3%. The
FEV1 and DLCO are small (<1%–2% from baseline), occur within the UKPDS reported a rate of 36.5% for risk of any hypoglycemic event,
first 3 months of initiation, and the defect is reversible with discontin- including mild, self-treated events. In the DCCT, tighter control
uation of therapy. A decline in FEV1 or DLCO of ≥20% occurred in produced a risk three times higher for severe hypoglycemia com-
1.5% versus 1.3%, and 5.1% versus 3.6% for Exubera and the compar- pared to conventional therapy. Glycemic goals should incorporate
ator group, respectively. Pulmonary function testing is recommended hypoglycemic risk versus the benefit of lowering the glucose when
at baseline, after 6 months of therapy, and annually thereafter, even if HbA1c levels are near normal, especially in type 1 DM.
no symptoms are present. If the FEV1 or DLCO declines by ≥20% on Minimization of risk for patients on insulin should include educa-
followup testing, the test should be repeated, and if confirmed, tion about the signs and symptoms of hypoglycemia, proper treat-
Exubera should be discontinued other inhaled insulin systems are in ment of hypoglycemia, and blood glucose monitoring. Blood glucose
development.67 Other inhaled insulin systems are in development. monitoring is essential for those on insulin, and is particularly of
value in patients with hypoglycemia unawareness. Patients with
Efficacy. The efficacy of traditional insulins (e.g., regular and NPH hypoglycemia unawareness do not experience the normal sympa-
insulins) is unequivocal. Insulin analog efficacy is measured via the thetic symptoms of hypoglycemia (tachycardia, tremulousness, and
same ways as traditional insulins. Insulin analogs in most studies often, sweating). Initial hypoglycemia symptoms are neuroglyco-
have not shown superior HbA1c levels when compared to traditional penic in nature (confusion, agitation, loss of consciousness, and/or
insulins but are often preferred by patients and practitioners progression to coma). Patients with hypoglycemia unawareness
because of their ability to more closely mimic normal insulin often should at least temporarily raise their glycemic goals (requiring
secretion profiles. Lispro, aspart, glulisine, and Exubera are advan- a reduction in insulin dose) and check their blood glucose level prior
tageous because of the ability to administer within 10 minutes of a to any activities that can be dangerous with a low blood sugar (e.g.,
meal, as compared to the recommendation to inject regular insulin driving and certain sports, among others). Proper treatment of
approximately 30 minutes prior. Rapid-acting analogs have shown hypoglycemia dictates ingestion of carbohydrates, with glucose being
superior postprandial lowering of glucose when compared to regu- preferred. Unconsciousness is an indication for either IV glucose, or
lar insulin. Both detemir and glargine insulin injected at bedtime glucagon injection, which increases glycogenolysis in the liver. Glu-
have shown significantly less nocturnal hypoglycemia when com- cagon use would be appropriate in any situation in which the patient
pared to NPH injected at bedtime. does not have or cannot have ready IV access for glucose administra-
An educated patient in conjunction with a skilled practitioner can tion. Education for reconstitution and injection of glucagon is
achieve excellent glycemic control with insulin therapy. Efficacy recommended for close friends and family of a patient who has
with insulin therapy is related to achieving glycemic control while recurrent neuroglycopenic events. The patient and close contacts
minimizing the risk of potential side effects, specifically hypoglyce- should be informed that it can take 10 to 15 minutes for the injection
mia and weight gain. Insulin is recommended in patients with: to start increasing glucose levels, and patients often vomit during this
extremely high FPG levels (>280 to 300 mg/dL) or HbA1c, patients time. Proper positioning to avoid aspiration should be emphasized.
with ketonuria or ketonemia, symptomatic patients (weight loss Weight gain is predominantly from increased truncal fat, and
with polyuria, polydipsia, and/or nocturia), GDM, and if deemed tends to be related to daily dose and plasma insulin levels present.
appropriate by the clinician and patient.68–71 Weight gain is undesirable in most type 2 DM patients, but can be
Microvascular Complications. Insulin has been shown to be as seen as beneficial in underweight patients with type 1 DM. Weight
efficacious as any oral agent for treating DM. The UKPDS, which gain appears to be related to intensive insulin therapy, and can be
used sulfonylureas or insulin, showed equal efficacy in lowering the somewhat minimized by physiologic replacement of insulin.
risk of microvascular events in newly diagnosed type 2 DM.61 Two forms of lipodystrophy, although much less common today
Similarly, in type 1 DM the DCCT showed efficacy in reducing in people with diabetes, still occur. Lipohypertrophy is caused by
microvascular complications.60 many injections into the same injection site. Because of insulin’s
anabolic actions, a raised fat mass is present at the injection site with
Macrovascular Complications. The connection between high resultant variable insulin absorption. Lipoatrophy, in contrast, is
insulin levels (hyperinsulinemia), insulin resistance, and cardiovas- thought to be caused by insulin antibodies, with destruction of fat
cular events incorrectly leads some clinicians to believe that insulin at the site of injection. Injection away from the site with more
therapy can cause macrovascular complications. The UKPDS and purified insulin is recommended, although several reports of lipoat-
DCCT found no differences in macrovascular outcomes with inten- rophy with lispro have been reported.
sive insulin therapy. One study, the Diabetes Mellitus, Insulin
Glucose Infusion in Acute Myocardial Infarction study,72 reported Drug-Drug Interactions. There are no significant drug-drug
reductions in mortality with insulin therapy. This group assessed interactions with injected insulin, although other medications that
the effect of an insulin-glucose infusion in type 2 DM patients who can affect glucose control can be considered. Detemir does not
had experienced an acute myocardial infarction. Those randomized appear to have albumin binding interactions, as it occupies only a
to insulin infusion followed by intensive insulin therapy lowered small percent of albumin binding sites. Table 77–11 lists common
their absolute mortality risk by 11% over a mean followup period of medications known to affect blood glucose levels.
 1219

TABLE 77-11 Medications That Can Affect Glycemic Controla disposition. Unlike GLP-1, exenatide does not increase gastric
secretions.

CHAPTER 77
Effect on
Drug Glucose Mechanism/Comment Pharmacokinetics. Exenatide concentrations are detectable in
Angiotensin-converting Slight reduction Improves insulin sensitivity
plasma within 10 to 15 minutes after subcutaneous injection, and the
enzyme inhibitors drug has a time of maximal concentration (tmax) of ~2 hours and a
Alcohol Reduction Reduces hepatic glucose production plasma half life of ~3.3 to 4.0 hours. Exenatide plasma concentrations
Interferon alfa Increase Unclear increase in a dose-dependent manner and plasma exenatide concen-
Diazoxide Increase Decreases insulin secretion, trations are detectable for up to 10 hours postinjection, although
decreases peripheral glucose use pharmacodynamically, effects last for approximately 6 hours. Bio-
Diuretics Increase Can increase insulin resistance availability of exenatide after injection in the abdomen, upper arm, or

Diabetes Mellitus
Glucocorticoids Increase Impairs insulin action the thigh is similar. Elimination of exenatide is primarily by glomer-
Nicotinic acid Increase Impairs insulin action, increases ular filtration with subsequent proteolytic degradation. When
insulin resistance
exenatide is administered to subjects with worsening degrees of renal
Oral contraceptives Increase Unclear
insufficiency, there is a progressive prolongation of the half-life, and
Pentamidine Decrease, then Toxic to β cells; initial release of
increase stored insulin, then depletion in dialysis patients, plasma clearance of exenatide is markedly
Phenytoin Increase Decreases insulin secretion reduced. The incidence of GI side effects appears to be increased in
β-Blockers Can increase Decreases insulin secretion individuals with impaired renal function, possibly because of higher
Salicylates Decrease Inhibition of I-kappa-B kinase-beta plasma levels, thus caution is advised.
(IKK-beta) (only high doses, e.g., No significant differences in exenatide pharmacokinetics have
4–6 g/day) been observed with obesity, race, gender, or advancing age (up to 73
Sympathomimetics Slight increase Increased glycogenolysis and gluco- years old).
neogenesis
Clozapine and Increase Decrease insulin sensitivity; weight Efficacy. The average HbA1c reduction is approximately 0.9% with
olanzapine gain exenatide, although, similar to oral agents, it is dependent on the
a
baseline HbA1c values. Three phase III trials reported similar HbA1c
This list is not inclusive of all medications reported to cause glucose changes.
reduction in patients on metformin, sulfonylureas, or both.
Exenatide significantly decreases postprandial glucose excursions
but has only a modest effect on FPG values. If a patient has
Dosing and Administration. The dose of insulin for any person
significant elevations in FPG levels, these should be corrected with
with altered glucose metabolism must be individualized. In type 1
other agents, and the exenatide added on. Exenatide can allow some
DM, the average daily requirement for insulin is 0.5 to 0.6 units/kg,
patients to lose weight. The average weight loss in controlled trials
with approximately 50% being delivered as basal insulin, and the
was 1 to 2 kg over 30 weeks, without dietary advice being given to
remaining 50% dedicated to meal coverage. During the honeymoon
the patients, although long-term, open-label followup on 10 mcg
phase it can fall to 0.1 to 0.4 units/kg. During acute illness or with
twice daily shows continued weight loss for at least 2.5 years.
ketosis or states of relative insulin resistance, higher dosages are
Exenatide, through decreasing appetite and slowing gastric empty-
warranted. In type 2 DM a higher dosage is required for those
ing, can reduce the number of calories a patient eats at a meal.
patients with significant insulin resistance. Dosages vary widely
depending on underlying insulin resistance and concomitant oral Microvascular Complications. Exenatide reduces the HbA1c
insulin sensitizer use. Strategies on how to initiate and monitor level, which have been shown to be related to the risk of microvas-
insulin therapy will be described later in the therapeutics section. cular complications.
Storage. It is recommended that unopened injectable insulin be Macrovascular Complications. No published clinical trials
refrigerated (2.2° to 7.7°C [36° to 46°F]) prior to use. The manufac- have examined the effect of exenatide on cardiovascular outcomes.
turer’s expiration date printed on the insulin is used for unopened, However, improvements in several cardiovascular risk factors have
refrigerated insulin. Once the insulin is in use, the manufacturer- been reported. Plasma triglycerides (–37 ± 10 mg/dL) decreased
recommended expiration dates will vary based on the insulin and and, plasma HDL cholesterol (+4.5 ± 0.4 mg/dL) increased on
delivery device. Table 77–9 outlines manufacturer-recommended exenatide 10 mcg twice daily. Nonsignificant reductions in systolic
expiration dates for room temperature (15° to 30°C [59° to 86°F]) and diastolic blood pressure were observed. The greatest improve-
insulin, including Exubera. For financial reasons, patients can ment in cardiovascular risk factors was seen in subjects who had the
attempt to use insulins longer than their expiration dates, but greatest weight loss.73
careful attention must be paid to monitoring for glycemic control
Adverse Effects. The most common adverse effects associated
deterioration and signs of insulin decay (clumping, precipitates,
with exenatide are GI in nature. Nausea occurs in ~40% of subjects
discoloration, etc.) if this is attempted.
on 5 mcg, and ~45% to 50% of subjects on 10 mcg twice daily.
Exenatide Pharmacology. Exendin-4 is a 39-amino acid pep- Vomiting or diarrhea occurs in approximately 10% of patients
tide isolated from the saliva of the Gila monster (heloderma suspec- placed on exenatide. GI adverse effects appear to decrease over time,
tum) and shares approximately 50% amino acid sequence with but approximately 1 in 20 patients can have prolonged problems
human GLP-1. Exenatide is the synthetic analog to exendin-4. with one of the above side effects, possibly requiring discontinuation.
Exenatide (Byetta) has been shown to bind to GLP-1 receptors in As these adverse effects appear to be dose-related, the patient should
many parts of the body including the brain and pancreas. Exenatide be started on 5 mcg twice daily and titrated to 10 mcg twice daily
and GLP-1 have common glucoregulatory actions. Exenatide only if the adverse effects are mostly gone. Also, when the patient is
enhances glucose dependent insulin secretion while suppressing increased to the 10 mcg twice daily dose, these adverse effects can
inappropriately high postprandial glucagon secretion in the pres- recur for a short period of time. Many episodes of nausea would be
ence of elevated glucose concentrations, resulting in a reduction in better characterized as stomach fullness, and patients should be
hepatic glucose production. Exenatide reduces food intake, which instructed to eat slow and stop eating when full, or risk nausea and
can result in weight loss, and slows gastric emptying so that the rate vomiting. Also, weight loss appears not to be related to adverse
of glucose appearance into the plasma better matches the glucose effects but rather to a reduction in calories consumed. Exenatide
1220
provides glucose-dependent insulin secretion, thus hypoglycemic Macrovascular Complications. No published clinical trials have
rates when combined with metformin or a TZD are not increased, examined the effect of pramlintide on cardiovascular outcomes.
SECTION 8

but when combined with a sulfonylurea or insulin, significant

Adverse Effects. The most common adverse effects associated
hypoglycemia can occur. Although exenatide reduces glucagon when
with pramlintide are GI in nature. Nausea occurs in ~20% of type 2
the glucose is high, no suppression of counter-regulatory hormones
DM patients, and vomiting or anorexia occurs in approximately
has been noted during hypoglycemia. Exenatide antibodies can
10% of type 1 or type 2 DM patients. Nausea is more common in
occur, but generally decrease over time and do not affect glycemic
type 1 DM, occurring in ~40% to 50% of patients. GI adverse effects
control. In approximately 5% of patients, titers can increase over
appear to decrease over time and are dose related, thus starting at a
time, resulting in a blunting of glycemic control in approximately
low dose and slowly titrating as tolerated is recommended. Pramlin-
one-half of these patients.
tide alone does not cause hypoglycemia, but it is indicated for use in
Endocrinologic Disorders

Drug Interactions. Exenatide delays gastric emptying, thus it can patients on insulin, thus hypoglycemia can occur. The risk of severe
delay the absorption of other medications. Examples of medications hypoglycemia early in therapy is higher in type 1 DM than in type 2
that can be affected include oral pain medications and antibiotics DM patients. A twofold increase in severe hypoglycemic reactions in
dependent on threshold levels for efficacy. If rapid absorption of the type 1 DM patients has been reported.
medication is necessary, it is best to take the medication 1 hour
Drug Interactions. Pramlintide delays gastric emptying, thus it
before, or at least 3 hours after the injection of exenatide. In addition,
can delay the absorption of other medications. Examples of medica-
if the patient has gastroparesis, exenatide is not recommended.
tions that can be affected include oral pain medications and antibi-
Dosing and Administration. Exenatide dosing should be started otics dependent on threshold levels for efficacy. If rapid absorption
with 5 mcg twice daily, and titrated to 10 mcg twice daily in 1 month of the medication is necessary, it is best to take the mediation 1 hour
or when tolerability allows and if warranted. Exenatide should be before, or at least 3 hours after the injection of pramlintide.
injected 0 to 60 minutes before the morning and evening meals. If the
Dosing and Administration. Pramlintide dosing varies in type
patient does not eat breakfast, they can take the first injection of the
1 and type 2 DM. It is imperative that the prandial insulin dose, if
day at lunch. The peak effect of exenatide is at approximately 2 hours,
used, be reduced 30% to 50% when pramlintide is started to
so anecdotally the patient can get better appetite suppression if
minimize severe hypoglycemic reactions. Basal insulin may need to
injected 30 minutes to 1 hour prior to the meal. Storage and dosage
be adjusted only if the FPG is close to normal. In type 2 DM, the
availability information can be found in Table 77–9.
starting dose is 60 mcg prior to major meals, and can be titrated to
Pramlintide Pharmacology. Pramlintide (Symlin) is an anti- the maximally recommended 120 mcg dose as tolerated and war-
hyperglycemic agent used in patients currently treated with insulin. ranted based on postprandial plasma glucose concentrations. In
Pramlintide is a synthetic analog of amylin (amylinomimetic), a type 1 DM dosing starts at 15 mcg prior to each meal and can be
neurohormone co-secreted from the β cells with insulin. Pramlin- titrated up to a maximum of 60 mcg prior to each meal if tolerated
tide suppresses inappropriately high postprandial glucagon secre- and warranted. Pramlintide comes in a vial, allowing individualiza-
tion, reduces food intake, which can result in weight loss, and slows tion of titration at even smaller increments (by units) than the
gastric emptying so that the rate of glucose appearance into the package insert recommends. Each 2.5 units on a 100 units/mL
plasma better matches the glucose disposition. insulin syringe equals 15 mcg of pramlintide. In addition, pramlin-
tide has a pH of 4, and it is not recommended that pramlintide be
Pharmacokinetics. The absolute bioavailability of pramlintide
mixed with any other insulin, thus this potentially adds two to four
after subcutaneous injection is 30% to 40%. The tmax is approxi-
additional injections a day. Storage information can be found in
mately 20 minutes, but the maximal drug concentration (Cmax) is
Table 77–9.
dose dependent and appears to be linear. The half-life (t1/2) is
approximately 45 minutes, thus the pharmacodynamic duration of Sulfonylureas Pharmacology. The primary mechanism of action
action is approximately 3 to 4 hours. Pramlintide does not exten- of sulfonylureas is enhancement of insulin secretion. Sulfonylureas
sively bind to albumin, and should not have significant binding bind to a specific sulfonylurea receptor (SUR) on pancreatic β cells.
interactions. Metabolism is primarily by the kidneys, and one active Binding closes an adenosine triphosphate–dependent potassium ion
metabolite (2–37 pramlintide) has a similar half-life as the parent (K+) channel, leading to decreased potassium efflux and subsequent
compound. No accumulation has been seen in renal insufficiency, depolarization of the membrane. Voltage-dependent calcium ion
but caution is advised. Injection into the arm can increase exposure (Ca+2) channels open and allow an inward flux of Ca+2. Increases in
and variability of absorption, so injection into the abdomen or thigh intracellular Ca+2 cause translocation of secretory granules of insulin
is recommended. to the cell surface and resultant exocytosis of the granule of insulin.
Elevated secretion of insulin from the pancreas travels via the portal
Efficacy. The average HbA1c reduction is approximately 0.6% with
vein and subsequently suppresses hepatic glucose production.
pramlintide, although optimization of the insulin and pramlintide
doses can result in further drops in HbA1c. If the 120 mcg dose is used Classification. Sulfonylureas are classified as first-generation and
in type 2 DM patients on insulin, it can also result in 1.5 kg weight second-generation agents. The classification scheme is largely
loss. In type 1 DM patients, the average reduction in HbA1c was 0.4% derived from differences in relative potency, relative potential for
to 0.5%. Pramlintide decreases prandial glucose excursions but has selective side effects, and differences in binding to serum proteins
little effect on the FPG concentration. The main advantage of pram- (i.e., risk for protein-binding displacement drug interactions). First-
lintide is in type 1 DM, where it helps to stabilize wide postprandial generation agents consist of acetohexamide, chlorpropamide,
glycemic swings. The average weight loss in controlled trials was 1 to tolazamide, and tolbutamide. Each of these agents is lower in
2 kg, without dietary advice being given to the patients. Pramlintide, potency relative to the second-generation drugs: glimepiride, glipiz-
through decreasing appetite and slowing gastric emptying, can reduce ide, and glyburide (Table 77–12). It is important to recognize that
the number of calories a patient eats at a meal. all sulfonylureas are equally effective at lowering blood glucose
when administered in equipotent doses.
Microvascular Complications. Pramlintide reduces the HbA1c
level, which has been shown to be related to the risk of microvascu- Pharmacokinetics. All sulfonylureas are metabolized in the liver;
lar complications. some to active, others to inactive metabolites (see Table 77–12).
 1221

TABLE 77-12 Oral Agents for the Treatment of Type 2 Diabetes Mellitus

CHAPTER 77
Generic Name Recommended Starting
(generic ver- Dosage (mg/day) Equivalent
sion available? Therapeutic Maximum Dose Duration of Metabolism or
Y = yes, N = no) Brand Dose (mg) Nonelderly Elderly Dose (mg) (mg/day) Action Therapeutic Notes
Sulfonylureas
Acetohexamide Dymelor 250, 500 250 125–250 500 1,500 Up to 16 Metabolized in liver; metab-
(Y) hours olite potency equal to par-
ent compound; renally
eliminated

Diabetes Mellitus
Chlorpropamide Diabinese 100, 250 250 100 250 500 Up to 72 Metabolized in liver; also
(Y) hours excreted unchanged
renally
Tolazamide (Y) Tolinase 100, 250, 100–250 100 250 1,000 Up to 24 Metabolized in liver; metab-
500 hours olite less active than par-
ent compound; renally
eliminated
Tolbutamide Orinase 250, 500 1,000–2,000 500–1,000 1,000 3,000 Up to 12 Metabolized in liver to inac-
(Y) hours tive metabolites that are
renally excreted
Glipizide (Y) Glucotrol 5, 10 5 2.5–5 5 40 Up to 20 Metabolized in liver to inac-
hours tive metabolites
Glipizide (Y) Glucotrol XL 2.5, 5, 10, 20 5 2.5–5 5 20 24 hours Slow-release form; do not
cut tablet
Glyburide (Y) DiaBeta 1.25, 2.5, 5 5 1.25–2.5 5 20 Up to 24 Metabolized in liver; elimi-
Micronase hours nation 1/2 renal, 1/2 feces
Glyburide, Glynase 1.5, 3, 6 3 1.5–3 3 12 Up to 24 Equal control, but better
micronized (Y) hours absorption from micron-
ized preparation
Glimepiride (Y) Amaryl 1, 2, 4 1–2 0.5–1 2 8 24 hours Metabolized in liver to inac-
tive metabolites
Short-acting insulin secretagogues
Nateglinide (N) Starlix 60, 120 120 with 120 with meals NA 120 mg three Up to 4 Metabolized by cytochrome
meals times a day hours P450 (CYP450), CYP2C9,
and CYP3A4 to weakly
active metabolites; renally
eliminated
Repaglinide (N) Prandin 0.5, 1, 2 0.5–1 with 0.5–1 with NA 16 Up to 4 Metabolized by CYP3A4 to
meals meals hours inactive metabolites;
excreted in bile
Biguanides
Metformin (Y) Glucophage 500, 850, 500 mg twice Assess renal NA 2,550 Up to 24 No metabolism; renally
1,000 a day function hours secreted and excreted
Metformin Glucophage 500, 750, 500–1,000 Assess renal NA 2,550 Up to 24 Take with evening meal or
extended- XR 1,000 mg mg with function hours may split dose; can con-
release (Y) evening sider trial if intolerant to
meal immediate-release
Thiazolidinediones
Pioglitazone Actos 15, 30, 45 15 15 NA 45 24 hours Metabolized by CYP2C8 and
(N) CYP3A4; two metabolites
have longer half-lives than
parent compound
Rosiglitazone Avandia 2, 4, 8 2–4 2 NA 8 mg/day or 4 mg 24 hours Metabolized by CYP2C8 and
(N) twice a day CYP2C9 to inactive metabo-
lites that are renally excreted
α-Glucosidase inhibitors
Acarbose (N) Precose 25, 50, 100 25 mg one to 25 mg one to NA 25–100 mg three 1–3 hours Eliminated in bile
three times three times a times a day
a day day
Miglitol (N) Glyset 25, 50, 100 25 mg one to 25 mg one to NA 25–100 mg three 1–3 hours Eliminated renally
three times three times a times a day
a day day
Dipeptidyl peptidase-IV inhibitors (DPP-IV inhibitors)
Sitagliptin (N) Januvia 25, 50, 100 100 mg daily 25 to 100 mg NA 100 mg daily 24 hours 50 mg daily if: creatinine
daily based clearance >30 to <50 mL/
on renal minute
function 25 mg if: creatinine clear-
ance < 30 mL/min
(continued)
1222

TABLE 77-12 Oral Agents for the Treatment of Type 2 Diabetes Mellitus (continued)
SECTION 8

Generic Name Recommended Starting

(generic ver- Dosage (mg/day) Equivalent
sion available? Therapeutic Maximum Dose Duration of Metabolism or
Y = yes, N = no) Brand Dose (mg) Nonelderly Elderly Dose (mg) (mg/day) Action Therapeutic Notes
Combination products
Glyburide/met- Glucovance 1.25/250 2.5–5/500 1.25/250 twice NA 20 of glyburide, Combina- Use as initial therapy: 1.25/
formin (Y) 2.5/500 twice a day a day; assess 2,000 of met- tion medi- 250 mg twice a day
5/500 renal function formin cation
Glipizide/met- Metaglip 2.5/250 2.5–5/500 2.5/250; assess NA 20 of glipizide, Combina- Use as initial therapy: 2.5/
Endocrinologic Disorders

formin (N) 2.5/500 twice a day renal function 2,000 of met- tion medi- 250 mg twice a day
5/500 formin cation
Rosiglitazone/ Avandamet 1/500 1–2/500 1/500 twice a NA 8 of rosiglitazone; Combina- Past manufacturing prob-
metformin 2/500 twice a day day; assess 2,000 of met- tion medi- lems but recently reintro-
(N) 4/500 renal function formin cation duced to market. Can use
2/1,000 as initial therapy
4/1,000
Rosiglitazone/ Avandaryl 4/1 4/1 or 4/2 4/1 daily NA 8 mg of rosiglita- Combina- Recent labeling that it can
glimepiride 4/2 once a day zone, 8 mg of tion medi- increase cardiovascular
(N) 4/4 glimepiride cation events in patients with
concomitant heart fail-
ure—caution
Pioglitazone/ ACTOplus 15/500 15/500 to 15/500 daily to NA 45 mg of pioglita- Combina-
metformin Met 15/850 twice daily; zone, 2,550 mg tion medi-
(N) once or assess renal of metformin cation
15/850 twice daily function
Pioglitazone/ Duetact 30/2 30/2 or 30/4 30/2 daily to NA 45 mg pioglita- Combina- Maximum dose cannot be
glimepiride 30/4 daily avoid zone, 8 mg tion medi- given of either medication
(N) hypoglycemia glimepiride cation because of formulations
available
Sitagliptin/met- Janumet 50/500 50/500 twice Either given NA 100 mg sitagliptin Combina- Follow renal precautions for
formin (N) daily with twice daily; daily tion medi- metformin.
50/1,000 meals up assess renal cation
to 50/ function
1,000 twice prior to use
daily with
meals
Data from Gerich JE. Oral hypoglycemic agents. N Engl J Med 1989;321:1231–1245.

Cytochrome P450 (CYP) 2C9 is involved with the hepatic metabolism reach their glycemic goals. More than 75% of patients fall into the
of the majority of sulfonylureas. Agents with active metabolites or second group. Factors that portend a positive response include newly
parent drug that are renally excreted require dosage adjustment or use diagnosed patients with no indicators of type 1 DM, high fasting C-
with caution in patients with compromised renal function. The half- peptide levels, and moderate fasting hyperglycemia (<250 mg/dL). If
life of the sulfonylurea also relates directly to the risk for hypoglycemia. glycemic goals are met, a secondary failure rate of approximately 5%
The hypoglycemic potential is therefore higher with chlorpropamide to 7% per year can be expected.
and glyburide. The long duration of effect of chlorpropamide can be
particularly problematic in elderly individuals, whose renal function Microvascular Complications. Sulfonylureas showed a reduc-
declines with age, and therefore it has great potential for accumulation, tion of microvascular complications in type 2 DM patients in the
resulting in severe and protracted hypoglycemia. Individuals at high UKPDS.61 A more in-depth discussion follows later in the chapter.
risk for hypoglycemia (e.g., elderly individuals and those with renal
Macrovascular Complications. In the largest study to date, the
insufficiency or advanced liver disease) should be started at a very low
UKPDS, no significant benefit or harm was seen in newly diagnosed
dose of a sulfonylurea with a short half-life. Hypoglycemia on low-
type 2 DM patients given sulfonylureas over 10 years. The Univer-
dose sulfonylureas can dictate a short-acting insulin secretagogue
sity Group Diabetes Program study documented higher rates of
(nateglinide or repaglinide) in lieu of a sulfonylurea.
coronary artery disease in type 2 patients given tolbutamide, when
Efficacy. As mentioned earlier, when given in equipotent doses, all compared to patients given insulin or placebo, although this study
sulfonylureas are equally effective at lowering blood glucose. On has been widely criticized.74,75 Some sulfonylureas bind to the SUR-
average, HbA1c will decrease 1.5% to 2%, with FPG reductions of 60 2A receptor that is found in cardiac tissue. Binding to the SUR-2A
to 70 mg/dL. A majority of patients will not reach glycemic goals with receptor has been implicated in blocking ischemic preconditioning
sulfonylurea monotherapy. Patients who fail sulfonylurea usually fall via K+ channel closure in the heart. Ischemic preconditioning is the
into two groups: Those with low C-peptide levels and high (>250 mg/ premise that prior ischemia in cardiac tissue can provide greater
dL) FPG levels. These patients are often primary failures on sulfonyl- tolerance of subsequent ischemia. Thus patients with heart disease
ureas (<30 mg/dL drop of FPG) and have significant glucose toxicity potentially have one compensatory mechanism to protect the heart
or slow-developing type 1 DM. The other group is those with a good from ischemia blocked. Conclusions are controversial, and readers
initial response (>30 mg/dL drop of FPG), but which is insufficient to are referred to the pertinent articles for further discussion.76–78
 1223
Adverse Effects. The most common side effect of sulfonylureas is secretion. As glucose levels diminish to normal, stimulated insulin
hypoglycemia. The pretreatment FPG is a strong predictor of secretion diminishes.

CHAPTER 77
hypoglycemic potential. The lower the FPG is on initiation, the
Pharmacokinetics. Both nateglinide and repaglinide are rapid-
higher the potential for hypoglycemia. Also, in addition to the high-
acting insulin secretagogues that are rapidly absorbed (~0.5 to 1
risk individuals outlined in the pharmacokinetics section, those who
hour) and have a short half-life (1 to 1.5 hours). Nateglinide is
skip meals, exercise vigorously, or lose substantial amounts of
highly protein-bound, primarily to albumin, but also to α1-acid
weight are also more likely to experience hypoglycemia.
glycoprotein. Nateglinide is predominantly metabolized by CYP2C9
Hyponatremia (serum sodium <129 mEq/L) is reportedly associ-
(70%) and CYP3A4 (30%) to less active metabolites. Glucuronide
ated with tolbutamide, but it is most common with chlorpropamide
conjugation then allows rapid renal elimination. Repaglinide is
and occurs in as many as 5% of individuals treated. An increase in
mainly metabolized by the CYP3A4 system to inactive metabolites

Diabetes Mellitus
antidiuretic hormone secretion is the mechanism for hyponatremia.
that are excreted in the bile.
Risk factors include age >60 years, female gender, and concomitant
use of thiazide diuretics. Efficacy. In monotherapy, both significantly reduce postprandial
Weight gain is common with sulfonylureas. In essence, patients glucose excursions and reduce HbA1c levels. Repaglinide, dosed 4
who are no longer glycosuric and who do not reduce caloric intake mg three times a day, when compared to glyburide in diet-treated
with improvement of blood glucose will store excess calories. Other drug-naïve patients reduced HbA1c levels less (1% vs. 2.4%, from
notable, although much less common, adverse effects of sulfonyl- baseline, respectively).81 Nateglinide, dosed 120 mg three times a
ureas are skin rash, hemolytic anemia, GI upset, and cholestasis. day in a similar population reduced HbA1c values by 0.8%.82 The
Disulfiram-type reactions and flushing have been reported with lower efficacy of these agents versus sulfonylureas should be consid-
tolbutamide and chlorpropamide when alcohol is consumed. ered when patients are >1% above their HbA1c goal. These agents
can be used to provide increased insulin secretion during meals,
Drug Interactions. Several drugs are thought to interact with
when it is needed, in patients close to glycemic goals. Also, it should
sulfonylureas, and Table 77–13 summarizes them by proposed
be noted that addition of either agent to a sulfonylurea will not
mechanisms of action.79 Drug interactions from protein-binding
result in any improvement in glycemic parameters.
changes should occur shortly after the interacting medication is
given, as the concentration of free (thus active) sulfonylurea will Adverse Effects. Hypoglycemia is the main side effect noted with
acutely increase. First-generation sulfonylureas, which bind to pro- both agents. Hypoglycemic risk appears to be less than with sulfo-
teins ionically, are more likely to cause drug-drug interactions than nylureas. In part, this is because of the glucose-sensitive release of
second-generation sulfonylureas, which bind nonionically.80 The insulin. If the glucose concentration is normal, less glucose-stimu-
clinical importance of protein-binding interactions has been ques- lated release of insulin will occur. In two separate studies, nategli-
tioned, as the majority of these drug interactions have been found nide rates of hypoglycemia were 3% and repaglinide 15% versus
to truly be caused by hepatic metabolism. Drugs that are inducers or glyburide and glipizide rates of 15% and 19%, respectively. Weight
inhibitors of CYP2C9 should be monitored carefully when used gain of 2 to 3 kg has been noted with repaglinide, whereas weight
with a sulfonylurea. Additionally, other drugs known to alter blood gain with nateglinide appears to be <1 kg.
glucose should be considered (see Table 77–11).
Drug Interactions. Glycemic control and hypoglycemia should
Dosing and Administration. The usual starting dose and maxi- be closely monitored when inducers or inhibitors of CYP3A4 are
mum dose of sulfonylureas are summarized in Table 77–12. Lower given with repaglinide. Gemfibrozil, a common medication used to
dosages are recommended for most agents in elderly patients and treat hypertriglyceridemia in DM, more than doubles the half-life of
those with compromised renal or hepatic function. The dosage repaglinide and has resulted in prolonged hypoglycemic reactions.
should be titrated every 1 to 2 weeks (use a longer interval with Nateglinide appears to be a weak inhibitor of CYP2C9 based on
chlorpropamide) to achieve glycemic goals. This is possible because tolbutamide metabolism, although no significant drug-drug inter-
of the rapid increase of insulin secretion in response to the sulfonyl- actions have been reported.
urea. Of note, immediate-release glipizide’s maximal dose is 40 mg/
Dosing and Administration. Nateglinide and repaglinide should
day, but its maximal effective dose is about 10 to 15 mg/day. The
be dosed prior to each meal (up to 30 minutes prior). The recom-
maximal effective dose of sulfonylureas tends to be approximately
mended starting dose for repaglinide is 0.5 mg in subjects with
60% to 75% of their stated maximum dose.
HbA1c <8% or treatment-naïve patients, increased weekly to a total
Short-Acting Insulin Secretagogues Pharmacology. Although maximum daily dose of 16 mg (see Table 77–12). The maximal
the binding site is adjacent to the binding site of sulfonylureas, effective dose of repaglinide is likely 2 mg with each meal, as a dose
nateglinide and repaglinide stimulate insulin secretion from the β of 1 mg prior to each meal provides approximately 90% of the
cells of the pancreas, similarly to sulfonylureas. Repaglinide, a maximal glucose-lowering effect. Nateglinide should be dosed at
benzoic acid derivative, and nateglinide, a phenylalanine amino acid 120 mg prior to meals, and does not require titration. A 60-mg dose
derivative, both require the presence of glucose to stimulate insulin is available, but the HbA1c decrement is small (0.3% to 0.5%). If a
meal is skipped, the medication can be skipped, and meals
extremely low in carbohydrate content may not need a dose. Both
TABLE 77-13 Drug Interactions with Sulfonylureas agents can be used in patients with renal insufficiency and offer an
excellent alternative in patients experiencing hypoglycemia with
Interaction Drugs
low-dose sulfonylurea. Caution is advised for patients with moder-
Displacement from protein binding Warfarin, salicylates, phenylbutazone, sul- ate to severe hepatic impairment, as nateglinide has not been
sitesa fonamides studied and the half-life is prolonged with use of repaglinide.
Alters hepatic metabolism (cyto- Chloramphenicol, monoamine oxidase
chrome P450) inhibitors, cimetidine, rifampinb Biguanides Pharmacology. Metformin is the only biguanide
Altered renal excretion Allopurinol, probenecid available in the United States. Metformin has been used clinically
a for 45 years and has been approved in the United States since 1995.
Many of these drug interactions may be metabolism-based.
b
Inducer. Metformin enhances insulin sensitivity of both hepatic and periph-
Reproduced from Gerich.79 eral (muscle) tissues. This allows for an increased uptake of glucose
1224
into these insulin-sensitive tissues. The exact mechanisms of how serum creatinine of 1.4 mg/dL in women and 1.5 mg/dL in men or
metformin accomplishes insulin sensitization are still being investi- greater, is contraindicated, as it is renally eliminated. Elderly patients,
SECTION 8

gated, although adenosine 5-monophosphate–activated protein who often have reduced muscle mass, should have their glomerular
kinase activity, tyrosine kinase activity enhancement, and glucose filtration rate estimated by a 24-hour urine creatinine collection. If
transporter-4 all play a part. Metformin has no direct effect on the the estimated glomerular filtration rate is less than 70 mL/min,
β cells, although insulin levels are reduced, reflecting increases in metformin should not be given. Because of the risk of acute renal
insulin sensitivity. failure during intravenous dye procedures, metformin therapy should
be withheld starting the day of the procedure and resumed in 2 to 3
Pharmacokinetics. Metformin has approximately 50% to 60%
days, after normal renal function has been documented.
oral bioavailability, low lipid solubility, and a volume of distribution
that approximates body water. Metformin is not metabolized and Drug Interactions. Cimetidine competes for renal tubular secre-
Endocrinologic Disorders

does not bind to plasma proteins. Metformin is eliminated by renal tion of metformin and concomitant administration leads to higher
tubular secretion and glomerular filtration. The average half-life of metformin serum concentrations. At least one case report of lactic
metformin is 6 hours, although pharmacodynamically, metformin’s acidosis with metformin therapy implicates cimetidine. Other cat-
antihyperglycemic effects last >24 hours. ionic drugs may interact similarly such as procainamide, digoxin,
quinidine, trimethoprim, and vancomycin.84
Efficacy. Metformin consistently reduces HbA1c levels by 1.5% to
2.0%, FPG levels by 60 to 80 mg/dL, and retains the ability to reduce Dosing and Administration. Metformin immediate-release is
FPG levels when they are extremely high (>300 mg/dL). The usually dosed 500 mg twice a day with the largest meals to minimize
sulfonylureas’ ability to stimulate insulin release from β cells at GI side effects. Metformin can be increased by 500 mg weekly until
extremely high glucose levels is often impaired, a concept com- glycemic goals or 2,000 mg/day is achieved (see Table 77–12).
monly referred to as glucose toxicity. Metformin also has positive Metformin 850 mg can be dosed daily and then increased every 1 to
effects on several components of the insulin resistance syndrome. 2 weeks to the maximum dose of 850 mg three times a day (2,550
Metformin decreases plasma triglycerides and LDL-C by approxi- mg/day). Approximately 80% of the glycemic-lowering effect can be
mately 8% to 15%, as well increasing HDL-C very modestly (2%). seen at 1,500 mg, and 2,000 mg/day is the maximal effective dose.
Metformin reduces levels of plasminogen activator inhibitor-1 and Extended-release metformin can be initiated at 500 mg a day with
causes a modest reduction in weight (2 to 3 kg). the evening meal and titrated weekly by 500 mg as tolerated to a
single evening dose of 2,000 mg/day. Twice daily to three times a
Microvascular Complications. Metformin (n = 342) was com-
day dosing of extended-release metformin can help minimize GI
pared to intensive glucose control with insulin or sulfonylureas in
side effects and improve glycemic control. Metformin extended-
the UKPDS. No significant differences were seen between therapies
release 750 mg tablets can be titrated weekly to the maximum dose
with regard to reducing microvascular complications.
of 2,250 mg/day, although as stated above, 1,500 mg/day provides
 Macrovascular Complications. Although normal weight the majority of the glycemic-lowering effect.
type 2 DM subjects may not receive benefit, metformin reduced
macrovascular complications in obese subjects in the UKPDS.83 Thiazolidinediones Pharmacology. Thiazolidinediones are also
Metformin significantly reduced all-cause mortality and risk of referred to as TZDs or glitazones. Pioglitazone and rosiglitazone are
stroke versus intensive treatment with sulfonylureas or insulin. the two currently approved TZDs for the treatment of type 2 DM
Metformin also reduced diabetes-related death and myocardial (see Table 77–12). TZDs work by binding to the peroxisome
infarctions as opposed to the conventional treatment arm of the proliferator-activated receptor-γ (PPAR-γ), which are primarily
UKPDS. Metformin should be included in the therapy for all type 2 located on fat cells and vascular cells. The concentration of these
DM patients, if tolerated and not contraindicated, as it is the only receptors in the muscle is very low; thus this is unlikely to be the
oral antihyperglycemic medication proven to reduce the risk of total main site of action. TZDs enhance insulin sensitivity at muscle,
mortality and is generic. liver, and fat tissues indirectly. TZDs cause preadipocytes to differ-
entiate into mature fat cells in subcutaneous fat stores. Small fat
Adverse Effects. Metformin causes GI side effects, including
cells are more sensitive to insulin and more able to store FFAs. The
abdominal discomfort, stomach upset, and/or diarrhea in approxi-
result is a flux of FFAs out of the plasma, visceral fat, and liver into
mately 30% of patients. Anorexia and stomach fullness is likely part
subcutaneous fat, a less insulin-resistant storage tissue. Muscle
of the reason loss of weight is noted with metformin. These side
intracellular fat products, which contribute to insulin resistance,
effects are usually mild and can be minimized by slow titration. GI
also decline. TZDs also affect adipokines, (e.g., angiotensinogen,
side effects also tend to be transient, lessening in severity over several
tissue necrosis factor-α, interleukin-6, plasminogen activator inhib-
weeks. If encountered, make sure patients are taking metformin with
itor-1), which can positively affect insulin sensitivity, endothelial
or right after meals and reduce the dose to a point at which no GI side
function, and inflammation. Of particular note, adiponectin is
effects are encountered. Increases in the dose can be tried again in
reduced with obesity and/or diabetes but is increased with TZD
several weeks. Anecdotally, extended-release metformin (Gluco-
therapy, which improves endothelial function, insulin sensitivity,
phage-XR) can lessen some of the GI side effects. Metallic taste,
and has a potent antiinflammatory effect.
interference with vitamin B12 absorption, and hypoglycemia during
intense exercise have been documented but are clinically uncommon. Pharmacokinetics. Pioglitazone and rosiglitazone are well absorbed
Metformin therapy rarely (3 cases per 100,000 patient-years) with or without food. Both are highly (>99%) protein bound to
causes lactic acidosis. Any disease state that can increase lactic acid albumin. Pioglitazone is primarily metabolized by CYP2C8, and to a
production or decrease lactic acid removal can predispose to lactic lesser extent by CYP3A4 (17%), with the majority being eliminated
acidosis. Tissue hypoperfusion, such as that caused by congestive in the feces. Rosiglitazone is metabolized by CYP2C8, and to a lesser
heart failure, hypoxic states, shock, or septicemia, via increased extent by CYP2C9, then conjugated with two-thirds found in urine
production of lactic acid; and severe liver disease or alcohol, through and one-third in feces. The half-life of pioglitazone and rosiglitazone
reduced removal of lactic acid in the liver, all increase the risk of lactic is 3 to 7 hours and 3 to 4 hours, respectively. Two active metabolites
acidosis. The clinical presentation of lactic acidosis is often nonspe- of pioglitazone with longer half-lives deliver the majority of activity
cific flu-like symptoms, thus the diagnosis is usually made by labora- at steady state. Both medications have a duration of antihyperglyce-
tory confirmation. Metformin use in renal insufficiency, defined as a mic action of more than 24 hours.
 1225
Efficacy. Pioglitazone and rosiglitazone, given for approximately 6 recommended that an ALT be checked. ALT monitoring vigilance
months, reduce HbA1c values ~1.5% and reduce FPG levels by has been lowered, and it is now recommended that the ALT be

CHAPTER 77
approximately 60 to 70 mg/dL at maximal doses. Glycemic-lowering checked periodically at the practitioner’s discretion. Patients with
onset is slow, and maximal glycemic-lowering effects may not be seen ALT levels >2.5 times the upper limit of normal should not start
until 3 to 4 months of therapy. It is important to inform patients of either medication, and if the ALT is >3 times the upper limit of
this fact and that they should not stop therapy even if minimal glucose normal the medication should be discontinued.
lowering is initially encountered. The efficacy of both drugs is depen- Retention of fluid leads to many different possible side effects with
dent on sufficient insulinemia. If there is insufficient endogenous rosiglitazone and pioglitazone. The etiology of the fluid retention has
insulin production (β-cell function) or exogenous insulin delivery via not been fully elucidated but appears to include peripheral vasodila-
injections, neither will lower glucose concentrations efficiently. Inter- tion and/or improved insulin sensitization with a resultant increase in

Diabetes Mellitus
estingly, patients who are more obese, or who gain weight on either renal sodium and water retention. A reduction in plasma hemoglobin
medication tend to have a larger reduction in HbA1c values. Pioglita- (2% to 4%), attributed to a 10% increase in plasma volume, can result
zone consistently decreases plasma triglyceride levels by 10% to 20%, in a dilutional anemia, which does not require treatment. Edema is
whereas rosiglitazone tends to have a neutral effect. LDL-C concen- also commonly (4% to 5% in mono- or combination therapy)
trations tend to increase with rosiglitazone 5% to 15% but do not reported. When a TZD is used in combination with insulin, the
significantly increase with pioglitazone. Both appear to convert small, incidence of edema (~15%) is increased. TZDs are contraindicated in
dense low-density lipoprotein (LDL) particles, which have been patients with New York Heart Association class III and IV heart
shown to be highly atherogenic, to large, fluffy LDL particles that are failure, and great caution should be exercised when given to patients
less dense. Large, fluffy LDL particles may be less atherogenic, but any with class I and II heart failure or other underlying cardiac disease, as
increase in LDL must be of concern. Both drugs increase HDL pulmonary edema and heart failure have been reported. Edema tends
similarly, up to 3 to 9 mg/dL. TZDs also affect several components of to be dose related and if not severe, a reduction in the dose as well as
the insulin resistance syndrome. PAI-1 levels are decreased, and many use of diuretics (anecdotally spironolactone appears to help selected
other adipocytokines are affected, endothelial function improves, and patients) will allow the continuation of therapy in the majority of
blood pressure can decrease slightly. patients.88 In addition, rarely, TZDs have been reported to worsen
macular edema in the eye.
Microvascular Complications. TZDs reduce HbA1c levels, which
Weight gain, which is also dose related, can be seen with both
have been shown to be related to the risk of microvascular complications.
rosiglitazone and pioglitazone. Mechanistically, both fluid retention
Macrovascular Complications. Macrovascular complications and fat accumulation play a part in explaining the weight gain.
with TZDs are controversial. In the Prospective Pioglitazone Clinical TZDs, besides stimulating fat cell differentiation, also reduce leptin
Trial in Macrovascular Events (PROactive) study, pioglitazone 45 levels, which stimulate appetite and food intake. Average weight
mg was added to standard therapy in patients who had experienced gain varies, but a 1.5- to 4-kg weight gain is not uncommon. Rarely,
a macrovascular event or had peripheral vascular disease.85 The two a patient will gain large amounts of weight in a short period of time,
groups were well matched at baseline, and the reported average and this may necessitate discontinuation of therapy. Weight gain
observation time period was approximately 3 years. The primary positively predicts a larger HbAlc reduction but must be balanced
end point (reduction in death, myocardial infarction, stroke, acute with the well documented effects of long-term weight gain.
coronary syndrome, coronary revascularization, leg amputation, TZDs have also been associated with an increased fracture rate in
and leg revascularization) was reduced 10% (P = 0.095). The main the upper and lower limbs in postmenopausal women, but not men.
secondary end point (all-cause mortality, nonfatal myocardial inf- As opposed to comparative diabetes therapy, TZDs can double the
arction, or stroke) was reduced 16% (P = 0.027). The seemingly risk of fracture in this population. The underlying pathophysiology
dichotomous results relate to the inclusion of leg revascularization, is speculative but can relate to the effect of TZD in bone marrow,
which were increased in the pioglitazone group. Reasons for the with a reduction in osteoblast activity and an increase in bone
increase are speculative, but can relate to more testing and inspec- marrow fat. It would be prudent to consider a patient’s risk factors
tion because of peripheral edema. Also of note, the pioglitazone for fractures if prescribed a TZD and possibly have a lower thresh-
group had 209 nonadjudicated admissions for heart failure occur old for additional assessment in postmenopausal women.
versus 153 in the placebo group (P = 0.007), although fatal heart As a caution, anovulatory patients can resume ovulation on
failure was not increased. Several nonpublished meta-analyses of TZDs. Adequate pregnancy and contraception precautions should
rosiglitazone reported higher myocardial infarction rates with be explained to all women capable of becoming pregnant, as both
rosiglitazone. Recently, a hazard ratio of 1.43 (95% confidence agents are pregnancy category C.
intervals 1.03–1.98; P = 0.03) for the risk of a myocardial infarction
Drug Interactions. No significant drug interactions have been
with rosiglitazone versus other oral agents was reported, but has
noted with either medication. Neither pioglitazone nor rosiglita-
been widely criticized.86 A prospective cardiovascular outcome trial
zone appear to be inhibitors or inducers of CYP3A4 and CYP2C8 or
with rosiglitazone is underway, but the FDA will likely require a
CYP2C8 and CYP2C9, respectively, although drugs that are strong
black box warning about cardiovascular events with rosiglitazone.
inhibitors or inducers of these pathways (e.g., gemfibrozil or
Adverse Effects. Troglitazone, the first TZD approved, caused rifampin) necessitate close monitoring.
idiosyncratic hepatotoxicity and had 28 deaths from liver failure,
Dosing and Administration. The recommended starting dos-
which prompted removal from the U.S. market in March, 2000.
ages of pioglitazone and of rosiglitazone are 15 to 30 mg once daily
Approximately 1.9% of patients placed on troglitazone had alanine
and 2 to 4 mg once daily, respectively. Dosages can be increased
aminotransferase (ALT) levels more than three times the upper
slowly based on therapeutic goals and side effects. The maximum
limit of normal. The incidence, using these criteria for elevated liver
dose and maximum effective dose of pioglitazone is 45 mg, and
enzymes, with pioglitazone (0.25%) and rosiglitazone (0.2%) has
rosiglitazone is 8 mg once daily, although 4 mg twice a day can
been low. No evidence of hepatotoxicity was reported in an analysis
reduce HbAlc by 0.2% to 0.3% more as opposed to 8 mg once daily.
of more than 5,000 patients given rosiglitazone or pioglitazone.87
Several case reports of hepatotoxicity with rosiglitazone or pioglita- α-Glucosidase Inhibitors Pharmacology. Currently, there are
zone have been reported, but improvement in ALT was consistently two α-glucosidase inhibitors available in the United States (acar-
noted when the drug was discontinued. Prior to therapy, it is bose and miglitol). α-Glucosidase inhibitors competitively inhibit
1226
enzymes (maltase, isomaltase, sucrase, and glucoamylase) in the clearly been shown that in type 2 DM, GLP-1 levels are deficient.
small intestine, delaying the breakdown of sucrose and complex DPP-IV inhibitors partially reduce the inappropriately elevated
SECTION 8

carbohydrates.89,90 They do not cause any malabsorption of these glucagon postprandially and stimulate glucose-dependent insulin
nutrients. The net effect from this action is to reduce the postpran- secretion. As these agents block nearly 100% of the DPP-IV enzyme
dial blood glucose rise. activity for at least 12 hours, near normal, nondiabetic GLP-1 levels
are achieved. These drugs do not alter gastric emptying.
Pharmacokinetics. The mechanism of action of α-glucosidase
inhibitors is limited to the luminal side of the intestine. Some Pharmacokinetics. Sitagliptin appears to have rapid absorption,
metabolites of acarbose are systemically absorbed and renally with tmax and Cmax of approximately 1.5 hours. Absolute bioavailabil-
excreted, whereas the majority of miglitol is absorbed and renally ity after oral intake is approximately 87%. The t1/2 of sitagliptin is
excreted unchanged. approximately 12 hours, and 79% of the dose of sitagliptin is excreted
Endocrinologic Disorders

unchanged in the urine by active tubular secretion. Sitagliptin expo-

Efficacy. Postprandial glucose concentrations are reduced (40 to
sure is increased by approximately 2.3-, 3.8-, and 4.5-fold relative to
50 mg/dL), whereas fasting glucose levels are relatively unchanged
healthy subjects for patients with moderate renal insufficiency (creat-
(~10% reduction). Efficacy on glycemic control is modest (average
inine clearance 30 to <50 mL/min), severe renal insufficiency (creati-
reductions in HbAlc of 0.3% to 1%), affecting primarily postpran-
nine clearance <30 mL/min), and end-stage renal disease (on
dial glycemic excursions. Thus patients near target HbAlc levels with
dialysis), respectively. Pharmacodynamically, DPP-IV inhibition
near-normal FPG levels, but high postprandial levels, might be
appeared to mirror directly the plasma concentration of sitagliptin.
candidates for therapy.
Doses of 50 mg produced at least 80% inhibition of DPP-IV enzyme
Microvascular Complications. α-Glucosidase inhibitors mod- activity at 12 hours, and 100 mg produced 80% inhibition of DPP-IV
estly reduce HbAlc levels, which have been shown to be related to the enzyme activity at 24 hours. Food had no effect on absorption kinetics
risk of microvascular complications. of sitagliptin or vildagliptin.
Vildagliptin is rapidly and almost completely (85%) absorbed
Macrovascular Complications. The Study to Prevent Non–
after oral intake. Within 1 to 2 hours, tmax is achieved. The plasma t1/2
Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), in subjects
varies with dose and is approximately 1.5 to 4.5 hours over a range
with impaired glucose tolerance, reported a significant reduction in
or 25 mg to 200 mg. Approximately 55% of the drug is metabolized
the risk of cardiovascular events, although the total number of events
by hydrolysis, with the majority of the remaining drug eliminated
were small.91,92 No large cardiovascular study confirming these pre-
unchanged by the kidneys. Vildagliptin dose-dependently inhibits
liminary results has been done in prediabetes or diabetes patients.
the DPP-IV enzyme activity, approximately a 70% inhibition at 50
Adverse Effects. The GI side effects, such as flatulence, bloating, mg and 90% inhibition at 100 mg at 12 hours, with a continued 40%
abdominal discomfort, and diarrhea, are very common and greatly inhibition at 24 hours.
limit the use of α-glucosidase inhibitors. Mechanistically, these side
Efficacy. The average reduction in HbA1c with vildagliptin or sita-
effects are caused by distal intestinal degradation of undigested
gliptin is approximately 0.7% to 1% at a dose of 100 mg a day. The
carbohydrate by the microflora, which results in gas (carbon diox-
HbA1c decrement is dependent on the baseline value, with a larger
ide [CO2] and methane) production. α-Glucosidase inhibitors
reduction being seen with a higher baseline HbA1c. As they are well
should be initiated at a low dose and titrated slowly to reduce GI
tolerated, adjustment in the dose for adverse effects is unlikely.
intolerance. Beano, an α-glucosidase enzyme, can help to decrease
GI side effects but can decrease efficacy slightly.93 Microvascular and Macrovascular Complications. HbA1c
If a patient develops hypoglycemia within several hours of ingest- levels are reduced, which have been related to a reduction in
ing an α-glucosidase inhibitor, oral glucose is advised because the microvascular complications, but no outcome data are available to
drug will inhibit the breakdown of more complex sugar molecules. date.
Milk, with lactose sugar, can be used as an alternative when no
Drug-Drug Interactions. Both are unlikely to have significant
glucose is available, as acarbose only slightly (10%) inhibits lactase.
drug-drug interactions. Sitagliptin is metabolized approximately 20%
Rarely, elevated serum aminotransferase levels have been reported
by CYP3A4 with some CYP2C8 involvement but is neither an
with the highest doses of acarbose. It appeared to be dose and weight
inhibitor nor inducer of any CYP450 enzyme system. Sitagliptin is a
related and is the premise for the weight-based maximum doses.
p-glycoprotein substrate, but had negligible effects on digoxin kinet-
Dosing and Administration. Dosing for both miglitol and ics, and cyclosporine A increased the area under the curve (AUC) by
acarbose are similar. Initiate with a very low dose (25 mg with one only 30%. Neither drug is extensively plasma protein bound. Vilda-
meal a day); increase very gradually (over several months) to a gliptin is neither an inhibitor nor inducer of CYP450 enzymes.
maximum of 50 mg three times a day for patients ≤60 kg or 100 mg
Adverse Effects. Both drugs are very well tolerated, weight neu-
three times a day for patients >60 kg (see Table 77–12). Both α-
tral, and do not cause GI side effects. Mild hypoglycemia appears to
glucosidase inhibitors should be taken with the first bite of the meal
be the only significant adverse effect, and the rate is similar to
so that drug may be present to inhibit enzyme activity. Only patients
metformin. No significant increases in peripheral edema, hyperten-
consuming a diet high in complex carbohydrates will have signifi-
sion, or cardiac outcomes have been noted to date. In regards to long-
cant reductions in glucose levels. α-Glucosidase inhibitors are
term safety, DPP-IV enzymes metabolize a wide variety of peptides
contraindicated in patients with short-bowel syndrome or inflam-
(peptide YY [PYY], neuropeptide Y, growth hormone releasing hor-
matory bowel disease, and neither should be administered in
mone, and vasoactive intestinal polypeptide, and others) potentially
patients with serum creatinine >2 mg/dL, as this population has not
affecting other regulatory systems. DPP-IV (also known as CD26)
been studied.
plays an important role for T-cell activation and theoretically the
inhibition of DPP-IV could be associated with adverse immunologic
DPP-IV inhibitors Sitagliptin is currently approved for use in the
reactions. Additionally DPP-8/9 inhibition in animals produced mul-
United States, whereas vildagliptin has received an approvable letter
tiple toxicities. Both compounds have explored their binding to DPP-
from the FDA.
8/9, and have found minimal binding to these subtypes. Long-term
Pharmacology. DPP-IV inhibitors prolong the half-life of an safety data is still limited, but to date no adverse effects have been
endogenously produced glucagon-like peptide-1 (GLP-1). It has clearly linked to this issue.
 1227
Dosing and Administration. Vildagliptin will be dosed orally,
likely at 50 mg to 100 mg daily. Sitagliptin is dosed orally at 100 mg CLINICAL CONTROVERSY

CHAPTER 77
daily unless renal insufficiency is present. The 50 mg dose is
Preservation of β-cell function, and thus arresting the progres-
recommended if the creatinine clearance is 30 to less than 50 mL/
sion of type 2 diabetes, appears to be the future goal of
min, or 25 mg if less than 30 mL/min. Equivalent serum creatinine
treatment. The UKPDS clearly showed that sulfonylureas, met-
levels are: sitagliptin 50 mg daily in men, greater than 1.7 to 3.0 mg/
formin, and insulin are ineffective in stopping the progressive β-
dL, women, greater than 1.5 to 2.5 mg/dL; 25 mg daily in men,
cell failure. In animal models TZDs, exenatide, and DPP-IV
greater than 3.0 mg/dL, women, greater than 2.5 mg/dL. No short-
inhibitors have been able to arrest β-cell failure, and in humans,
term adverse effects have been noted with increased exposure.
short-term indirect β-cell function measures have improved.
Because of their excellent tolerability profile and a fairly flat dose-
Confirmatory human data showing arrest or delay of the pro-

Diabetes Mellitus
response curve, it seems logical that these drugs should be maxi-
gressive β-cell decline in type 2 DM is needed. Rosiglitazone data
mally dosed, unless cautions exist.
in prediabetes and newly diagnosed diabetes, although measured
by the homeostatic model assessment (HOMA)-β, has not
■ PIVOTAL TRIALS shown significant preservation of β-cell function. Long-term
Diabetes Control and Complications Trial data is underway with incretin based therapies.
 Much of the last century in diabetes care was dominated by the
debate over whether glycemic control actually was causative in Significant findings from the study include:
complications of DM. Animal studies and some human studies • Microvascular complications (predominantly the need for
suggested that the worse the glycemia the greater the risk of compli- laser photocoagulation on retinal lesions) are reduced by 25%
cations. But “the glucose hypothesis” was not ultimately accepted as when median HbAlc is 7% as compared to 7.9%.53
proven until the publication of the DCCT in 1993.60 One thousand
• A continuous relationship exists between glycemia and
four hundred forty-one patients with type 1 DM were divided into
microvascular complications, with a 35% reduction in risk for
two groups: those without complications (726 subjects, primary
each 1% decrement in HbAlc. No glycemic threshold for
prevention), and those with early microvascular complications (715
microvascular disease exists.96
subjects, secondary prevention). These two groups were then again
divided into two groups, one randomized to receive conventional • Glycemic control has minimal effect on macrovascular disease
therapy (one or two shots of insulin daily and infrequent SMBG with risk.61 Excess macrovascular risk appears to be related to con-
no attempt to change therapy based on home blood glucose read- ventional risk factors such as dyslipidemia and hypertension.97
ings), and the other to receive intensive therapy (three or more • Sulfonylureas and insulin therapy do not increase macrovascu-
injections of insulin daily or insulin pump, with frequent SMBG and lar disease risk.61
alteration of insulin therapy based on SMBG results, plus frequent • Metformin reduces macrovascular risk in obese patients.84
contact with a health professional). After 6.5 years mean followup
• Vigorous blood pressure control reduces microvascular and
with a difference in HbAlc between the two groups being ~2% (~9%
macrovascular events.97 There was no evidence for a threshold
vs. ~7%), retinopathy was decreased by 76% in the primary preven-
systolic blood pressure above 130 mm Hg for protection
tion cohort, with retinopathy progression reduced 54% in the
against complications. β-Blockers and ACE inhibitors appear
secondary prevention group. Neuropathy was decreased by 60% in
to be equally efficacious.98
both groups combined. Microalbuminuria was decreased 39%,
whereas macroproteinuria was reduced 54% with intensive therapy.
Hypoglycemia was more common and weight gain greater with ■ THERAPEUTICS
intensive therapy. A nonstatistically significant reduction in coro-  Knowledge of the patient’s quantitative and qualitative meal
nary events was seen in the intensively treated group as compared to patterns, activity levels, pharmacokinetics of insulin preparations
the conventional group. Followup studies 8 years after the DCCT and other injectables, and pharmacology of oral and antidiabetic
ended continued to show an advantage of good glycemic control agents for type 2 DM are essential to individualize the treatment
over what was previously considered conventional therapy.94 The plan and optimize blood glucose control while minimizing risks for
DCCT revolutionized therapy of DM, demanding that stricter glyce- hypoglycemia and other adverse effects of pharmacologic therapies.
mic control be the goal. Long-term followup of former DCCT
subjects in the Epidemiology of Diabetes Interventions and Compli- Type 1 DM
cations (EDIC) trial reported that, despite similar HbA1c values 11
years later, renal and cardiovascular outcomes continued to be lower The choice of therapy for type 1 DM is simple: All patients need
in intensively treated subjects from the DCCT as opposed to those insulin. However, how that insulin is delivered to the patient is a
who received conventional treatment.95 matter of considerable practice difference among patients and
clinicians. Historically, after the discovery of insulin by Banting and
Best in 1921, frequent injections of regular insulin (initially the only
Implications of the United Kingdom insulin available) were given. Modifications of insulin led to longer-
Prospective Diabetes Study acting insulin suspensions and the use by many patients of one or
The UKPDS was a landmark study for the care of patients with type 2 two shots of longer-acting insulin each day. Because SMBG and
DM, confirming the importance of glycemic control for reducing the HbAlc testing were not available at that time, patients and practitio-
risk of microvascular complications.61 More than 5,000 patients with ners had no idea how well their patients’ blood glucose concentra-
newly diagnosed type 2 DM were entered into the study. Patients were tions were controlled, other than a vague sense from an indirect
followed for an average of 10 years. The major portion of the study method, measurement of glucose in the urine. Although the renal
assessed “conventional therapy” (no drug therapy unless the patient threshold for glucose is relatively predictable in young healthy
was symptomatic or had FPG >270 mg/dL), versus intensive therapy subjects, it is highly variable in older patients and patients with renal
starting with either sulfonylureas or insulin, aimed at keeping the FPG disease. The advent of SMBG and HbAlc testing in the 1980s
<108 mg/dL. A subset of obese patients was studied using metformin revolutionized the care of diabetes, enabling patients and practitio-
as the primary therapeutic agent. ners to directly access blood glucose for assessment, and enabling
1228
the patient to make instantaneous changes in the insulin regimen if This is a reasonable classification. Clearly one injection of any
need be. Modern diabetes management would be impossible with- insulin preparation daily will in no way mimic normal physiology,
SECTION 8

out these two tools. and therefore is unacceptable. Similarly, two injections of any
Contemporary management of type 1 DM attempts to match insulin daily will fail to replicate normal insulin release patterns.
carbohydrate intake with glucose-lowering processes, most com- Injection regimens that begin to approximate physiologic insulin
monly insulin, as well as with exercise. Diet is still the cornerstone release start with “split-mixed” injections of a morning dose of NPH
of diabetes therapy, but unlike in previous years, attempts are made and regular insulin before breakfast, and again before the evening
to allow the patient to live as normal a life as possible. Understand- meal. The presumption is made that the morning NPH insulin gives
ing the principles of glucose input and glucose egress from the basal insulin for the day and covers the midday meal, the morning
blood will allow the practitioner and the patient great latitude in the regular insulin covers breakfast, the evening NPH insulin gives basal
Endocrinologic Disorders

management of patients with type 1 DM. insulin for the rest of the day, and the evening regular covers the
Simplistically speaking, one can break down normal insulin evening meal. If patients are very compulsive about consistency of
secretion into a relatively constant background level of insulin timing of their injections and meals and intake of carbohydrate,
(basal) for the fasting and postabsorptive period, and prandial such a strategy can be successful. However, most patients are not
spikes of insulin after eating (bolus) (Fig. 77–8).99 Insulin sensitivity sufficiently predictable in their schedule and food intake to allow
and insulin secretion are not constant throughout the day, render- “tight” glucose control with such an approach.
ing the basal concept inaccurate. However, in most clinical situa- The first modification that is frequently made to such a regimen
tions, this approach provides a useful paradigm for understanding is the movement of the evening NPH to bedtime (now three total
and applying insulin treatment for type 1 DM. The other basic injections per day) because the fasting glucose in the morning is too
principle to consider is that the timing of insulin onset, peak, and high. This approach improves glycemic control and reduces
duration of effect must match meal patterns and exercise schedules hypoglycemia, sufficiently intensifying the insulin therapy for some
to achieve near-normal blood glucose values throughout the day. patients.100 However, many patients need a more intense approach
Historically, complexity of insulin regimens has usually been that also allows greater flexibility in their lifestyle.
related to the number of injections of insulin administered per day. The basal-bolus concept is an attempt to replicate normal
insulin physiology with a combination of intermediate- or long-
acting insulin to give the basal component, and short-acting insulin
Breakfast Lunch Supper to give the bolus component. Various strategies have been used for
75
the former, including once- or twice-daily NPH or detemir, or
(mcU/mL)

50 Insulin once-daily insulin glargine. Most type 1 DM patients require two

Insulin

shots of all of the above insulins except insulin glargine. Also, all of
25 the above insulins, with the exception of insulin glargine, have some
Basal degree of peak effect that must be considered in planning meals and
0 insulin
activity. Insulin glargine or insulin detemir is a feasible basal insulin
150 Glucose supplement for most patients with type 1 DM. The bolus insulin
component is given before meals with regular insulin, insulin lispro,
100 insulin aspart, or insulin glulisine. The rapid onset of action and
(mg/dL)
Glucose

Basal
short time course of rapid-acting insulin analogs more closely
50
glucose replicate normal physiology. This approach allows the patient to
0
vary the amount of insulin injected, depending on the preprandial
7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 SMBG level, the anticipated activity (upcoming exercise can reduce
AM Time of day PM insulin requirement), and anticipated carbohydrate intake. Most
patients will have a prescribed dose of insulin preprandially that
they vary by use of a sliding scale. This type of adjusted scale insulin
Intensive insulin therapy regimens
is intended to optimize the insulin regimen. In light of the negative
7AM 11AM 5PM Bedtime connotation of the term sliding scale (usually referring to giving
1. 2 doses,a R R, L, A, E, GLU R, L, A, E, GLU
or rapid acting +N +N
insulin only after the blood glucose increases, rather than treating
+N the underlying disorder), a better descriptor for the adjusted-dose
2. 3 doses, R or R, L, A, E, GLU R, L, A, E, GLU R, L, A, E, GLU insulin is variable-dose prandial insulin, correction factor, or insulin
rapid acting +N +N
+N
algorithm. A rough correction factor can be calculated by taking
3. 4 doses, R or R, L, A, E, GLU R, L, A, E, GLU R, L, A, E, GLU N
1,500 divided by the total daily dose of insulin. This gives the
rapid acting approximate glucose lowering (mg/dL) effect of one unit of insulin.
+N Carbohydrate counting is a very effective tool for determining the
4. 4 doses R or R, L, A, E, GLU R, L, A, E, GLU R, L, A, E, GLU N
rapid acting +N
amount of insulin to be injected preprandially. Although general
+N algorithms give rough guidelines, each patient will have to adjust the
5. 4 doses,b R R, L, A, E, GLU R, L, A, E, GLU R, L, A, E, GLU G or Db prescribed preprandial insulin dosage to achieve optimal glucose
or rapid acting (G may be given
control. A rough estimate of how much carbohydrate (grams) one
+ long acting anytime every 24
hours) unit of rapid-acting insulin will cover is to divide 500 by the total
Adjusted Basal daily dose of insulin.
6. CS-ll pump Bolus Bolus Bolus
Empirically, patients can begin on ~0.6 unit/kg per day with basal
a
Many clinicians may not consider this intensive insulin therapy insulin 50% of total dose and prandial insulin 20% of total dose
b
May be given BID in type 1 DM= 5 doses prebreakfast, 15% prelunch, and 15% presupper. Type 1 DM
FIGURE 77-8. Relationship between insulin and glucose over the course patients generally require between 0.5 and 1 unit/kg per day. The
of a day and how various insulin regimens could be given. (A, aspart; CS- need for significantly higher amounts of insulin suggests the pres-
II, continuous subcutaneous insulin infusion; D, detemir; E, Exubera; G, ence of insulin antibodies or insulin resistance (coexistent endo-
glargine; GLU, glulisine; L, lispro; N, NPH; R, regular.) crinopathy or type 2 DM).
 1229
Obviously, insulin pump therapy (continuous subcutaneous Several common errors can occur in the therapy of patients with
insulin infusion [CSII], generally using lispro or aspart insulin to type 1 DM, causing erratic glucose fluctuations:

CHAPTER 77
diminish aggregation) is the most sophisticated form of basal bolus
• Failure to take into account peaks of insulin action when using
insulin delivery system. CSII can be slightly more efficacious in
a peaking insulin and planning meals and/or activity. Eating
achieving good glycemic control than multiple-dose insulin injec-
should be planned around the peaks of the insulin.
tions.101,102 Extensive discussion of this mode of therapy is beyond
the scope of this text.103 Nevertheless, the basic principles for • Random rotation of insulin injection sites. There is sufficient
implementation are the same. The one advantage of pump therapy variability of insulin absorption from site to site that this
is that the basal insulin dose can be varied, consistent with changes practice alone can cause wide glucose swings. The most consis-
in insulin requirements throughout the day. In selected patients, tent absorption of insulin is from the abdominal wall. We try
to get our patients to take all their injections in the abdomen.

Diabetes Mellitus
this feature will allow greater glycemic control with CSII. However,
insulin pumps require even greater attention to detail and frequency If the patient is unable or unwilling to follow this advice, then
of SMBG than four injections daily.104 In appropriately selected systematic site rotation is the next preferable option. The
patients willing to pay sufficient attention to detail of SMBG and patient always gives the insulin injection in the same region of
insulin administration, CSII can be a very useful form of therapy. the body the same time of the day each day. For instance, the
Intensive therapy (basal-bolus) to all adult patients with type 1 arms are always used every morning. Needless to say, the
DM at the time of diagnosis is recommended to reinforce the patient would not inject in a limb and then go out and exercise
importance of glycemic control from the outset rather than change that limb, increasing blood flow and insulin absorption.
strategies over time after lack of control. Occasional patients with an • Overinsulinization is a very common problem. The answer to
extended honeymoon period may need less intense therapy initially all high blood glucose is not necessarily more insulin, as the
but should be converted to basal-bolus therapy at the onset of patient may be insulinopenic, or may be “rebounding” from a
glycemic lability. For patients insisting on two injections daily, NPH previous low glucose and treating it with excessive amounts of
and regular insulin (starting at 0.6 units/kg with two-thirds in the carbohydrate. Fastidious SMBG, particularly during the night
morning, two-thirds of morning dose as NPH, and one-half of (or selected use of continuous glucose monitoring) will help
evening dose as NPH) may be sufficient. Regardless of the regimen sort this out. Also, practitioners sometimes do not adequately
chosen, gross adjustments in the total insulin dose can be made differentiate type 1 DM from type 2 DM when using insulin.
based on HbAlc measurements and symptoms such as polyuria, Patients with type 1 DM are insulinopenic but have normal
polydipsia, and weight gain or loss. Finer insulin adjustments can be insulin sensitivity. Patients with type 2 DM have varying
determined on the basis of the results of frequent SMBG. degrees of insulin resistance. Therefore one unit change in the
All patients receiving insulin should have extensive education in dose of insulin for a patient with type 1 DM can have a dramatic
the recognition and treatment of hypoglycemia. Yearly (or more effect on glucose concentrations, whereas in some patients with
often) questioning about the recognition of hypoglycemia is war- type 2 DM 10 to 20 times that amount of insulin can have little
ranted. Documentation of frequency of hypoglycemia, particularly effect on glucose. Large changes in insulin dose in patients with
that requiring assistance of another person, visit to an emergent or type 1 DM are not usually indicated unless the patient’s blood
urgent care facility, or hospitalization, should be recorded. In type 1 glucose control is very poor. Widely erratic SMBG results and/
DM, the development of hypoglycemia unawareness is common. It or weight gain often suggest overinsulinization.
can result from progression of disease with autonomic neuropathy. • When in doubt, always double check the patient’s technique
Loss of adrenergic warning signs in such a situation is a relative for insulin dosing, insulin injection, and SMBG. Sometimes
contraindication to intensive insulin therapy. More commonly, type the simplest of errors results in miserable glycemic control.
1 DM patients have loss of warning signs because of a presumed
Pramlintide in type 1 DM patients who continue to have erratic
lower set point for release of counterregulatory hormones as a result
postprandial control despite consideration or implementation of
of frequent episodes of hypoglycemia (“hypoglycemia begets
the above strategies can be appropriate. It is imperative at initiation
hypoglycemia”).105 In such situations, more normal hypoglycemia
of therapy with pramlintide that each dose of prandial insulin (rapid
awareness can be restored by reduction or redistribution of the
acting analog or regular insulin) be reduced by 30% to 50%, or
insulin dose to eliminate significant hypoglycemic episodes. A recent
severe hypoglycemic reactions have occurred. Pramlintide should
publication has found that short-term treatment with theophylline
be judiciously titrated based on GI adverse effects and postprandial
will improve hypoglycemia awareness.106 This therapy should not
glycemic goals. As pramlintide is not recommended for mixing, you
routinely be employed but can be considered in refractory cases.
are adding an additional prandial injection at each meal. A patient
Children and pubescent adolescents are relatively protected from
who is cognizant of the hypoglycemic risk, GI side effects, and
microvascular complications and must be managed with consider-
effective strategies to reduce both is needed.
ation of what is practical. Therefore it is not unreasonable to use less
Islet cell and whole pancreas transplantation are occasionally
intense management (two shots per day, premixed insulins) until
used in patients, usually renal transplants, who require immuno-
the patient is postpubertal.107
suppressive therapy for other reasons.110 There has been consider-
Occasional patients have antibodies to injected insulin, but the
able interest in islet cell transplantation since investigators in
significance of the antibodies is usually minimal.108 Human insulin
Edmonton reported success without using glucocorticoids as
therapy has not totally eliminated insulin allergies, although most
immunosuppressive agents.111 Some of these patients are able to
patients have a local reaction that will dissipate over time. If the
come off insulin altogether.
allergic reaction does not improve or is systemic, insulin desensiti-
zation can be carried out.109 Protocols for desensitization are avail-
able from major insulin manufacturers. Although more common in Type 2 DM
the animal insulin era, lipohypertrophy is still seen in some patients Pharmacotherapy for type 2 DM has changed dramatically in the last
with long-standing type 1 DM. Such patients give their insulin few years with the addition of several new drug classes and recom-
injections in the same site to minimize discomfort. Because insulin mendations to achieve more stringent glycemic control. Symptomatic
absorption from an area of lipohypertrophy is unpredictable, avoid- patients may initially require treatment with insulin or combination
ance of injections into these areas is mandatory. oral therapy to reduce glucose toxicity (which can reduce β-cell
1230
insulin secretion and worsen insulin resistance). Patients with HbAlc intolerant of, or has a contraindication to, metformin as an insulin
~7% or less are usually treated with therapeutic lifestyle measures and sensitizer, understanding that TZDs should be used with caution in
SECTION 8

an agent that will not cause hypoglycemia. Those with HbAlc >7% but heart failure.
<8% could be initially treated with single oral agents, or low dose The paradigm of treatment is slowly changing, as potentially
combinations. Patients with higher initial HbAlc can benefit from preserving β-cell function, thus arresting the progressive nature of
initial therapy with two oral agents, or even insulin. type 2 DM, is becoming a priority. In the UKPDS, insulin, met-
Depending on patient motivation and adherence to therapeutic formin, or sulfonylureas did not halt β-cell failure. TZDs, exenatide,
lifestyle changes, most patients with HbAlc greater than 9% to 10% vildagliptin, and sitagliptin can potentially preserve β-cell func-
will likely require therapy with two or more agents to reach glycemic tion.113,114 Despite long-term success at preventing diabetes or treat-
goals. Treatment of type 2 DM often necessitates use of multiple ing newly diagnosed diabetes, HOMA-β measures have not shown
β-cell benefit with rosiglitazone. Long-term β-cell studies with pio-
Endocrinologic Disorders

therapeutic agents (combination therapy), to obtain glycemic goals.

The best initial oral therapy for patients with type 2 DM is widely glitazone are underway. If positive human results are found long-
debated. Based on the results of the UKPDS and safety record, obese term, any of these medications could become potential first-line
patients (>120% ideal body weight) without contraindications therapy. For dual therapy, HbAlc reductions vary according to the
should be started on metformin titrated to ~2,000 mg/day.112 Near- medication added to the current therapy (Table 77–14). After a
normal weight patients can be treated with insulin secretagogues. patient has inadequate control on two drugs, adding a third drug can
Failure of initial therapy should result in addition rather than be considered. Triple therapy with a TZD is often instituted, but a
substitution (reserve substitution for intolerance to a drug because significant number of patients either have inadequate glycemic
of side effects) of another class of drug. For cost and glycemic improvement or significant side effects. An alternative is to add
efficacy reasons, metformin and an insulin secretagogue are often exenatide, DPP-IV inhibitor, basal insulin, or even the prandial
first- and second-line therapy, although combination with other inhaled insulin, Exubera. Therapy should be guided by the HbA1c,
agents for potential cardioprotection or potential β-cell preserva- FPG, cost, additional benefits (such as weight loss), and avoidance of
tion may be preferred. Initial oral combination therapy for patients contraindications and side effects. If the HbA1c is >8.5% to 9% on
with HbAlc >9% to 10% should be considered, and several oral multiple therapies, insulin therapy should be considered first. If the
combination products are available. Oral combination agents that patient is obese and the HbA1c is ≤8.5%, addition of exenatide or
have metformin in combination with a sulfonylurea are often very potentially a DPP-IV inhibitor can be considered. Sulfonylureas are
effective in lowering initially high HbA1c levels. Figure 77–9 is an often stopped when insulin is added, but continuing the sulfonylurea
algorithm developed by the Texas Diabetes Council for glycemic is permissible until multiple daily injections are started, at which
control. TZDs can be substituted in situations in which a patient is time it should definitely be discontinued.

Glycemic Control Algorithm

Initial monotherapy options:
Metformin1,7
TZDs
Glycemic Control Algorithm for Type 2 DM in Children1 and Adults Sulfonylureas7
Insulin (see Insulin Algorithm)2
Targets Other monotherapy options:
Nonsulfonylurea secretagogues–
A1C ≤6.5% Initial intervention2–4 Nateglinide or repaglinide
Fasting SMBG ≤110 mg/dL Diabetes education, α-Glucosidase inhibitors–
2-hr PP SMBG ≤140–180 mg/dL medical nutrition, and exercise5 acarbose or miglitol

Dual-therapy options:
Targets met Fasting SMBG/PP targets Sulfonylurea + metformin7
not met after 1 month Metformin + TZD
A1C every 3–6 months
Begin monotherapy Sulfonylurea or metformin +
Dual therapy Dual therapy exenatide
or dual therapy4,6
Monotherapy
Other combination options:
Targets met Insulin (see Insulin algorithm)2
Targets not met after 3 months Nonsulfonylurea secretagogues–
Continue therapy
A1C every 3–6 months Begin dual therapy Nateglinide or repaglinide
α−Glucosidase inhibitors–
acarbose or miglitol
Targets met Targets not met after 3 months
Continue therapy Add third oral agent or exenatide if A1c<8.5%;
A1c every 3–6 months OR
Add insulin for any A1c > target (see Insulin
Algorithm); consider referral to endocrinologist

1Metformin is the only FDA-approved oral diabetic agent in children (≥age 10); other agents may be used at the discretion of the clinician. 2See

Insulin Algorithm for Type 2 Diabetes Mellitus in Children and Adults. 3If initial presentation with glucose ≥260 mg/dL in symptomatic patient,
consider insulin or insulin analog as initial intervention, probably with dual therapy. 4Monotherapy with sulfonylurea or metformin does not sustain
HbA1c reductions (UKPDS study); dual therapy certainly indicated if initial glucose ≥210 mg/dL or HbA1c ≥9.0%. 5These interventions should be
maintained lifelong; see Medical Nutrition, Weight Loss, and Exercise Algorithms. 6If initial dual therapy is initiated, decide on add-on therapy
options within 3 months if glycemic targets are not met. 7Sulfonylureas and metformin are the most studied and least expensive oral diabetes
agents; glipizide ER and glimepiride have a lower incidence of hypoglycemia than glyburide. Publication #45-11265.

FIGURE 77-9. Glycemic control algorithm for type 2 diabetes mellitus (DM) in children and adults. See www.texasdiabetescouncil.org
for current algorithms. (A1c, glycosylated hemoglobin; ER, extended release; PP, postprandial; SMBG, self-monitoring of blood
glucose; TZD, thiazolidinedione; UKPDS, United Kingdom Prospective Diabetes Study.) (Reprinted with permission from the
Texas Diabetes Council.)
 1231

TABLE 77-14 Add-On Dual Therapy: Average HbAlc Reductionsa sions and have only a modest effect on the FPG. Thus, if the patient’s
fasting glucose is significantly elevated, additional therapy to lower

CHAPTER 77
Change Number Number the FPG will often be needed. Metformin, sulfonylureas, repaglinide,
in HbAlc of of
TZDs, and basal insulin all effectively lower the FPG.
Drug Combination (%) Studies Subjects
Virtually all patients with type 2 DM ultimately become relatively
Sulfonylurea + metformin –2.2 8 458 insulinopenic and will require insulin therapy. Insulin therapy for
Sulfonylurea + insulin –1.9 17 88 type 2 DM has changed dramatically in the last few years. Specifically,
Meglitinide + thiazolidinedione –1.7 1 434
patients are often “transitioned” to insulin by using a bedtime
Metformin + insulin –1.7 8 138
injection of an intermediate- or long-acting insulin, and using oral
Sulfonylurea + α-glucosidase inhibitor –1.6 3 177
Metformin + meglitinide –1.4 3 226
agents primarily for control during the day.115,116 This strategy leads

Diabetes Mellitus
Insulin + α-glucosidase inhibitor –1.2 1 20 to less hyperinsulinemia during the day and is associated with less
Insulin + thiazolidinedione –1.2 7 850 weight gain than the more traditional insulin strategies. Because most
Sulfonylurea + thiazolidinedione –1.1 12 1,315 patients are insulin resistant, insulin sensitizers are commonly used
Metformin + exenatide –0.8 2 1,070 with insulin therapy. Patients with type 2 DM are usually well
Metformin + vildagliptin –0.7 1 416 buffered against hypoglycemia. Patients should be monitored for
Metformin + thiazolidinedione –0.9 3 284 hypoglycemia by asking about nocturnal sweating, nightmares (both
Metformin + α-glucosidase inhibitor –0.4 3 173 indicative of nocturnal hypoglycemia), palpitations, tremulousness,
HbA1c, glycosolated hemoglobin. and neuroglycopenic symptoms, as well as SMBG. When bedtime
a
Reductions are averages and do not imply superiority or inferiority of a combination. insulin plus daytime oral medications fail to achieve glycemic goals, a
Adapted from American Diabetes Association. Dyslipidemia management in adults with diabetes. conventional multiple daily dose insulin regimen while continuing
Diabetes Care 2004;27:568-571.
the insulin sensitizers is often tried. Alternatively, off-label use of
exenatide for prandial control can be considered, if covered by
Exenatide and DPP-IV inhibitors add a new mechanistic way to insurance. Concerns and problems with insulin administration as
lower blood glucose. Exenatide is advantageous because it can allow addressed in the section on type 1 DM generally relate to the therapy
weight loss in type 2 DM patients, but is a twice-a-day injection and of type 2 DM. However, patients with type 2 DM rarely have
has some GI adverse effects. DPP-IV inhibitors are advantageous hypoglycemia unawareness. Also, the variability of insulin resistance
because they are orally active, weight neutral, and are very well means that insulin doses can range from 0.7 to 2.5 units/kg or more.
tolerated but lack long-term safety data. It should be remembered Figure 77–10 is an algorithm for insulin therapy options in type 2
that both classes work mainly to lower postprandial glucose excur- diabetes developed by the Texas Diabetes Council.

INSULIN ALGORITHM FOR TYPE 2 DIABETES MELLITUS

IN CHILDREN1 AND ADULTS

Treatment Naïve1;
ACB: Before breakfast
Targets* Symptomatic;
Oral Agent Failure; Oral Agent Failure; ACS: Before supper
A1c ≤6.5% FPG≥260mg/dL in adults or
A1c above target but FPG: Fasting plasma glucose
FPG/SMBG ≤110 mg/dL A1C ≥10%, ketoacidosis or recent A1c≥8.5%
<8.5% HS: Bedtime
2-hr PPG/SMBG ≤140–180 mg/dL rapid wt loss in children
LAI: Long-acting insulin = Glargine
*Individualizations is PCP: Primary care provider
recommended for those with chronic 3, 6
OPTIONS
2, 3
3 OPTIONS PPG: Postprandial plasma glucose
diseases or other comorbidities OPTIONS SAI: Short-acting insulin = Regular
(in order of preference) (in order of preference)
associated with high risk for (in order of preference) 5 (peak action 3–4 hrs); Lispro or
hypoglycemic events, especially 1. Once-daily Insulin 4 1. Multi-dose Insulin
1. Once-daily Insulin 2. Intensive Insulin Aspart (peak action 1½ hr)
younger children† and elderly. 2 Multi-dose Insulin(pediatric) 5
3. Intensive Insulin 2. Multi-dose Insulin Management
5 SMBG: Self-monitored blood glucose
†American Diabetes Association.
Clinical Practice Recommendation 2005. Management 3. Intensive Insulin 3. Once-daily Insulin
4 SQ: Subcutaneous
5
Diabetes Care. 2005;28 (suppl 1): S22. Management TDI: Total daily insulin in units

Once-daily Insulin Therapy (QDI) Multi-dose Insulin Therapy (MDI)10 Intensive Diabetes Management—
At bedtime (HS): NPH(pen/vial) or -2 shots Physiologic Insulin Delivery10
q daily Long-acting insulin (LAI) Split mix NPH + Short-acting insulin (SAI) (vial) 1:1 basal:bolus ratio SQ
(pen/vial) or Pramlintide10,12
(2:1 ratio AM, 1:1 ratio PM; or SAI sliding Basal: NPH at ACB, ACS or HS(or
Before supper (ACS): NPH mix with Consider as
scale7) QID)(pen/vial); or long-acting
short-acting insulin (SAI) adjunct
or premix 70/30; 75/25 or 50/50 (pen/vial) insulin (LAI)) q daily (pen/vial)
(2:1 ratio or sliding scale7) (vial) therapy to
-3 shots (especially if nocturnal hypoglycemia) Bolus: Short-acting insulin (SAI) at
or premix 70/30 or 75/25 pen/vial) insulin in
SAI: ACB and ACS sliding scale7 (pen/vial) each meal (especially Lispro/
starting dose8: 0.1–0.25 units/kg; patients
Aspart) (pen/vial)
or 6–10 units for elderly/thin/ Glycemic
+
Glycemic Premeal insulin dose includes: unable to
complicated patients Targets NPH: ACB and HS (pen/vial)or LAI: q daily(pen/vial) Targets 1. Insulin to cover carbohydrate stabilize
Escalate dose every 2-3 days to Starting dose8: 0.3–0.5 units/kg/day (or if post-
Not Met Not ingested11
attain SMBG/FPG target values; After current dose >0.5 units/kg/day, take 80% of Met prandial
2. Additional insulin to correct for
consider HS SMBG in adjusting 6–12 Weeks QDI dosage) divided 2/3 as NPH/LAI; 1/3 as After glucose.
high SMBG (1 unit SAI lowers PG
dose of ACS mix/premix (SAI SAI; titrate to achieve glycemic targets 3-6 [mg/dL] by approximately 1500/
component) Months TDI for Regular, 1800/TDI for
Suggested titrations schedule9 Lispro/Aspart)
If fasting SMBG Starting dose8: 0.3–0.5 units/kg/day
>180 mg/dL + 6 units (or if current dose >0.5 units/kg/day.
Follow A1c every 3–6 months and Adjust Regimen
141–180 mg/dL + 4 units take 80% of total NPH dosage as
to Maintain Glycemic Targets
121–140 mg/dL + 2 units glargine [basal]; bolus dose = 80% of
(Insulin Requirement May Decrease as A1c improves)
100–120 mg/dL + 1 units glargine dose divided tid)
<80 mg/dL – 2 units

Footnotes 3 7
1 Combining metformin with insulin therapy has been ~1-2 units for every 50 mg/dL above target SMBG; Regular insulin to be given 30–60 minutes AC meal
See Glycemic Control Algorithm 8
shown to result in less weight gain and better glycemic Dosages may differ in children and adolescents; consider referral to pediatric
for Type 2 Diabetes Mellitus in
control with lower insulin requirements endocrinologist/comprehensive diabetes specialty team
Children and Adults 4 9
2 Continue combination oral agent therapy ± sulfonylurea Go lower and slower for thin/elderly/complicated patients
Consider simultaneous 5 10
Continue metformin (± 3rd oral agent); probably Consider referral to pediatric/adult endocrinologist/diabetes specialty team (option—
combination oral agent therapy
discontinue sulfonylurea insulin pump, Pramlintide)
6 11
PCP may decide to “ease” patient with poor beta-cell Typical “carb” bolus = 1 unit SAI covers 500/TDI x g carbohydrates from meal (~ 10–15g);
reserve into insulin therapy initially with QDI strongly recommend referral to Registered/Licensed Dietitian or Certified Diabetes
See web site (http://www,texasdiabetescouncil.org) for latest version and disclaimer. Educator with experience in diabetes nutrition counseling (see Worksheet D.)
12
See reverse side for more information. IMPORTANT: See package insert for dosing.

FIGURE 77-10. Insulin algorithm for type 2 diabetes mellitus (DM) in children and adults. See www.texasdiabetescouncil.org for current
algorithms. (Reprinted with permission from the Texas Diabetes Council.)
1232
The availability of short-acting insulin secretagogues, rapid- whether dietary interventions are successful. If FPG is >105 mg/dL,
acting insulin analogs, human insulin inhalation powder, exenatide, or 1-hour postprandial plasma glucose levels are >155 mg/dL, or if
SECTION 8

DPP-IV inhibitors, and α-glucosidase inhibitors, all of which target 2-hour postprandial plasma glucose levels are >130 mg/dL, insulin
postprandial glycemia, has reminded practitioners that glycemic therapy is usually begun. One shot of NPH or a mixture of NPH and
control is a function of fasting and preprandial glycemia and regular insulin in a 2:1 ratio given before breakfast may be adequate
postprandial glycemic excursions.117 Therefore postprandial glucose to reach glucose targets. Titration of insulin and switching to more
measurements may need more emphasis if the HbAlc is near the complicated regimens is guided by SMBG results. Use of basal
glycemic goal. Currently, it remains controversial whether targeting insulins other than NPH is still debated, but with the ease of use of
after-meal glucose excursions will have more of an effect on compli- detemir or glargine insulin, their use in GDM will likely increase. In
cations risk than more conventional strategies. Importantly, post- addition, pump therapy for the duration of the pregnancy is often
Endocrinologic Disorders

prandial excursions proportionally contribute more than the FPG instituted, as it can obtain excellent glycemic control and is quickly
to the HbAlc percentage when the HbAlc nears goals, and thus will adjustable. In spite of the long-standing labeling of sulfonylureas as
need to be targeted for optimal glycemic control in many patients. contraindicated in pregnancy, one randomized, open-label, con-
Also controversial are the American College of Endocrinology/ trolled trial evaluated the efficacy of glyburide as compared to
American Association of Clinical Endocrinologists postprandial insulin initiated after 11 weeks’ gestation.119 Adequate control of
glycemic goals (see Table 77–8). These guidelines use epidemiologic blood glucose was achieved as compared to traditional insulin
studies with post–glucose challenge glucose measurements in dia- therapy, with less hypoglycemia in the glyburide group. No evidence
betic and nondiabetic subjects to state that postprandial glycemia is of any difference in complications, specifically cord-serum insulin
a better predictor of macrovascular disease risk in DM.118 In concentrations, incidence of macrosomia (birth weight of 4 kg or
contrast, the ADA continues to recommend peak postprandial more), cesarean delivery, or neonatal hypoglycemia between regi-
blood glucose levels less than 180 mg/dL. mens were noted. Glyburide was not detected in the cord serum of
any infant. As the study limited enrollment beyond 11 weeks’
■ SPECIAL POPULATIONS gestation, no conclusions regarding teratogenicity can be made
from this study. The ADA cites this study in a position paper and
Children and Adolescents with Type 2 DM mentions its usefulness, but also warns that it is not a labeled use of
Type 2 DM is increasing in adolescence.10 Obesity and physical the drug and suggests further studies are needed to establish its
inactivity seem to be particular culprits in the pathogenesis of this safety.12 Patients with GDM should be evaluated 6 weeks after
disease. Given the many years that the patient will have to live with delivery to ensure that normal glucose tolerance has returned.
diabetes, and recent evidence that the timeline for complications Because these patients’ long-term risk for the development of type 2
may mimic that of older adults, extraordinary efforts should be DM is considerable, periodic assessment after that is warranted.
expended on lifestyle modification measures in an attempt to
normalize glucose levels. Failing that strategy, the only labeled oral ■ SPECIAL SITUATIONS
agent for use in children (10 to 16 years of age) is metformin,
although sulfonylureas are also commonly used in therapy. TZDs Sick Days
have not been studied in children, but studies to ascertain safety and Acute self-limited illness rarely presents a major problem for
efficacy are currently underway. Off-label use of exenatide, as it patients with type 2 DM but can be a significant challenge for
potentially helps the child to lose weight, is also increasing, but the insulinopenic type 1 DM patients.120 Although caloric intake gener-
long-term effects of this therapeutic modality are unknown. In ally declines, insulin sensitivity also decreases, meaning that it can
adolescent females, the possibility of future pregnancy should be take greater amounts of insulin to control blood glucose concentra-
considered in the prescription of any drug regimen. tions. Patients need to be adept at frequent SMBG, checking urine
ketones, use of short-acting insulin, and understanding that sugar
Elderly Patients with DM intake in this situation is not “bad” but can be necessary to “cover”
Elderly patients with newly diagnosed DM (almost always type 2 the insulin therapy given to keep the patient out of diabetic
DM) present a different therapeutic challenge. Consideration of the ketoacidosis. We encourage patients to continue their usual insulin
risks of hypoglycemia in this population and the probable life span regimen and to use supplemental rapid-acting insulin based on
should help determine if less-stringent glycemic goals should be set. SMBG results, with further additional insulin given if ketonuria
Thinner, older patients can primarily be treated with shorter-acting develops. Sugar and electrolyte solutions, such as sports drinks, can
insulin secretagogues, low-dose sulfonylureas (preferably not long- be used to maintain hydration, to provide needed electrolytes if
acting ones), DPP-IV inhibitors, or α-glucosidase inhibitors. The there are significant GI or urinary losses, and to provide sugar to
risk for lactic acidosis, which increases with older age and the age- keep the patient from developing hypoglycemia because of the extra
related decline in renal function, makes metformin therapy more insulin that is usually needed. In contrast, type 2 patients may need
problematic. In a patient whom weight gain or loss may not be to switch to sugar-free drinks if blood glucose levels are continually
unwelcome, TZDs or exenatide, respectively, can be considered. elevated. Most patients can be taught how to sufficiently manage
DPP-IV inhibitors or α-glucosidase inhibitors can be advantageous sick days and avoid hospitalization.
because of low risk of hypoglycemia. Simple insulin regimens such
as an injection of basal insulin daily can be appropriate for glycemic Diabetic Ketoacidosis and Hyperosmolar
control in elderly patients with newly diagnosed DM. Hyperglycemic State
Diabetic ketoacidosis and hyperosmolar hyperglycemic state are
Gestational DM true diabetic emergencies.121,122 A comprehensive discussion of their
GDM is diagnosed as previously described. Dietary therapy to treatment is beyond the scope of this chapter. In patients with
minimize wide fluctuations in blood glucose is of paramount known diabetes, diabetic ketoacidosis is usually precipitated by
importance.5 Intensive educational efforts are usually necessary. insulin omission in type 1 DM, and intercurrent illness, particularly
Pregnant women without DM maintain plasma glucose concentra- infection, in both type 1 and type 2 DM. However, patients with
tions between 50 and 130 mg/dL. Frequent SMBG is needed to tell type 1 or type 2 DM (the latter being usually nonwhites or Hispan-
 1233
123
ics) can present at initial presentation. It is possible that some of mortality in type 2 diabetes patients with acute myocardial
the patients deemed to have type 2 DM actually have type 1 infarctions126 who receive constant intravenous insulin during the

CHAPTER 77
idiopathic DM. Patients with diabetic ketoacidosis can be alert, acute phase of the event to maintain near-normal glucose concen-
stuporous, or comatose at presentation. The hallmark diagnostic trations. Similar mortality results have been documented in some
laboratory values include hyperglycemia, anion gap acidosis, and intensive care unit settings using intravenous insulin and tight
large ketonemia or ketonuria. Afflicted patients have fluid deficits of glucose control.127,128 Currently the American College of Endocri-
several liters and sodium and potassium deficits of several hundred nology recommends preprandial levels <110 mg/dL, and postpran-
milliequivalents. Restoration of intravascular volume acutely with dial level <180 mg/dL, but the ADA lists these data as evidence
normal saline, followed by hypotonic saline to replace free water, based level B.129 Many protocols for IV insulin infusion are cur-
potassium supplements, and constant infusion insulin restore the rently available, and implementation for an inpatient setting should

Diabetes Mellitus
patient’s metabolic status relatively quickly. A flow sheet is often use a well established protocol. It is prudent to stop metformin in all
helpful in tracking the fluid and insulin therapies and laboratory patients who arrive in acute care settings until full elucidation of the
parameters in these patients. Bicarbonate administration is gener- reason for presentation can be ascertained, as contraindications to
ally not needed and may be harmful, especially in children.124 metformin are prevalent in hospitalized patients.130
Treatment of the inciting medical condition is also vital. Hourly
bedside monitoring of glucose and frequent monitoring (every 2 to Perioperative Management
4 hours) of potassium is essential. Metabolic improvement is
manifested by an increase in the serum bicarbonate or pH. Serum Surgical patients can experience worsening of glycemia for reasons
phosphorus usually starts high and plummets to lower-than-normal similar to those listed above for intercurrent medical illness.131
levels, although replacing phosphorus, although not unreasonable, Patients on oral agents can need transient therapy with insulin to
is of questionable benefit in most patients. Fluid administration control blood glucose. In patients requiring insulin, scheduled doses
alone will reduce the glucose concentration, so a decrement in of insulin or continuous insulin infusions are preferred. For patients
glucose values does not necessarily mean that the patient’s meta- who can eat soon after surgery, the time-honored approach of giving
bolic status is improving. Rare patients will require larger amounts one-half of the usual morning NPH insulin dose with dextrose 5% in
of insulin than those usually given (5 to 10 units/h). We double the water intravenously is acceptable, with resumption of scheduled
patient’s insulin dose if the serum bicarbonate has not improved insulin, perhaps at reduced doses, within the first day. For patients
after the first 4 hours of insulin therapy. Constant infusion of a fixed requiring more prolonged periods without oral nutrition and for
dose of insulin and the administration of intravenous glucose when major surgery, such as coronary artery bypass grafting and major
the blood glucose level decreases to <250 mg/dL is preferable to abdominal surgery, constant infusion intravenous insulin is pre-
titration of the insulin infusion based on the glucose level. The latter ferred. Use of intravenous insulin infusion has been shown to reduce
strategy may delay clearance of the ketosis and prolong treatment. deep sternal wound infections in patients undergoing coronary artery
The insulin infusion should be continued until the urine ketones bypass grafting. Metformin should be discontinued temporarily after
clear and the anion gap closes. Long-acting insulin should be given any major surgery until it is clear that the patient is hemodynamically
1 to 3 hours prior to discontinuing the insulin infusion. Intramus- stable and normal renal function is documented.
cular regular insulin or subcutaneous insulin lispro or aspart given
every 1 to 2 hours can be used rather than an insulin infusion in Reproductive-Age Women and Preconception
patients without hypoperfusion. Patients can develop hyperchlo- Care for Women
remic metabolic acidosis with treatment if they have been given
An increasing prevalence of DM has been noted in reproductive-age
large volumes of normal saline in the course of their treatment.
women.132,133 Prepregnancy planning is absolutely mandatory, as
Such a situation does not require any specific treatment.
organogenesis is largely completed within 8 weeks, so good glycemic
Hyperosmolar hyperglycemic state usually occurs in older patients
control should be obtained prior to conception. Unfortunately,
with type 2 DM, at times undiagnosed, or in younger patients with
major congenital malformations because of poor glucose control
prolonged hyperglycemia and dehydration or significant renal insuf-
remain the leading cause of mortality and serious morbidity in
ficiency. Large ketonemia is usually not seen, as residual insulin
infants of mothers with type 1 or type 2 diabetes. For women with
secretion suppresses the production of ketones. Infection or another
DM controlled by lifestyle measures alone, conversion to insulin as
medical illness is the usual precipitant. Fluid deficits are usually
soon as the pregnancy is confirmed is appropriate. For women with
greater and blood glucose concentrations higher (at times >1,000
polycystic ovary disease who ovulate and become pregnant with
mg/dL) in these patients than in patients with diabetic ketoacidosis.
insulin sensitizer therapy, conversion to insulin is mandatory as
Blood glucose levels should be lowered very gradually with hypo-
soon as pregnancy is confirmed. Insulin is the only acceptable
tonic fluids and low-dose insulin infusions (1 to 2 units/h). Rapid
pharmacologic therapy during pregnancy for women with DM in
correction of the glucose levels, a drop greater than 75 to 100 mg/dL
the United States. In Europe, metformin and glyburide are some-
per hour, is not recommended, as it can result in cerebral edema.
times used in pregnancy for type 2 DM, but their use is controver-
This is especially true for children with diabetic ketoacidosis. Mortal-
sial in the United States. Patients previously treated with insulin can
ity is high with the hyperosmolar hyperglycemic state.
need intensification of their regimen to achieve therapeutic goals.
Normal pregnancy is associated with a decrease in the blood glucose
Hospitalization for Intercurrent Medical Illness concentration as fuel is diverted to the fetus. Pregnant patients will
Patients on oral agents can need transient therapy with insulin to be ingesting both meals and snacks daily. SMBG is generally
achieve adequate glycemic control. In patients requiring insulin, intensified to try to reach glycemic targets and reduce fetal and
patients should receive scheduled doses of insulin with additional maternal morbidity. Whether preprandial or postprandial glucose
short-acting insulin. “Sliding-scale” insulin is to be discouraged, as concentrations should be the target of therapy is hotly debated.
it is notorious for not controlling glucose and for sometimes Ketosis should be avoided, requiring urine monitoring for ketones
resulting in therapeutic misadventures, with wide swings in the in the morning and if the blood sugar is >200 mg/dL.
blood glucose as the patient “bounces” from hypoglycemia to There has been some concern about the safety of insulin analogs
hyperglycemia.125 In-hospital mortality is increased in many hyper- in pregnancy, both for fetal development and advancement of
glycemic conditions. At least one study documented a reduction in microvascular complications. One study has shown no increase in
1234
retinopathy or progression of same with the use of insulin lispro in
pregnancy.134 effective, with a 58% lower relative risk of progression to
SECTION 8

diabetes, metformin 850 mg twice a day reduced the risk by 31%,

■ SPECIAL TOPICS and was essentially as effective as diet and exercise in young/
obese subjects. Rosiglitazone, acarbose, and even orlistat all
Prevention of DM have, to one extent or another, been able to delay the onset of
Efforts to prevent type 1 DM with immunosuppressives135 or type 2 DM. Despite these data, there are no FDA-approved drugs
injected136 or oral insulin therapy137 have been unsuccessful. The for the delay or prevention of diabetes. The ADA-recommended
Diabetes Prevention Program138 confirmed that modest weight loss medications, in conjunction with lifestyle, for the delay or
in association with exercise can have a dramatic impact on insulin prevention of type 2 DM include metformin. It should be
Endocrinologic Disorders

sensitivity and the conversion from impaired glucose tolerance to remembered that medications require monitoring and can have
type 2 diabetes. In this study approximately 2,000 individuals with serious side effects. Many feel they are simply treating diabetes
impaired glucose tolerance were randomized to lifestyle changes early, as β-cell dysfunction can be documented in early impaired
(diet, exercise, and weight loss) as opposed to usual care. The study, glucose tolerant subjects. Other than troglitazone, which is not
which was originally planned to be ongoing for 5 years, was stopped on the market, no medication has clearly shown β-cell preserva-
after 2.8 years because the results were so conclusive. The usual care tion. It is logical to try to use medications if they alter the decline
group developed diabetes at the rate of 11% each year. The lifestyle of β-cell function, but this is currently off-label use and any
arm developed diabetes at a rate of 5% per year, a 58% reduction in attempt to use medication in these situations should be clearly
the risk of developing diabetes.138 Surprisingly, a modest amount of and frankly discussed with the patient.
diet and exercise yielded impressive results. The exercise program in
the lifestyle group was walking 30 minutes, 5 days each week. The Patient Education
mean weight loss over the 2.8 year study period was only 3.6 kg (8
 It is not satisfactory to give patients with DM brief instructions
lb). Similar results were seen in the Finnish Diabetes Study.139 In the
with a few pamphlets and expect them to manage their disease
Diabetes Prevention Program138 discussed above, approximately adequately. Thinking that diabetes education is limited to one or two
1,000 of the study patients were randomized to metformin therapy. encounters is misguided; education is a lifetime exercise. Successful
The metformin-treated patients showed a 1.8-kg (4-lb) weight loss treatment of DM involves lifestyle changes for the patient (e.g.,
138
Interestingly, young and overweight individuals on metformin medical nutrition therapy, physical activity, self-monitoring of blood
had a greater reduction in the risk of developing diabetes than glucose and possibly of urine for ketones, and taking prescribed
normal weight and older study patients.138 medications). The patient must be involved in the decision-making
Metformin and acarbose92 appear to mostly be treating early process and must learn as much about the disease and associated
diabetes, because when the drugs were stopped, diabetes rates were complications as possible. Emphasis should be placed on the evi-
close to the conversion rates for placebo. In contrast, the Troglita- dence that indicates that complications can be prevented or mini-
zone in the Prevention of Diabetes (TRIPOD) study140 evaluated the mized with glycemic control and management of risk factors for
ability of troglitazone to prevent the development of diabetes in cardiovascular disease. Recognition of the need for proper patient
women with a history of gestational diabetes. The rate of develop- education to empower them into self-care has generated programs
ment of diabetes in the placebo arm of the study was approximately for certification in diabetes education. Certified diabetes educators
12% per year, compared to about 5% in the treatment group. Total must document their patient education hours and sit for a certifica-
preservation of β-cell function was demonstrated over a 5-year tion examination that assesses the knowledge, tasks, and skills of an
period in women who had near normal β-cell function at baseline educator in order to become certified. An increasing number of
and who initially responded to the drug.140 The preservation of β-cell nurses, pharmacists, dietitians, and physicians are becoming certified
function was observed for at least 8 months after the drug had been diabetes educators to document to the public that they meet a
discontinued. The Diabetes Reduction Assessment with Ramipril minimum standard for diabetes education and to fulfill quality
and Rosiglitazone Medication (DREAM) trial evaluating rosiglita- initiatives in meeting guidelines for education recognition.144
zone and/or ramipril treatment for the delay or prevention of type 2
DM in impaired glucose tolerant subjects was recently pub-
lished.141,142 Rosiglitazone 8 mg daily, over approximately 3 years, ■ TREATMENT OF CONCOMITANT
reduced the incidence of type 2 diabetes by 60%. In addition, a 37% CONDITIONS AND COMPLICATIONS
nonsignificant increase in cardiovascular events was reported. Rami- Retinopathy
pril 15 mg daily did not significantly prevent the conversion to
diabetes. It is possible that longer exposure could have made a Patients with established retinopathy should see an ophthalmologist
difference, but the study was stopped prematurely. It should be or optometrist trained in diabetic eye disease.145 A dilated eye
noted that no pharmacologic agents are currently FDA approved or examination is required to fully evaluate diabetic eye disease. Early
recommended for prevention of type 2 diabetes, though the ADA background retinopathy can reverse with improved glycemic con-
recommends metformin in conjunction with lifestyle changes if the trol. More advanced retinopathy will not regress with improved
patient is younger, obese, has a family history of diabetes, dyslipi- glycemia and can actually worsen with short-term improvements in
demia, hypertension, or a HbA1c above 6%.143 Prevention studies are glycemia. Studies are underway to determine whether medical
therapy independent of glucose control will prevent the develop-
still underway using pioglitazone, nateglinide, and valsartan.
ment of advanced retinopathy. Laser photocoagulation has mark-
edly improved sight preservation in diabetic patients.

CLINICAL CONTROVERSY Neuropathy

DM is associated with a substantially higher risk of morbidity
Peripheral neuropathy is the most common complication seen in type
and mortality. Pharmacologic prevention or delay of type 2 DM
2 DM patients in outpatient clinics.146 Paresthesias, numbness, or pain
has been widely discussed since the release of the Diabetes
can be the predominant symptom. The feet are involved far more
Prevention Program results. Although lifestyle changes were
often than the hands. Improved glycemic control can alleviate some of
 1235
the symptoms. If neuropathy is painful, symptomatic therapy is important for retarding the progression of established nephropathy.
empiric, including low-dose tricyclic antidepressants, anticonvulsants ACE inhibitors and angiotensin receptor blockers, considered first-

CHAPTER 77
(gabapentin, pregabalin, carbamazepine, and maybe phenytoin), line recommended treatment modalities, have shown efficacy in
duloxetine, venlafaxine, topical capsaicin, and various pain medica- preventing the clinical progression of renal disease in patients with
tions, including tramadol and nonsteroidal antiinflammatory drugs. type 2 DM.148–150 Diuretics frequently are necessary because of the
Recently, another anticonvulsant, topiramate, has shown promise in volume-expanded state of the patient and are recommended sec-
the reduction of symptoms, with the positive side effect of weight loss ond-line therapy. The ADA and the National Kidney Foundation
in type 2 diabetes patients, although tolerability is problematic. The blood pressure goal of <130/80 mm Hg can be difficult to achieve.
numb variant of peripheral neuropathy is not treated with medication. Three or more antihypertensives are often needed to treat to goal
Clinical manifestations of diabetic autonomic neuropathy include blood pressures.

Diabetes Mellitus
resting tachycardia, exercise intolerance, orthostatic hypotension, con-
stipation, gastroparesis, erectile dysfunction, sudomotor dysfunction Peripheral Vascular Disease and Foot Ulcers
(anhidrosis, heat intolerance, gustatory sweating, and/or dry skin),
Claudication and nonhealing foot ulcers are common in type 2 DM
impaired neurovascular function, and hypoglycemic autonomic fail-
patients.151 Smoking cessation, correction of lipid abnormalities,
ure. Gastroparesis can be a severe and debilitating complication of
and antiplatelet therapy are important strategies in treating claudi-
DM. Improved glycemic control, discontinuation of medications that
cants. Pentoxifylline or cilostazol can be useful in selected patients.
slow gastric motility, and the use of metoclopramide (preferably for
Revascularization is successful in selected patients. Local débride-
only a few weeks at a time) or erythromycin can be helpful. Gastric
ment and appropriate footwear and foot care are vitally important
pacemakers as therapeutic hardware are rarely used, although avail-
in the early treatment of foot lesions. In more advanced lesions,
able. Orthostatic hypotension can require pharmacologic manage-
topical treatments can be of benefit. Diabetic foot care is an
ment with mineralocorticoids or adrenergic agonist agents. In severe
excellent example of the adage, “an ounce of prevention is worth a
cases, supine hypertension is extreme, mandating that the patient sleep
pound of cure.”
in a sitting or semirecumbent position. Patients with cardiac auto-
nomic neuropathy are at a higher risk for silent myocardial infarction
and mortality. The hallmark of diabetic diarrhea is its nocturnal Coronary Heart Disease
occurrence. Diabetic diarrhea frequently responds to a 10- to 14-day The risk for coronary heart disease (CHD) is two to four times
course of an antibiotic such as doxycycline or metronidazole. In more greater in diabetic patients than in nondiabetic individuals. CHD is the
unresponsive cases, octreotide can be useful. Erectile dysfunction is major source of mortality in patients with DM. Recent studies suggest
common in diabetes, and initial treatment should include a trial of one that multiple risk-factor intervention (lipids, hypertension, smoking
of the oral medications currently available to treat erectile dysfunction. cessation,152 and antiplatelet therapy)153 will reduce the burden of
People with diabetes often require the highest doses of these medica- excess macrovascular events. Epidemiologic data suggest that CHD
tions to have an adequate response. Sudomotor dysfunction, as earlier prevention guidelines for type 2 DM apply equally to patients with
defined, results in loss of sweating and resultant dry, cracked skin. Use type 1 DM.154 β-Blocker therapy supplies an even greater protection
of hydrating creams and ointments is needed. from recurrent CHD events in diabetic patients than in nondiabetic
subjects. Masking of hypoglycemic symptoms is a greater problem in
Microalbuminuria and Nephropathy type 1 DM patients than in patients with type 2 DM.
DM, and particularly type 2 DM, is the biggest contributor statisti- Lipids The Collaborative Atorvastatin Diabetes Study (CARDS) ran-
cally to the development of end-stage renal disease in the United domized diabetes subjects with no documented cardiovascular disease
States.147 The ADA recommends a screening urinary analysis for to atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410). The trial
albumin at diagnosis in persons with type 2 DM. Precise onset of type was stopped 2 years early (mean duration of followup was 3.9 years)
2 DM can rarely be ascertained, and patients will often present at after meeting the primary efficacy end point of major cardiovascular
diagnosis with microvascular complications. In type 1 DM, microal- events, which were reduced by 37% (P = 0.001). All-cause death was
buminuria rarely occurs with short duration of disease or before reduced 27% (P = 0.059) and potentially could have had its signifi-
puberty. Screening individuals with type 1 DM should begin with cance influenced by the early stoppage of the trial.155 The Heart
puberty and after 5 years’ disease duration. There are three methods Protection Study randomized 5,963 patients age >40 years with diabe-
for assessing microalbuminuria: (1) measurement of the urine albu- tes and total cholesterol >135 mg/dL. A significant 22% reduction
min-to-creatinine ratio in a random spot collection (preferably the (95% confidence interval [CI], 13–30) in the event rate for major
first morning void); (2) 24-hour timed collection; and (3) timed (e.g., cardiovascular events was seen with simvastatin 40 mg per day. This
4-hour or 10-hour overnight) collection. Microalbuminuria on a spot was evident even at lower LDL levels (<116 mg/dL), and suggests that
urine specimen is defined as a ratio of 30 to 300 mg/g albumin-to- ~30% reduction in LDL levels regardless of starting LDL levels can be
creatinine. On timed collections, microalbuminuria is defined as 30 appropriate.156 The proper use of fibrates in diabetes continues to be
to 300 mg/24 hours or an albumin excretion rate of 20 to 200 mcg/ controversial. The diabetic subgroup in the Veterans Administration
min. Because of day-to-day variability, microalbuminuria should be HDL Intervention Trial (VA-HIT) of CHD patients with low HDL-C
confirmed on at least two of three samples over 3 to 6 months. and low LDL-C showed approximately 22% reduction in CHD events
Additionally, when assessing urine protein or albumin, conditions in diabetic patients with known CHD when HDL-C was increased by
that can cause transient elevations in urinary albumin excretion approximately 6% by gemfibrozil.157 The Fenofibrate Intervention and
should be excluded. These conditions include: intense exercise, recent Event Lowering in Diabetes (FIELD) was conducted in 9,795 subjects
urinary tract infections, hypertension, short-term hyperglycemia, (22% with previously documented cardiovascular disease) with type 2
heart failure, and acute febrile illness.147 DM given fenofibrate 200 mg daily or placebo. A relative reduction of
In type 2 DM, the presence of microalbuminuria is a strong risk 11% (P = 0.16) was seen in any coronary event in conjunction with a
factor for macrovascular disease and is frequently present at the slight increase in the risk of all-cause mortality. (0.7%, P = 0.18).
time of diagnosis. Microalbuminuria is a weaker predictor for Reasons for this have been speculated on, including the increased use
future kidney disease in type 2 versus type 1 DM. of statins in the placebo group, but it continues to be controversial.158
Glucose and blood pressure control are most important for the The National Cholesterol Education Program Adult Treatment
prevention of nephropathy, and blood pressure control is the most Panel III (NCEP-ATP III)159 guidelines classify the presence of DM
1236

TABLE 77-15 Classification of Lipid and Lipoprotein Levels

in Adults their well documented renoprotective effects. Currently, angio-
SECTION 8

tensin receptor blockers have less robust data to support cardio-

Treatment
vascular reduction compared to other therapeutic choices, yet the
Parameter Goal (in order of preference)
data that exists appears to be positive in patients with type 2 DM.
LDL cholesterol <100 mg/dL Lifestyle; HMG-CoA reductase Also, in the diabetic subset of the Antihypertensive and Lipid-
<70 mg/dLa inhibitors; cholesterol Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),
absorption inhibitor; niacin diuretics have shown equivalent results to an ACE inhibitor. The
or fenofibrate
ADA currently recommends the use of any class (ACE inhibitors,
HDL cholesterol Men Women Lifestyle; nicotinic acid; fibric
>40 mg/dL >50 mg/dL acid derivatives
angiotensin receptor blockers, β-blockers, diuretics, or calcium
Endocrinologic Disorders

Triglycerides <150 mg/dL Lifestyle; glycemic control; channel blockers) of antihypertensive medication that has shown
fibric acid derivatives; high- benefit in prevention of poor cardiovascular outcomes. Choice of
dose statins (in those with monotherapy may not be important, as an average of two to three
high LDL) antihypertensive medications are needed to reach blood pressure
goals.
HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density
lipoprotein.
a
Can be optimal goal in patients with preexisting cardiovascular disease. Transplantation
Data from American Diabetes Association. Dyslipidemia managment in adults with diabetes.
Diabetes Care 2004;27:568–571. Whole pancreas and islet cell transplantation are still relatively
experimental procedures in patients with type 1 DM; those with
as a CHD risk equivalent, and therefore recommend that LDL-C be end-stage renal disease also receive kidney transplantation.164
lowered to <100 mg/dL. An optional LDL goal in high-risk DM
patients, such as those who already have CHD, has been updated to
PHARMACOECONOMIC CONSIDERATIONS
be <70 mg/dL.160 Unlike previous guidelines, more consideration is
now given to HDL-C and triglycerides. The primary target is the As described in the introduction, the direct and indirect costs of DM
treatment of LDL-C. After the LDL-C goal is reached (usually with are substantial. Much of the indirect costs are related to loss of
a statin), triglycerides are possibly considered for pharmacologic productivity because of the significant morbidity (hospitalizations,
management, assuming unresponsiveness to glycemic control loss of vision, lower extremity amputations, kidney failure, and
efforts, weight management, and exercise. In such situations, a non- cardiovascular events) associated with the disease. For a disease that
HDL-C goal is established (a surrogate for all apolipoprotein B– affects about 9% of the population, it is responsible for 11% to 12%
containing particles). The non-HDL-C goal for patients with DM is of health expenditures. With evidence from the DCCT and UKPDS
<130 mg/dL. Niacin or a fibrate can be added to reach that goal if to support intensive blood glucose control to reduce the risk of
triglycerides are 201 to 499 mg/dL. Niacin or a fibrate can also be complications, the question of cost effectiveness comes into play.
added if the LDL-C goal is reached, but the patient has low HDL-C An economic model based on the DCCT approximates that
(<40 mg/dL). Patients with marked hypertriglyceridemia (≥500 mg/ 120,000 persons in the United States would meet criteria for
dL) are at risk for pancreatitis. Efforts to reduce triglycerides with intensive intervention. The cost of implementing intensive therapy
glycemic control, elimination of other secondary causes (including over the lifetime of the population is estimated at $4 billion dollars.
medications), and drug therapy (fibrate and/or niacin) are effective The benefits of this strategy are net gains of 920,000 years of sight,
treatment strategies. The ADA also recommends similar LDL goals 691,000 years free from end-stage renal disease, and 678,000 years
but places raising HDL as the second priority (Table 77–15). The free from lower extremity amputations. The incremental cost per
definitive role of pharmacologic therapy of HDL-C and/or hyper- year of life gained is $28,661.165 This is well within the limits of a
triglyceridemia in type 2 DM patients (beyond that seen with statin cost-effective strategy and compares favorably to treatment of high
therapy) has yet to be proven in clinical trials. blood pressure or hypercholesterolemia.
Economic analysis of intensive therapy for type 2 DM is more
Hypertension complex. Outcomes must also factor in the burden of cardiovascu-
The role of hypertension in increasing microvascular and macrovas- lar disease as the major cause of mortality. One model analyzed the
cular risk in patients with DM has been confirmed in the UKPDS97 health benefits and economics of treating type 2 DM with the goal
and Hypertension Optimization Treatment161 trials. The ADA rec- of achieving normoglycemia but using outcomes based on the
ommends aggressive goals for blood pressure (<130/80 mm Hg) in DCCT trial results. Accounting for the prevalence of cardiovascular
patients with DM.8 ACE inhibitors and angiotensin receptor block- disease in type 2 DM, an estimate of $16,002 incremental cost per
ers are generally recommended for initial therapy. The National quality-adjusted life year gained was obtained. The limitation of this
Kidney Foundation also suggests that the blood pressure goal be less analysis is that although the UKDPS did demonstrate an improve-
than 130/80 mm Hg, as well as recommending diuretics as second- ment in diabetes-related outcomes, the overall efficacy on microvas-
line therapy in patients with diabetic kidney disease.162 Many cular disease complications was not mirrored by the DCCT.
patients require multiple agents, on average three agents, to obtain Two economic analyses were performed on data generated from
goals, so diuretics, calcium channel blockers, and β-blockers fre- the UKPDS, one assessing cost effectiveness of an intensive blood
quently are useful as second and third agents. Blood pressure goals glucose control policy in type 2 DM, and the other assessing
are generally more difficult to achieve than glycemic goals or lipid improved blood pressure control in hypertensive patients with type
goals in most diabetic patients.163 2 DM. In the first analysis, outcome was measured as the incremen-
tal cost per event-free year gained within the trial. Based on trial
outcomes and assumptions, the incremental cost in the intensive
CLINICAL CONTROVERSY treatment group per event-free year gained is $1,366. Although
intensive treatment costs were higher, the cost per event-free year
Initial therapy choices for hypertension in DM usually include
gained appears cost-effective. The second analysis showed the incre-
ACE inhibitors or an angiotensin receptor blocker because of
mental cost per extra year free from microvascular and macrovascu-
 1237
lar end points from intensive blood pressure control in a standard BMI: body mass index
clinical practice model to be $1,498. The incremental cost per life

CHAPTER 77
CHD: coronary heart disease
year gained was estimated at $619, again demonstrating the cost-
CSII: continuous subcutaneous insulin infusion
effectiveness of intensive intervention.166,167
CYP450: cytochrome P450
DCCT: Diabetes Control and Complications Trial
EVALUATION OF THERAPEUTIC OUTCOMES
DM: diabetes mellitus
MONITORING OF THE DPP-IV: dipeptidyl peptidase IV
PHARMACEUTICAL CARE PLAN DREAM: Diabetes Reduction Assessment with Ramipril and Rosig-

Diabetes Mellitus
litazone Medication (study)
A comprehensive pharmaceutical care plan for the patient with DM
will integrate considerations of goals to optimize blood glucose FFA: free fatty acid
control and protocols to screen for, prevent, or manage microvas- GDM: gestational diabetes mellitus
cular and macrovascular complications. In terms of standards of GIP: glucose-dependent insulin-releasing peptide
care for persons with DM, one can review the document published
GLP-1: glucagon-like peptide-1
by the ADA that outlines initial and ongoing assessments for
patients with DM.8 For quality-of-care measures, one can refer to HbAlc: hemoglobin Alc
the National Diabetes Quality Improvement Alliance website at HDLC: high-density lipoprotein cholesterol
www.nationaldiabetesalliance.org, whose members include many of IFG: impaired fasting glucose
the governmental and physician organizations concerned with dia-
betes quality-of-care measures. IGT: impaired glucose tolerance
The major performance measures, such as Health Plan Employer LADA: latent autoimmune diabetes in adults
Data and Information Set (HEDIS), should assess the ability to meet LDLC: low-density lipoprotein cholesterol
current standards of care and recognize the minimal treatment goals
MODY: maturity onset diabetes of youth
for glycemia, lipids, and hypertension, and provide targets for
monitoring and adjusting pharmacotherapy as discussed in various NCEP-ATP: National Cholesterol Education Program Adult Treat-
sections above. Publicly reported quality measures continue to ment Panel
move closer to current guidelines. Glycemic control (percentage of NHANES III: The Third National Health and Nutrition Evaluation
patients with HbA1c <7%), lipid (percentage of patients with LDL Survey
<100 mg/dL), and hypertension (percentage of patients with blood NPH: neutral protamine Hagedorn
pressure <130/80 mm Hg) are now quality measures congruent
OGTT: oral glucose tolerance test
with the current goals recommended by the ADA. Glycemic control
is paramount in managing type 1 or type 2 DM but as readily PAI-1: activator-1 plasminogen-inhibitor
identified from the above discussion, it requires frequent assess- PPAR-γ : peroxisome proliferator activator receptor-γ
ment and adjustment in diet, exercise, and pharmacologic therapies. PROactive: Prospective Pioglitazone Clinical Trial in Macrovascular
Minimally, HbAlc should be measured twice a year in patients Events
meeting treatment goals on a stable therapeutic regimen. Quarterly
assessments are recommended for those whose therapy has changed SMBG: self-monitored blood glucose
or who are not meeting glycemic goals. Fasting lipid profiles should STOP-NIDDM: Study to Prevent Non–Insulin-Dependent Diabetes
be obtained as part of an initial assessment and thereafter at each Mellitus
followup visit if not at goal, annually if stable and at goal, or every 2 SUR: sulfonylurea receptor
years if the lipid profile suggests low risk. Documenting regular
TRIPOD: Troglitazone in the Prevention of Diabetes
frequency of foot exams (each visit), urine albumin assessment
(annually), dilated ophthalmologic exams (yearly or more fre- TZD: thiazolidinedione
quently with identified abnormalities), and office visits for followup UKPDS: United Kingdom Prospective Diabetes Study
are also important. Assessment for pneumococcal vaccine adminis- VAT: visceral adipose tissue
tration, annual administration of influenza vaccine, and routine
assessment for and management of other cardiovascular risks (i.e.,
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