Diabetes Mellitus

7/1/2014
Pharmacotherapy: A Pathophysiologic Approach, 9e >
Chapter 57. Diabetes Mellitus

Curtis L. Triplitt; Thomas Repas; Carlos Alvarez
Key Concepts
Diabetes mellitus (DM) is a group of metabolic disorders of fat, carbohydrate, and protein metabolism
that results from defects in insulin secretion, insulin action (sensitivity), or both.
The incidence of type 2 DM is increasing. This has been attributed in part to a Western-style diet,
increasing obesity, sedentary lifestyle, and an increasing minority population.
The two major classifications of DM are type 1 (insulin deficient) and type 2 (combined insulin
resistance and relative deficiency in insulin secretion). They differ in clinical presentation, onset, etiology,
and progression of disease. Both are associated with microvascular and macrovascular disease
complications.
Diagnosis of diabetes is made by four criteria: fasting plasma glucose126 mg/dL (7 mmol/L), a 2hour value from a 75-g oral glucose tolerance test 200 mg/dL (11.1 mmol/L), a casual plasma glucose
level of 200 mg/dL (11.1 mmol/L) with symptoms of diabetes, or a hemoglobin A1c [HbA1c ] 6.5%
(0.065; 48 mmol/mol Hb). The diagnosis should be confirmed by repeat testing if obvious hyperglycemia
is not present.
Goals of therapy in DM are directed toward attaining normoglycemia (or appropriate glycemic control
based on the patients comorbidities), reducing the onset and progression of retinopathy, nephropathy,
and neuropathy complications, intensive therapy for associated cardiovascular risk factors, and improving
quality and quantity of life.
Metformin should be included in the therapy for all type 2 DM patients, if tolerated and not
contraindicated, as it is the only oral antihyperglycemic medication proven to reduce the risk of total
mortality, according to the United Kingdom Prospective Diabetes Study (UKPDS).
Intensive glycemic control is paramount for reduction of microvascular complications (neuropathy,
retinopathy, and nephropathy) as evidenced by the Diabetes Control and Complications Trial (DCCT) in
type 1 DM and the UKPDS in type 2 DM. The UKPDS also reported that control of hypertension in patients
with diabetes will not only reduce the risk of retinopathy and nephropathy but also reduce cardiovascular
1/88
7/1/2014
risk.
Short-term (3 to 5 years), intensive glycemic control does not lower the risk of macrovascular events as
reported by the Action in Diabetes and Vascular Disease, Action to Control Cardiovascular Risk in
Diabetes, and Veterans Administration Diabetes Trial trials. Microvascular event reduction may be
sustained, and macrovascular events reduced by improved early glycemic control, as evidenced by the
UKPDS and DCCT follow-up studies. Significant reductions in macrovascular risk may take 15 to 20 years.
This sustained reduction in microvascular risk and new reduction in macrovascular risk has been coined
metabolic memory.
Knowledge of the patients quantitative and qualitative meal patterns, activity levels, pharmacokinetics
of insulin preparations, and pharmacology of oral and injected antihyperglycemic agents is essential to
individualize the treatment plan and optimize blood glucose control while minimizing risks for hypoglycemia
and other adverse effects of pharmacologic therapies.
Type 1 DM treatment necessitates insulin therapy. Currently, the basalbolus insulin therapy or pump
therapy in motivated individuals often leads to successful glycemic outcomes. Basalbolus therapy includes
a basal insulin for fasting and postabsorptive control, and rapid-acting bolus insulin for mealtime coverage.
Addition of mealtime pramlintide in patients with uncontrolled or erratic postprandial glycemia may be
warranted.
Type 2 DM treatment often necessitates use of multiple therapeutic agents (combination therapy),
including oral and/or injected antihyperglycemics and insulin, to obtain glycemic goals due to the persistent
reduction in -cell function over time. Slowing, but not arresting, -cell failure has been shown with
thiazolidinediones and the glucagon-like peptide-1 (GLP-1) agonist class of medications.
Aggressive management of cardiovascular disease risk factors in type 2 DM is necessary to reduce the
risk for adverse cardiovascular events or death. Smoking cessation, use of antiplatelet therapy as a
secondary prevention strategy and in select primary prevention situations, aggressive management of
dyslipidemiaprimary goal to lower low-density lipoprotein cholesterol (<100 mg/dL [<2.59 mmol/L]) and
secondarily to raise high-density lipoprotein cholesterol to 40 mg/dL (1.03 mmol/L)and treatment of
hypertension (again often requiring multiple drugs) to <130/80 mm Hg are vital.
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 minutes five times a week,
and weight loss form the backbone of successful prevention. No medication is currently FDA approved for
prevention of diabetes, although several, including metformin, acarbose, pioglitazone, and rosiglitazone,
have clinical trials demonstrating a delay of diabetes onset.
Patient education and ability to demonstrate self-care and adherence to therapeutic lifestyle and
pharmacologic interventions are crucial to successful outcomes. Multidisciplinary teams of healthcare
professionals including physicians (primary care, endocrinologists, ophthalmologists, and vascular
surgeons), podiatrists, dietitians, nurses, pharmacists, social workers, behavioral health specialists, and
2/88
7/1/2014
certified diabetes educators are needed, as appropriate, to optimize these outcomes in persons with DM.
Learning Objectives
1. Define diabetes mellitus.
2. Describe differences in epidemiology of type 1 and type 2 diabetes mellitus based on age, sex,
race/ethnicity, and family history.
3. List the plasma glucose levels that diagnose a patient with impaired fasting glucose, impaired glucose
tolerance, gestational diabetes, or diabetes mellitus and the hemoglobin A1c values that denote high risk of
diabetes or diabetes mellitus.
4. Compare and contrast type 1 and type 2 diabetes presentation, onset, characteristics, progression, and
pathophysiology.
5. Apply evidence-based recommendations to nonpharmacologic and pharmacologic treatment interventions
and goals for diabetes mellitus.
6. Understand common laboratory, procedures, and physical examination components that should be
performed on initial evaluation of a person with diabetes mellitus.
7. Identify key elements to the success of nonpharmacologic interventions for the treatment of type 1 and type
2 diabetes mellitus.
8. Understand the pharmacology, pharmacokinetics, side effects, drug interactions, and proper dosing of
commonly used medications for diabetes mellitus.
9. Learn about the implications of key clinical trials in the management of glucose, hypertension, and
dyslipidemia for the treatment of diabetes mellitus.
10. Construct and individualize rationale therapeutic regimens, and follow-up of these regimens, for treatment
of type 1 and type 2 diabetes mellitus.
11. Know the specialized needs for the treatment of diabetes mellitus in special populations (adolescents,
elderly, gestational diabetes, having diabetes while pregnant, people with human immunodeficiency virus,
and hospitalizations).
12. Identify common concomitant conditions and complications associated with diabetes mellitus and describe
goals, treatments, and monitoring parameters for each.
13. Develop treatment regimens (nonpharmacologic and pharmacologic) for common concomitant conditions
and complications associated with diabetes mellitus.
14. Understand proper counseling and education of a patient with diabetes mellitus to maximize outcomes.
15. Evaluate therapeutic outcomes by describing common quality of care measures used and the optimal
numbers for each measure.
3/88
7/1/2014
Diabetes Mellitus: Introduction

Diabetes mellitus (DM) is a heterogeneous group of metabolic disorders characterized by hyperglycemia. It
is associated with abnormalities in carbohydrate, fat, and protein metabolism and may result in chronic
complications including microvascular, macrovascular, and neuropathic disorders. It is estimated that in 2010,
26 million Americans 20 years old have DM, with as many as one fourth of these patients being undiagnosed,
and an additional 79 million at high risk for the development of diabetes. The economic burden of DM
approximated $218 billion in 2007, for diabetes and prediabetes. This is representative of an annual cost for
each citizen of the United States of $700. DM is the leading cause of blindness in adults aged 20 to 74 years
and the leading cause of end-stage renal disease in the United States. It also accounts for approximately
65,000 lower extremity amputations annually. Finally, a cardiovascular event is responsible for two thirds of
deaths in individuals with type 2 DM and is the leading cause of death in type 1 DM of long duration.1
Optimal management of the patient with DM will reduce or prevent complications, decreasing morbidity and
mortality while improving quality of life. Research, clinical trials, and drug development efforts over the past
several decades have provided valuable information that applies directly to improving outcomes in patients with
DM and have expanded the therapeutic armamentarium. Additionally, interventions in an attempt to prevent
complications and the onset of diabetes have been reported for type 1 and 2 DM.
Epidemiology
Type 1 DM accounts for 5% to 10% of all cases of DM and is most often due to autoimmune destruction of the
pancreatic cells.2 Although type 1 DM most frequently develops in childhood or early adulthood, new cases
occur at any age.
Type 1 DM is thought to be initiated by the exposure of a genetically susceptible individual to an environmental
agent. The development of -cell autoimmunity occurs in less than 10% of the genetically susceptible
population and progresses to type 1 DM in less than 1% of that population.3 There is a direct relation to the
prevalence of -cell autoimmunity and the incidence of type 1 DM in various populations. The countries of
Sweden, Sardinia, and Finland have the highest prevalence of islet cell antibody (ICA; 3% to 4.5%) and are
associated with the highest incidence of type 1 DM: 22 to 35 per 100,000.4 The prevalence of type 1 DM is
increasing, but the cause of this increase is not fully understood.
Markers of -cell autoimmunity are detected in 14% to 33% of persons with adult-onset diabetes. This type of
DM is referred to as latent autoimmune diabetes in adults (LADA) and presents with early failure of oral agents
and need for insulin therapy.4
Idiopathic type 1 DM is a nonautoimmune form of diabetes frequently seen in minorities, especially Africans and
Asians, with intermittent insulin requirements.2
Secondary forms of DM occur due to a variety of causes.2 Maturity onset diabetes of youth (MODY) is due to
one of six genetic defects. Endocrine disorders such as acromegaly and Cushings syndrome may also cause
diabetes. Any disease of the exocrine pancreas such as cystic fibrosis, pancreatitis, and hereditary
hemochromatosis can damage cells and impair insulin secretion. These unusual causes, however, only
cause 1% to 2% of the total cases of DM. Please see Other Specific Types of Diabetes (<5% of Diabetes)
below for further discussion.
Type 2 DM accounts for up to 90% of all cases of DM. Overall the prevalence of type 2 DM in the United States
is about 11.3% in persons aged 20 or older; this prevalence is increasing. It is estimated that for every four
4/88
7/1/2014
persons who are diagnosed with DM, one person remains undiagnosed.1
There are multiple risk factors for the development of type 2 DM, including family history (i.e., parents or
siblings with diabetes); obesity (i.e., 20% over ideal body weight, or body mass index [BMI] 25 kg/m2); chronic
physical inactivity; race or ethnicity (see list below); history of impaired glucose tolerance (IGT), impaired
fasting glucose (IFG), or hemoglobin A1c (HbA1c ) 5.7% to 6.4% (0.057 to 0.064; 39 to 46 mmol/mol Hb) (see
Diagnosis of Diabetes below); hypertension (140/90 mm Hg in adults); high-density lipoprotein (HDL)
cholesterol (HDL-C) 35 mg/dL (0.91 mmol/L) and/or a triglyceride level 250 mg/dL (2.83 mmol/L); history
of gestational diabetes mellitus (GDM) (see Classification of Diabetes below) or delivery of a baby weighing >9
lb (>4 kg); history of vascular disease; presence of acanthosis nigricans; and polycystic ovary disease.5
The prevalence of type 2 DM increases with age and varies widely among various racial and ethnic
populations. The prevalence of type 2 DM is especially increased in Native Americans, Hispanic Americans,
Asian Americans, African Americans, and Pacific Islanders. While the prevalence of type 2 DM increases with
age, the disorder is increasingly being diagnosed in adolescence. Much of the rise in adolescent type 2 DM is
related to an increase in overweight/obesity and sedentary lifestyle, in addition to genetic predisposition.6 Most
cases of type 2 DM are polygenetic; the underlying pathophysiology remains uncertain7 (Figs. 57-1 and 57-2).
5/88
7/1/2014
National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes by age among adults 20
years of age: United States, 20052008. (Centers for Disease Control and Prevention, 2011 National Diabetes
Fact Sheet athttp://www.cdc.gov/diabetes/pubs/factsheet11.htm.)
6/88
7/1/2014
Rate of new cases of type 1 and type 2 diabetes among youth aged <20 years, by race/ethnicity, 20022005.
(NHW, non-Hispanic whites; NHB, non-Hispanic blacks; H, Hispanics; API, Asians/Pacific Islanders; AI, American
Indians.) (Centers for Disease Control and Prevention, 2011 National Diabetes Fact Sheet at
http://www.cdc.gov/diabetes/pubs/factsheet11.htm.)
GDM complicates approximately 7% of all pregnancies in the United States.8 Most women become
normoglycemic after pregnancy; however, 30% to 50% may develop prediabetes or type 2 DM later in life.
Pathogenesis, Diagnosis, and Classification

Classification of Diabetes
Diabetes is a metabolic disorder characterized by resistance to the action of insulin, insufficient insulin
secretion, or both.2 The clinical manifestation of these disorders is hyperglycemia. The vast majority of diabetic
patients are classified into one of two broad categories: type 1 diabetes caused by an absolute deficiency of
insulin or type 2 diabetes defined by the presence of insulin resistance with an inadequate compensatory
increase in insulin secretion. Women who develop diabetes due to the stress of pregnancy are classified as
having gestational diabetes. Finally, uncommon types of diabetes caused by infections, drugs,
endocrinopathies, pancreatic destruction, and known genetic defects are classified separately (Table 57-1).
Table 57-1 Etiologic Classification of Diabetes Mellitusa
1. Type 1 diabetes b (-cell destruction, usually leading to absolute insulin deficiency)
7/88
7/1/2014
Immune-mediated
Idiopathic
2. Type 2 diabetes a (may range from predominantly insulin resistance w ith relative insulin deficiency to a predominantly insulin
secretory defect w ith insulin resistance)
3. Other specific types
Genetic defects of -cell function
Chromosome 20q, HNF-4 (MODY 1)
Chromosome 7p, glucokinase (MODY 2)
Other rare forms
Chromosome 13q, insulin promoter factor-1 (MODY 4)
Chromosome 2q, neurogenic differentiation 1/-cell e-box transactivator 2 (MODY 6)
Chromosome 9q, carboxyl ester lipase (MODY 7)
Mitochondrial DNA
Genetic defects in insulin action
Type A insulin resistance
Leprechaunism
Rabson-Mendenhall syndrome
Lipoatrophic diabetes
Diseases of the exocrine pancreas
Pancreatitis
Trauma/pancreatectomy
Neoplasia
Cystic fibrosis
Hemochromatosis
Fibrocalculous pancreatopathy
8/88
7/1/2014
Endocrinopathies
Acromegaly
Cushings syndrome
Glucagonoma
Pheochromocytoma
Hyperthyroidism
Somatostatinoma
Aldosteronoma
Drug or chemical induced
Vacor (Pyriminil)
Pentamidine
Nicotinic acid
Glucocorticoids
Thyroid hormone
Diazoxide
-Adrenergic agonists
Thiazides
Phenytoin
-Interferon
Others
Infections
Congenital rubella
Cytomegalovirus
Others
Uncommon forms of immune-mediated diabetes
Stiff-man syndrome
Anti-insulin receptor antibodies
9/88
7/1/2014
Other genetic syndromes sometimes associated w ith diabetes

Dow ns syndrome
Klinefelters syndrome
Turners syndrome
Wolframs syndrome
Friedreichs ataxia
Huntingtons chorea
Laurence-Moon-Bieldel syndrome
Myotonic dystrophy
Porphyria
Prader-Willi syndrome
4. Gestational diabetes m ellitus (GDM)
aOther rare forms may exist for all categorizations.

b Patients w ith any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not in itself classify
the patient.
Adapted from Diabetes Care 1997;20:11831197. Reproduced by permission of the American Diabetes Association.2
Type 1 Diabetes
This form of diabetes results from autoimmune destruction of the cells of the pancreas. Evidence of -cell
autoimmunity, including ICAs, antibodies to glutamic acid decarboxylase, islet protein tyrosine phosphatase-like
molecule IA2, and/or antibodies to insulin, is present at the time of diagnosis in 90% of individuals. Type 1
diabetes is often thought to most commonly present in children and adolescents; however, it can occur at any
age. Younger individuals typically have a more rapid rate of -cell destruction and often present with
ketoacidosis. Adults may maintain sufficient insulin secretion to prevent ketoacidosis for many years; this is
referred to as latent autoimmune diabetes in adults.3,4
Type 2 Diabetes
Type 2 DM is characterized by a combination of some degree of insulin resistance and a relative lack of
insulin secretion (being insufficient to normalize plasma glucose levels), with progressively lower insulin
secretion over time. Most individuals with type 2 diabetes exhibit abdominal obesity, which itself causes insulin
resistance. In addition, hypertension, dyslipidemia (high triglyceride levels and low HDL-C levels), and elevated
plasminogen activator inhibitor-1 (PAI-1) levels, which contribute to a hypercoagulable state, are often present
in these individuals. Due in part to these factors, patients with type 2 diabetes are at increased risk of
developing macrovascular complications in addition to microvascular complications. Type 2 diabetes has a
strong genetic predisposition and is more common in all ethnic groups other than those of European
ancestry.4,5
10/88
7/1/2014
Gestational Diabetes Mellitus

GDM is defined as glucose intolerance that is first recognized during pregnancy. Hormone changes during
pregnancy result in increased insulin resistance, and GDM may ensue when the mother cannot adequately
compensate with increased insulin secretion to maintain normoglycemia. In most, glucose intolerance occurs
near the beginning of the third trimester, although risk assessment and intervention when appropriate should
begin from the first prenatal visit due to the risk of undiagnosed diabetes. If DM is diagnosed prior to
pregnancy, this is not GDM, but rather pregnancy with preexisting DM. Clinical detection is important, as
therapy will reduce perinatal morbidity and mortality.2
Other Specific Types of Diabetes (<5% of Diabetes)
Genetic Defects
MODY is characterized by impaired insulin secretion in response to a glucose stimulus with minimal or no
insulin resistance. Patients typically exhibit mild hyperglycemia at an early age, but diagnosis may be delayed,
depending on the severity of presentation. The disease is inherited in an autosomal dominant pattern with at
least six different loci identified to date (MODY 2 and 3 are most common). The production of mutant insulin
molecules has been identified in a few families and results in mild glucose intolerance.2
Several genetic mutations have been described in the insulin receptor and are associated with insulin
resistance. Type A insulin resistance refers to the clinical syndrome of acanthosis nigricans, virilization in
women, polycystic ovaries, and hyperinsulinemia. In contrast, anti-insulin receptor antibodies may block the
binding of insulin. This was referred to in the past as type B insulin resistance. Endocrinopathies, pancreatic
exocrine dysfunction, drugs, and infections, among others, may also result in hyperglycemia (Table 57-1).
Screening
Type 1 Diabetes Mellitus
The prevalence of type 1 DM is low in the general population. Due to the acute onset of symptoms in most
individuals at time of diagnosis, screening for type 1 DM in the asymptomatic general population is not
recommended.5 Screening for -cell autoantibody status in high-risk family members may be appropriate;
however, such screening is most often recommended in the context of clinical trials for the prevention of type 1
DM.
The American Diabetes Association (ADA) recommends screening for type 2 DM at any age in individuals who
are overweight (BMI 25 kg/m2) and have at least one other risk factor for the development of type 2 DM. Risk
factors, in addition to being overweight or obese, include physical inactivity, first-degree relative with diabetes
or high-risk ethnicity/race, women who have delivered a baby >9 lb (>4 kg) or a history of GDM, hypertension,
high triglycerides, low HDL, women with polycystic ovary syndrome, diagnosed with prediabetes, acanthosis
nigricans, or a history of cardiovascular disease (CVD; see also Epidemiology above). The recommended
screening test is the fasting plasma glucose (FPG), HbA1c , or 2-hour oral glucose tolerance test (OGTT).
Adults without risk factors should be screened starting at age 45 years, as age itself is a risk factor for type 2
DM. The optimal time between screenings is not known, and the index of suspicion for the presence of diabetes
should guide the clinician. Repeat testing every 3 to 5 years is cost-effective.5
Children and Adolescents
Despite a lack of clinical evidence to support widespread testing of children for type 2 DM, it is clear that more
children and adolescents are developing type 2 DM. The ADA, by expert opinion, recommends that overweight
11/88
7/1/2014
(defined as BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal)
youths with at least two of the following risk factors: a family history of type 2 diabetes in first- and seconddegree relatives; Native Americans, African Americans, Hispanic Americans, and Asians/South Pacific
Islanders; those with signs of insulin resistance or conditions associated with insulin resistance (acanthosis
nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight); or
maternal history of diabetes or GDM during the childs gestation be screened. Screening should be done every
3 years starting at 10 years of age or at the onset of puberty if it occurs at a younger age.5
Gestational Diabetes
Risk assessment for GDM should occur at the first prenatal visit. Due to the increasing incidence of obesity and
undiagnosed DM, it is reasonable to screen women with risk factors for the development of diabetes as soon as
feasible. If the initial screening is negative, they should undergo retesting at 24 to 28 weeks gestation.
Screening for GDM is done with a standard 75-g OGTT. The diagnosis of GDM is confirmed when any one
plasma glucose value measured at baseline (fasting), 1 hour, or 2 hours meets the diagnostic criteria. These
criteria are unique to GDM (Table 57-2).2,5,8
Table 57-2 Screening for and Diagnosis of Gestational Diabetes Mellitus with a 75-g Glucose Load
Tim e
Plasm a Glucose
Fasting
92 mg/dL (5.1 mmol/L)
1 hour
180 mg/dL (10 mmol/L)
2 hours
One abnormal value = diagnostic of GDM. Should be performed at 2428 w eeks gestation unless the patient has overt diabetes. The test
should be done in the morning after an 8- to 14-hour fast.
See reference 2.
Diagnosis of Diabetes
The diagnosis of diabetes requires the identification of a glycemic cut point, which discriminates normals
from diabetic patients. The cut points are meant to reflect the level of glucose above which microvascular
complications have been shown to increase. Cross-sectional studies have shown a consistent increase in the
risk of developing retinopathy at a fasting glucose level above 99 to 116 mg/dL (5.5 to 6.4 mmol/L), a 2-hour
postprandial level above 125 to 185 mg/dL (6.9 to 10.3 mmol/L), and a HbA1c above 5.9% to 6.0%. (0.059 to
0.060; 41 to 42 mmol/mol Hb). Current diagnostic criteria are slightly above these cut points (Table 57-3).2
Table 57-3 Criteria for the Diagnosis of Diabetes Mellitusa
1. HbA 1c 6.5% (0.065; 48 mmol/mol Hb). The test should be performed in a laboratory using a method that is National Glycohemoglobin
Standardization Program (NGSP) certified and standardized to the DCCT assay a
2. Fasting plasma glucose126 mg/dL (7 mmol/L). Fasting is defined as no caloric intake for at least 8 hours a
3. 2-hour plasma glucose200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the World Health
Organization, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in w ater a
4. In a patient w ith classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose concentration 200 mg/dL (11.1
mmol/L)
aIn the absence of unequivocal hyperglycemia, criteria 13 should be confirmed by repeat testing.
12/88
7/1/2014
The HbA1c was not recommended in the past due to many nonstandardized assays. Most laboratories now use
a method that is National Glycohemoglobin Standardization Program (NGSP) certified and standardized to the
Diabetes Control and Complications Trial (DCCT) assay, which allows for cross-application of their results. If
standardized, the HbA1c is logical for the diagnosis of diabetes as it measures glycemic exposure over the past
2 to 3 months, in contrast to a single-day, single-point glucose evaluation. In addition, patients do not have to
be fasting and the test is easily monitored. An HbA1c of 6% to 6.4% (0.060 to 0.066; 42 to 46 mmol/mol Hb)
denotes a 10-fold increase in risk of diabetes, yet does not consistently identify patients with IFG or IGT. In
addition, there are slight race differences in normal HbA1c levels. One-third fewer individuals with diabetes are
identified using the A1C 6.5% (0.065; 48 mmol/mol Hb) versus a FPG 126 mg/dL (7 mmol/L), yet more
providers may be more likely to diagnose diabetes from an A1C than from an obviously elevated FPG level.
The ADA continues to recommend three other glucose criteria for the diagnosis of DM in nonpregnant adults
(Table 57-3). If the patient has obvious hyperglycemia and diabetes, reconfirming the diagnosis by one of the
above criteria is not required.2
Increased Risk of Diabetes or Prediabetes
As shown in Table 57-4, the ADA identified a HbA1c value of 5.7% to 6.4% (0.057 to 0.064; 39 to 46 mmol/mol
Hb) to define an increased risk for diabetes. The HbA1c lower limit of 5.7% (0.057; 39 mmol/mol Hb) was chosen
due to its good specificity, although it has a low sensitivity, to identify patients at increased risk for diabetes.
IFG continues to be defined as a plasma glucose of at least 100 mg/dL (5.6 mmol/L) but less than 126 mg/dL
(7 mmol/L). IGT is defined as a 2-hour glucose value 140 mg/dL (7.8 mmol/L), but less than 200 mg/dL (11.1
mmol/L) during a 75-g OGTT.2,5
Table 57-4 Categorizations of Abnormal Glucose Status
Fasting plasma glucose (FPG)
Impaired fasting glucose (IFG)
100125 mg/dL (5.66.9 mmol/L)
Diabetes mellitus a
FPG 126 mg/dL (7 mmol/L)
2-hour postload plasma glucose (oral glucose tolerance test)
Impaired glucose tolerance (IGT)
2-hour postload glucose 140199 mg/dL (7.811 mmol/L)
Diabetes mellitus a
2-hour postload glucose200 mg/dL (11.1 mmol/L)
HbA1c
Increased risk of diabetes mellitus
HbA 1c 5.76.4% (0.0570.064; 3946 mmol/mol Hb)
Diabetes mellitus a
13/88
7/1/2014
HbA 1c 6.5% (0.065; 48 mmol/mol Hb)
aDiagnosis to be confirmed if not unequivocal hyperglycemia (see Table 57-3).
Serial measurements, at clinician-defined intervals, can help to identify patients moving toward diabetes, and
those who are stable. Patients who have even minor increases in glucose or HbA1c values over time should be
followed closely. Also, the HbA1c measurement can be affected by anemias and several hemoglobinopathies,
which necessitates the use of one of the plasma glucose criterion in these individuals.
Pathogenesis
Type 1 DM results from pancreatic -cell failure with absolute deficiency of insulin secretion. Most often this is
due to immune-mediated destruction of pancreatic cells, but rare unknown or idiopathic processes may also
contribute. There often is a long preclinical period of immune-mediated -cell destruction later followed by
onset of hyperglycemia when 80% to 90% of the cells have been destroyed. Occasionally there is a period of
transient remission called the honeymoon phase, before established disease develops along with the
requirement for lifelong insulin therapy and the potential risk of diabetes-related complications (Fig. 57-3).
Scheme of the natural history of the -cell defect in type 1 diabetes mellitus. (Copyright 2008 American
Diabetes Association. From Medical Management of Type 1 Diabetes, 5th ed.Reprinted with permission from
the American Diabetes Association.)
14/88
7/1/2014
It is thought that in order for type 1 DM to develop, there must be a trigger in a genetically susceptible
individual. However, it is unknown whether there are one or more inciting factors such as cows milk (or lack of
breast-feeding), or viral, dietary, or other environmental exposures that initiate the autoimmune process.2,3
Vitamin D deficiency has been observed to be more prevalent in patients who develop type 1 DM; however,
further study is needed to confirm a role in causation.9
The autoimmune process is mediated by macrophages and T lymphocytes with circulating autoantibodies to
various -cell antigens. The most commonly detected antibody associated with type 1 DM is the ICA. Other
autoantibodies include insulin, glutamic acid decarboxylase 65, and zinc transporter 8 (ZnT8). These
antibodies are generally considered markers of disease rather than mediators of -cell destruction. They have
been used to identify individuals at risk for type 1 DM and in evaluating disease prevention strategies.3
More than 90% of newly diagnosed persons with type 1 DM have one of these antibodies, as will up to 4% of
unaffected first-degree relatives. Once insulin autoantibodies are detected, there is an increased risk of
development of additional autoantibodies and progression to diabetes. -Cell autoimmunity may precede the
diagnosis of type 1 DM by up to 9 to 13 years. Autoimmunity may remit in some individuals, or can progress to
absolute -cell failure in others. Other autoimmune disorders frequently associated with type 1 DM include
Hashimotos thyroiditis, Graves disease, Addisons disease, vitiligo, and celiac sprue. The extent of
involvement can range from no other associated disorders to autoimmune polyglandular failure.
There are strong genetic linkages to the DQA and B genes and certain human leukocyte antigens (HLAs).
Some are associated with increased risk (DR3 and DR4) while others are protective (DRB1*04008-DQB1*0302
and DRB1*0411-DQB1*0302) on chromosome 6.10 Additional candidate gene regions have been identified on
other chromosomes as well. Because twin studies do not show 100% concordance, environmental factors such
as infectious, chemical, and dietary agents likely also contribute to the expression of the disease.
The autoimmune destruction of pancreatic -cell function results in hyperglycemia due to an absolute
deficiency of insulin. Insulin lowers blood glucose (BG) by a variety of mechanisms, including stimulation of
tissue glucose uptake, suppression of glucose production by the liver, and suppression of free fatty acid (FFA)
release from fat cells.11 The suppression of FFAs plays an important role in glucose homeostasis. Increased
levels of FFAs inhibit the uptake of glucose by muscle and stimulate hepatic gluconeogenesis.12
Normal Metabolism
In the fasting state 75% of total body glucose disposal takes place in noninsulin-dependent tissues such as
the brain, neurons, and others. Brain glucose uptake occurs at the same rate during fed and fasting periods.
The remaining 25% of glucose metabolism takes place in the liver and muscle, which is dependent on insulin. In
the fasting state approximately 85% of glucose production is derived from the liver, and the remaining amount
is produced by the kidney. Glucagon, produced by pancreatic cells, is secreted in the fasting state to oppose
the action of insulin and stimulate hepatic glucose production and glycogenolysis. Glucagon and insulin
secretion are closely linked; one increases while the other decreases to keep plasma glucose levels normal. In
the fed state, carbohydrate ingestion increases the plasma glucose concentration and stimulates insulin
release from the pancreatic cells. The resultant hyperinsulinemia (a) suppresses hepatic glucose production,
(b) stimulates glucose uptake by peripheral tissues, and (c) suppresses glucagon release (in conjunction with
incretin hormones). The majority (80% to 85%) of glucose is taken up by muscle, with only a small amount
(4% to 5%) being metabolized by adipocytes.7,13,14
Although fat tissue is responsible for only a small amount of total body glucose disposal, it plays a very
important role in the maintenance of total body glucose homeostasis. Small increments in the plasma insulin
15/88
7/1/2014
concentration exert a potent antilipolytic effect, leading to a marked reduction in the plasma FFA levels. The
decline in plasma FFA concentrations results in an increased glucose uptake in muscle and reduces hepatic
glucose production indirectly.
Type 2 Diabetes
Individuals are characterized by multiple defects including (a) defects in insulin secretion; (b) insulin resistance
involving muscle, liver, and the adipocyte; (c) excess glucagon secretion; (d) glucagon-like peptide-1 (GLP-1)
deficiency and possibly resistance.7
Impaired Insulin Secretion
The pancreas in people with a normal-functioning cell is able to adjust its secretion of insulin to maintain
normal plasma glucose levels. In nondiabetic individuals, insulin increases in proportion to the severity of the
insulin resistance and plasma glucose remains normal. Impaired insulin secretion is a hallmark finding in T2DM.
In early -cell dysfunction, first-phase insulin release, seen with an IV bolus of glucose, is deficient. First-phase
insulin is released if there is stored insulin in the cell and acts to prime the liver to nutrient intake. Absent
first-phase insulin necessitates an increase in second-phase insulin to compensate for hyperglycemia. When
the insulin released can no longer normalize plasma glucose, dysglycemia, including prediabetes and diabetes,
can ensue. Both -cell mass and function in the pancreas are reduced. -Cell failure is progressive, and starts
years prior to the diagnosis of diabetes. People with T2DM lose 5% to 7% of -cell function per year of
diabetes. The reasons for this loss are likely multifactorial including (a) glucose toxicity; (b) lipotoxicity; (c)
insulin resistance; (d) age; (e) genetics; and (f) incretin deficiency. Age results in declining -cell
responsiveness and possibly mass. -Cell failure predisposition is also present in high-risk ethnicity/races.
Glucotoxicity involves glucose levels chronically exceeding 140 mg/dL (7.8 mmol/L). The cell is unable to
maintain elevated rates of insulin secretion, and releases less insulin as glucose levels increase (Fig. 574).7,13,14
16/88
7/1/2014
The relationship between fasting plasma insulin and fasting plasma glucose in 177 normal-weight individuals.
Plasma insulin and glucose increase together up to a fasting glucose of 140 mg/dL (7.8 mmol/L). When the
fasting glucose exceeds 140 mg/dL (7.8 mmol/L), the cell makes progressively less insulin, which leads to an
overproduction of glucose by the liver and results in a progressive increase in fasting glucose. (Reprinted from
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin N Am 2004;88:787835, Copyright 2004,
with permission from Elsevier.)
Incretins
In the type 2 diabetic patient, decreased postprandial insulin secretion is due to both impaired pancreatic -cell
function and a reduced stimulus for insulin secretion from gut hormones. The role gut hormones play in insulin
secretion is best shown by comparing the insulin response to an oral glucose load versus an isoglycemic IV
glucose infusion. In nondiabetic control individuals 73% more insulin is released in response to an oral glucose
load compared with reproducing the oral glucose loads plasma glucose curve by giving IV glucose. This
increased insulin secretion in response to an oral glucose stimulus is referred to as the incretin effect and
suggests that gut-derived hormones when stimulated by glucose lead to an increase in pancreatic insulin
secretion. In type 2 diabetic patients, this incretin effect is blunted, with the increase in insulin secretion only
being 50% of that seen in nondiabetic control individuals. It is now known that two hormones, GLP-1 and
glucose-dependent insulinotropic polypeptide (GIP), are responsible for over 90% of the increased insulin
secretion seen in response to an oral glucose load. Patients with type 2 diabetes remain sensitive to GLP-1
while GIP levels are normal or elevated in T2DM.7
17/88
7/1/2014
GLP-1 is secreted from the L cells, with the highest L-cell concentration in the distal intestinal mucosa, in
response to mixed meals. Since GLP-1 levels rise within minutes of food ingestion, neural signals and possibly
proximal GI tract receptors stimulate GLP-1 secretion. The insulinotropic action of GLP-1 is glucose dependent,
and for GLP-1 to enhance insulin secretion, glucose concentrations must be higher than 90 mg/dL (5 mmol/L).
In addition to stimulating insulin secretion, GLP-1 suppresses glucagon secretion, slows gastric emptying, and
reduces food intake by increasing satiety. These effects of GLP-1 combine to limit postprandial glucose
excursions. GIP is secreted by K cells in the intestine and may have a role with insulin secretion during nearnormal glucose levels and may act as an insulin sensitizer in adipocytes. However, GIP has no effect on
glucagon secretion, gastric motility, or satiety. The half-lives of GLP-1 and GIP are short (<10 minutes). Both
hormones are rapidly inactivated by removal of two N-terminal amino acids by the enzyme dipeptidyl peptidase4 (DPP-4). GLP-1 levels appear to decrease as glucose values increase from normal to type 2 DM, and it is
unlikely to be a primary defect that causes diabetes in the majority of T2DM. Genetically a minority may have
the TCF7L2 gene defect, which is associated with a decreased response to GLP-1.7
Insulin Resistance
Liver
In type 2 diabetic subjects with mild to moderate fasting hyperglycemia (140 to 200 mg/dL, 7.8 to 11.1 mmol/L),
basal hepatic glucose production is increased by 0.5 mg/kg/min. Consequently, during the overnight sleeping
hours the liver of an 80-kg diabetic individual with modest fasting hyperglycemia adds an additional 35 g of
glucose to the systemic circulation. This increase in fasting hepatic glucose production is the cause of fasting
hyperglycemia.13,14
Following glucose ingestion, insulin is secreted into the portal vein and carried to the liver, where it reduces
hepatic glucose output. T2DM patients also fail to suppress glucagon in response to a meal and may even
have a paradoxical rise in glucagon levels. Thus, hepatic insulin resistance and hyperglucagonemia result in
continued production of glucose by the liver. Therefore, T2DM patients have two sources of glucose in the
postprandial state: one from the diet and one from continued glucose production from the liver. These sources
of glucose may result in marked hyperglycemia.
Peripheral (Muscle)
Muscle is the major site of postprandial glucose disposal in humans, and approximately 80% of total body
glucose uptake occurs in skeletal muscle. In response to a physiologic increase in plasma insulin
concentration, muscle glucose uptake increases linearly, reaching a plateau value of 10 mg/kg/min. Even in
lean T2DM, the onset of insulin action is delayed for 40 minutes, and the ability of insulin to stimulate leg
glucose uptake is reduced by 50%. Impaired intracellular insulin signaling is a well-established abnormality, with
notable impairments at almost every step of activation due to insulin resistance, lipotoxicity, and glucotoxicity.
The compensatory hyperinsulinemia required to overcome impaired insulin signaling (insulin resistance) can
activate an alternative pathway through MAP kinase, which may be involved in atherosclerosis. Mitochondrial
dysfunction may also play a role in muscle insulin resistance. Mitochondrial function and/or density appear to
be lower in type 2 DM. This may result in less energy expenditure and an increased risk of dysfunction with
high-fat diets (Fig. 57-5).13,14
18/88
7/1/2014
Whole-body glucose disposal, a measure of insulin resistance, is reduced 40% to 50% in obese nondiabetic
and lean type 2 diabetic individuals. Obese diabetic individuals are slightly more resistant than lean diabetic
patients. (From DeFronzo RA. Diabetes Reviews 1977;5:177269.)
Peripheral (Adipocyte)
In obese nondiabetic and T2DM, basal plasma FFA levels are increased and fail to suppress normally after
glucose ingestion. FFAs are stored as triglycerides in adipocytes and serve as an important energy source
during conditions of fasting. Insulin is a potent inhibitor of lipolysis, and restrains the release of FFAs from the
adipocyte by inhibiting the hormone-sensitive lipase enzyme. It is now recognized that chronically elevated
plasma FFA concentrations can lead to insulin resistance in muscle and liver, and impair insulin secretion. In
addition to FFAs that circulate in plasma in increased amounts, T2DM patients have increased stores of
intracellular fat products in muscle and liver, and the increased fat content correlates closely with the presence
of insulin resistance in these tissues. Excess lipolysis from fat can also contribute to gluconeogenesis indirectly
through glycerol and FFAs.7,13,14
Cellular Mechanisms of Insulin Resistance
Obesity and Insulin Resistance
Weight gain leads to insulin resistance in most, and obese nondiabetic individuals with risk factors often have
the same degree of insulin resistance as lean T2DM patients. Subsets of obese, but metabolically normal
patients (6% to 30%) do exist, as well as nonobese, but metabolically abnormal patients, so broad
categorization of risk for a patient needs to be confirmed by further examination.
19/88
7/1/2014
The term visceral adipose tissue (VAT) refers to fat cells located within the abdominal cavity and includes
omental, mesenteric, retroperitoneal, and perinephric adipose tissue. VAT has been shown to correlate with
insulin resistance and explain much of the variation in insulin resistance seen. It represents 20% of fat in men
and 6% of fat in women. Central obesity can be easily assessed using waist circumference, which is a good
surrogate marker for VAT. This fat tissue has been shown to have a higher rate of lipolysis than subcutaneous
fat, resulting in an increase in FFA production. These fatty acids are released into the portal circulation and
drain into the liver, where they stimulate the production of very-low-density lipoproteins and decrease insulin
sensitivity in peripheral tissues.13,14
VAT also produces a number of adipocytokines, such as TNF-, interleukin 6, angiotensinogen, PAI-1, and
resistin, which contribute to insulin resistance, hypertension, and hypercoagulability. These factors drain into
the portal circulation and reduce insulin sensitivity in peripheral tissues. The fat cell also has the capability of
producing at least one adipocytokine that improves insulin sensitivity: adiponectin. This factor is made in
decreasing amounts as an individual becomes more obese. In animal models, adiponectin decreases hepatic
glucose production and increases fatty acid oxidation in muscle.
The Metabolic Syndrome
The metabolic syndrome is a risk indicator, but not an absolute risk indicator, because it does not specifically
account for all risk factors, such as age, sex, and low-density lipoprotein cholesterol (LDL-C) levels, or directly
measure hypercoagulability of the proinflammatory condition. Patients with metabolic syndrome do have a
higher risk for CVD, and at least a fivefold increase in their risk of type 2 DM, if they do not already have type 2
DM. The metabolic syndrome does not identify synergism among identified risk factors, but rather additive risk,
leading many to question its relevance above adequate risk factor identification and aggressive treatment. It
may be useful to certain clinicians to package risk factors into the metabolic syndrome to encourage
aggressive management.
The most recent definition of metabolic syndrome was adopted by multiple organizations in 2009 (Table 575).15,16
Table 57-5 Defining the Metabolic Syndrome
Defining the Metabolic Syndrom e NCEP-ATP III: Five Com ponents of the Metabolic Syndrom e (Individuals Having at Least
Three Com ponents Meet the Criteria for Diagnosis)
Risk Factor
Defining Level
Abdominal obesity
Men
Waist circumference
Women
>102 cm (>40 in)

>88 cm (>35 in)
Triglycerides
150 mg/dL (1.70 mmol/L)
High-density lipoprotein C
Men
<40 mg/dL (<1.03 mmol/L)
Women
<50 mg/dL (<1.29 mmol/L)
Blood pressure
130/85 mm Hg
Fasting glucose
2009 Statem ent of the International Diabetes Federation Task Force on Epidem iology and Prevention; National Heart, Lung,
and Blood Institute; Am erican Heart Association; World Heart Federation; International Atherosclerosis Society; and
International Association for the Study of ObesityCriteria for Clinical Diagnosis of the Metabolic Syndrom e (Individuals having
at Least Three Com ponents Meet the Criteria for Diagnosis)
Measure
Categorical Cut Points
Elevated w aist circumferencea
Population- and country-specific definitions
Elevated triglycerides (drug treatment for elevated

triglycerides is an alternate indicator)b
Reduced HDL-C (drug treatment for reduced HDL-C is an

alternate indicator)b
40 mg/dL (1.03 mmol/L) in males 50 mg/dL

(1.29 mmol/L) in females
Elevated blood pressure: systolic 130 mm Hg and/or diastolic 80 mm Hg (antihypertensive drug treatment in a patient w ith a history of
20/88
7/1/2014
hypertension is an alternate indicator)

Elevated fasting glucosec (drug treatment of elevated
100 mg/dL (2.59 mmol/L)
glucose is an alternate indicator)

Current Recom m ended Waist Circum ference Thresholds for Abdom inal Obesity by Organization
Population
Organization (Reference)
Men (All
values )
Wom en (All
values )
Europid
IDF
94 cm
80 cm
White
WHO
94 cm
(increased
risk)
80 cm
(increased risk)
102 cm (still
higher risk)
88 cm (still
higher risk)
United States
AHA/NHLBI (ATP III)
102 cm
88 cm
Canada
Health Canada
102 cm
88 cm
European
European CV Societies
102 cm
88 cm
Asia (including Japanese)
IDF
90 cm
80 cm
Asia
WHO
90 cm
80 cm
Japan
Japanese Obesity Society
85 cm
90 cm
China
Cooperative Task Force
85 cm
80 cm
Middle East
Mediterranean IDF
94 cm
80 cm
Sub-Saharan African
IDF
94 cm
80 cm
Central/South American
IDF
90 cm
80 cm
aIt is recommended that the IDF cut points be used for non-Europeans and either the IDF or AHA/NHLBI cut points used for people of European
origin until more data are available.
b The most commonly used drugs for elevated triglycerides and reduced HDL-C are fibrates and nicotinic acid. A patient taking one of these
drugs can be presumed to have high triglycerides and low HDL-C. High-dose omega-3 fatty acids presume high triglycerides.
c Most patients w ith type 2 diabetes mellitus w ill have the metabolic syndrome by the proposed criteria.
Reproduced from reference 15. Reprinted with permission from reference 16, 2009 American Heart Association, Inc.
Metabolic Syndrome: Fact or Fiction?

The term metabolic syndrome was first coined in the late 1970s and associated with CVD. This disease has
been studied extensively and also referred to as the insulin resistance syndrome, dysmetabolic syndrome,
and syndrome X. In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)
III formally defined the metabolic syndrome as a clustering of risk factors that include at least three of the
following: elevated blood pressure, abdominal obesity, elevated triglycerides, low high-density lipoproteins, and
elevated BG.15 Since the metabolic syndrome was formally defined, several other organizations including the
International Diabetes Federation (IDF), American Heart Association (AHA), National Heart, Lung, and Blood
Institute (NHLBI), and the World Heart Federation, among others, have released statements to further refine
the proposed definition.16
It is estimated that 34% of adults in the United States have the metabolic syndrome17 and are considered to be
at high risk of developing CVD and DM.18 This epidemic has also been described in children and adolescents19
and is expected to expand as the US obesity rates continue to climb.
However, in 2005 the ADA in conjunction with the European Association for the Study of Diabetes released a
joint statement critical of the clinical utility of the metabolic syndrome.20 They concluded in their statement that
there is no doubt that CVD risk factors cluster in certain individuals, although they assert the definition is
imprecise and its use as a CVD marker is questionable. They also state that there is critical information missing
to warrant its designation as a syndrome. A swift rebuttal from the AHA and NHLBI was released weeks later
encouraging the continued use of the metabolic syndrome concept.21 In their statement, the authors stressed
21/88
7/1/2014
that the metabolic syndrome is not considered a singular entity and that it is a syndrome with no single
pathogenesis. The authors of the statement also argue that the distinction of the metabolic syndrome should
allow clinicians to approach patients as a whole with an emphasis on intensive lifestyle management. Those in
the diabetes community and who authored the ADA/EASD statement contend that there is no additional benefit
from identifying these clusters of CVD risk factors over measuring and treating them individually. They maintain
the lack of predictive capabilities limits the metabolic syndromes utility as a CVD marker.
The use of the metabolic syndrome in clinical practice remains a controversy. Clinicians should always take
care to individualize therapy for patients who present with high CVD risk. Patients individual goals, values, and
resources should be considered when tailoring a treatment plan.
Clinical Presentation
The clinical presentations of type 1 DM and type 2 DM are very different. Autoimmune type 1 DM can occur at
any age. Approximately 75% will develop the disorder before age 20 years, but the remaining 25% develop the
disease as adults. Individuals with type 1 DM are often thin and are prone to develop diabetic ketoacidosis
(DKA) if insulin is withheld, or under conditions of severe stress with an excess of insulin counterregulatory
hormones.2,3,5 Symptoms in patients with type 1 DM such as polyuria, polydipsia, polyphagia, weight loss, and
lethargy accompanied by hyperglycemia are the most common initial presentation. In the outpatient setting,
many patients initially present with vague complaints such as weight loss and fatigue. Polyuria, polydipsia, and
polyphagia may not be apparent unless a comprehensive history is taken. Twenty percent to 40% of patients
with type 1 DM present with DKA after several days of polyuria, polydipsia, polyphagia, and weight loss. This
presentation is common in patients from a low socioeconomic background. Rarely, type 1 DM patients are
diagnosed without multiple symptoms or DKA when they have blood tests drawn for other reasons. This rare
presentation typically occurs when patients have a first-degree family member with type 1 DM and are closely
monitored.
Patients with type 2 DM often present without symptoms, even though complications tell us that they may have
been hyperglycemic for several years.10 Often these patients are diagnosed secondary to unrelated blood
testing. Lethargy, polyuria, nocturia, and polydipsia can be seen at diagnosis in type 2 diabetes, but significant
weight loss at diagnosis is less common. More often, patients with type 2 DM are overweight or obese.
Clinically, DM is a spectrum of diseases ranging from absolute insulin deficiency to relative insulin deficiency,
and patients can have normal to grossly abnormal insulin sensitivity. Classical clinical presentation
characteristics should be used in conjunction with other definitive laboratory data to properly classify patients
(see also Classical Clinical Presentation of Diabetes Mellitus below).
Clinical Presentation: Diabetes Mellitusa
Characteristic
Type 1 DM
Type 2 DM
Age
<30 yearsb
>30 yearsb
Onset
Abrupt
Gradual
Body habitus
Lean
Obese or history of obesity
Insulin resistance
Absent
Present
Autoantibodies
Often present
Rarely present
Symptoms
Symptomaticc
Often asymptomatic
Ketones at diagnosis
Present
Absentd
Need for insulin therapy
Immediate
Years after diagnosis
Acute complications
Diabetic ketoacidosis
Hyperosmolar hyperglycemic state
Microvascular complications at diagnosis
No
Common
Macrovascular complications at or before diagnosis
Rare
Common
aClinical presentation can vary w idely.

22/88
7/1/2014
b Age of onset for type 1 DM is generally <20 years of age, but can present at any age. The prevalence of type 2 DM in children, adolescents,
and young adults is increasing. This is especially true in ethnic and minority children.
c Type 1 may present acutely w ith symptoms of polyuria, nocturia, polydipsia, polyphagia, and w eight loss.
dType 2 children and adolescents are more likely to present w ith ketones, but after the acute phase may be treated w ith oral agents. Prolonged
fasting can also produce ketones in individuals.
Treatment: Diabetes Mellitus

Desired Outcome
The primary goals of DM management are to reduce the risk for microvascular and macrovascular disease
complications, to ameliorate symptoms, to reduce mortality, and to improve quality of life.5 Early treatment with
near-normal glycemia will reduce the risk for development of microvascular disease complications, but
aggressive management of traditional cardiovascular risk factors (i.e., smoking cessation, treatment of
dyslipidemia, intensive blood pressure control, and antiplatelet therapy) is needed to reduce the likelihood of
development of macrovascular disease. Hyperglycemia not only increases the risk for microvascular disease
but also contributes to poor wound healing, compromises white blood cell function, alters capillary function, and
leads to classic symptoms of DM. DKA and hyperosmolar hyperglycemic state (HHS) are severe manifestations
of poor diabetes control, almost always requiring hospitalization. Reducing the potential for microvascular
complications is targeted by adherence to therapeutic lifestyle intervention (i.e., diet and exercise programs)
and drug therapy regimens, as well as attaining blood pressure goals. Minimizing weight gain and
hypoglycemia, especially severe hypoglycemia, and altering the glycemic goal to match the patients morbidities
are necessary. Evidence-based guidelines, as published by the ADA, may help in the attainment of these goals
(Table 57-6).5
Table 57-6 Selected American Diabetes Association Evidence-Based Recommendationsa
Recom m endation
Specific Recom m endation
Area
Evidence
Levelb
Screening for
diabetes
Screen overw eight or obese at any age; screen those w ithout risk factors beginning at age 45 years
To screen for diabetes a FPG, 2-hour 75-g OGTT, or HbA 1c is appropriate
Interval betw een screenings should be individualized based on risk, or every 3 years
Monitoring
Home blood glucose monitoring is recommended for patients on multidose insulin or pump therapy at least prior B
to meals and snacks, and before events such as driving
Subjects on other therapeutic interventions, including oral agents, may perform home blood glucose
monitoring, but ongoing instruction to patient on how to adjust therapy based on monitoring must be in place
Quarterly HbA 1c in individuals not meeting glycemic goals, tw ice yearly in individuals meeting glycemic goals
should be performed
In adults, measure fasting lipid profile at least annually
Perform an annual urine albumin excretion in type 1 diabetes w ith duration 5 years. Type 2 DM from
diagnosis
Perform a screen for distal symmetrical polyneuropathy at diagnosis in type 2 DM and after 5 years duration
in type 1 DM; screen at least annually thereafter
A dilated eye examination should be performed w ithin 5 years of diagnosis in type 1 DM, and shortly after
B
diagnosis in type 2 DM, w ith follow -up every year, or every 23 years as recommended by an eye specialist
Glycemic goals
HbA 1c goal for patients in general is <7% (<0.07; <53 mmol/mol Hb)
HbA 1c goal should be individualized, w ith <6.5% (<0.065; <48 mmol/mol Hb) if achieved w ithout significant
hypoglycemia or adverse effects in younger, long life expectancy, and no CVD patient
Less stringent HbA 1c goal (<8% [<0.08; <64 mmol/mol Hb]) may be appropriate in patients w ith a history of
severe hypoglycemia, limited life expectancy, advanced microvascular/macrovascular complications or

comorbidities, or in difficult to reach goal patients despite adequate therapy
23/88
7/1/2014
Hospital: Critically ill: 140180 mg/dL (7.810 mmol/L) (A), or more stringent guidelines dow n to 110140 See text
mg/dL (6.17.8 mmol/L) if w ithout hypoglycemia (C)
Noncritically ill: No clear evidence but in general premeal BG <140 mg/dL (<7.8 mmol/L) and random BG
<180 mg/dL (<10 mmol/L) (E)
Treatm ent
Prevention of type 2 Patients w ith IGT (A), IFG (E), or an A1C of 5.76.4% (0.0570.064; 3946 mmol/mol Hb) (E) should attempt
diabetes
w eight loss (510%), increasing physical activity
See text
Metformin may be considered in obese, <60-year-old patients, and w omen w ith prior GDM w ith IGT (A), IFG
(E), or an A1C 5.76.4% (0.0570.064; 3946 mmol/mol Hb) (E)
See text
Medical nutrition
therapy
Physical activity
Weight loss is recommended for all insulin-resistant/overw eight or obese individuals. Either low -carbohydrate, A
low -fat calorie-restricted diets, or Mediterranean diets may w ork
In patients w ith know n CVD consider ACE inhibitor therapy (C), as w ell as aspirin and statin therapy (A)
See text
Saturated fat should be <7% of total calories
Monitoring carbohydrate intake by carbohydrate counting, exchanges, or experienced estimation is

recommended to achieve glycemic goals
Routine supplementation w ith antioxidants, such as vitamins E and C, is not advised due to lack of efficacy
150 min/w k of moderate-intensity exercise spread over at least 3 days and w ith no more than 2 days w ithout A
exercise
Resistance training of large muscle groups should be 2 times per w eek
Systolic blood pressure should be treated to <140 mm Hg
Diastolic blood pressure should be treated to <80 mm Hg
Initial drug therapy should be w ith an ACE inhibitor or ARB
Nephropathy
In treatment of nonpregnant patients w ith modest (30299 mg/day) (C) or higher levels (300 mg/day) (A) of
urinary albumin excretion, either ACE inhibitors or ARBs are recommended
See text
Dyslipidemia
The primary goal is an LDL <100 mg/dL (<2.59 mmol/L) if w ithout overt CVD
Statin therapy should be added to lifestyle, regardless of baseline lipid levels if patient has CVD, or is >40
years of age and has one other CVD risk factor
In patients w ith overt CVD, using a statin to achieve a LDL <70 mg/dL (<1.81 mmol/L) is an option
Triglycerides low ered to <150 mg/dL (<1.70 mmol/L) and raising HDL to >40 mg/dL (>1.03 mmol/L) in men and
>50 mg/dL (1.29 mmol/L) in w omen is desirable
Use aspirin (75162 mg daily) for secondary cardioprotection
Use aspirin (75162 mg) for primary prevention in type 1 or 2 DM if the 10-year risk of CVD is >10%, the
patient is >50 (men) or >60 (w omen) w ith at least one additional risk factor present
Critically ill: By IV insulin protocol (E); noncritically ill: scheduled subcutaneous insulin w ith basal, nutritional,
and correction coverage (C)
See text
Blood pressure
Antiplatelet
Hospital
aBased on American Diabetes Association practice recommendations. Other evidence-based recommendations available.8
b Evidence levels: A, clear evidence from w ell-conducted, generalizable, randomized controlled trials that are adequately pow ered; B,
supportive evidence from w ell-conducted cohort studies or w ell-conducted casecontrol study; C, supportive evidence from poorly controlled
or uncontrolled studies or conflicting evidence w ith w eight of evidence supporting intervention; E, expert consensus or clinical experience.
General Approach to Treatment

Appropriate care requires goal setting for glycemia, blood pressure, lipid levels (goals described later in
chapter; see also Chaps. 3 and 11), regular monitoring for complications, dietary and exercise modifications,
medications, appropriate self-monitoring of blood glucose (SMBG), and laboratory assessment of the
aforementioned parameters.5 Glucose control alone does not sufficiently reduce the risk of macrovascular
complications in persons with DM.22
Glycemic Goal Setting and Hemoglobin A1c

Controlled clinical trials provide ample evidence that glycemic control is paramount in reducing microvascular
24/88
7/1/2014
complications in both type 1 DM23 and type 2 DM.24 HbA1c measurements are the gold standard for following
long-term glycemic control for the previous 2 to 3 months.5 Hemoglobinopathies, anemia, red cell membrane
defects, transfusions, and substantial increase or decrease of red blood cell life span in a patient can affect
HbA1c measurements. Identification of potential problems and then ensuring the test is performed in a
laboratory using a method that is NGSP certified and standardized to the DCCT assay (see www.ngsp.org) will
minimize issues. Other strategies such as measurement of fructosamine, which measures glycated plasma
proteins or glycated albumin, may be necessary to assess diabetes control in patients with altered red blood
cell life span, although they are less standardized, and not correlated to risk of complications.
The A1C-Derived Average Glucose study correlated multiple HbA1c and glucose readings to term the phrase
estimated average glucose (eAG). The eAG better correlates with HbA1c readings, and now is regularly
reported below HbA1c values on laboratory results. For example, a HbA1c of 6% or 7% (0.060 to 0.070; 42 to
53 mmol/mol Hb) correlates with an average glucose of 126 or 154 mg/dL (7 or 8.5 mmol/L), respectively, and
online calculators and graphs are easily found.25
Less stringent HbA1c goals (>7% [>0.070; >53 mmol/mol Hb]) may be appropriate in patients with a history of
severe hypoglycemia, limited life expectancy, advanced microvascular/macrovascular complications or
comorbidities, at-risk elderly, dementia, or in younger children. A HbA1c target of <7% (<0.070; <0.53 mmol/mol
Hb) is appropriate for others (Table 57-7), and lower values should be targeted if significant hypoglycemia,
weight gain, and other adverse effects can be avoided.5 Glycemic control recommendations for different age
groups of type 1 DM patients are based on the risk of hypoglycemia, the relatively low risk of complications
prior to puberty, and psychological and/or developmental issues (Table 57-7).
Table 57-7 Glycemic Goals of Therapy by Organization
Biochem ical Index
ADA
Hemoglobin A 1c
<7% (<0.07; <53 mmol/mol/Hb)a 6.5% (0.065; 48 mmol/mol Hb)
ACE and AACE
Preprandial plasma glucose
70130 mg/dL (3.97.2 mmol/L) <110 mg/dL (<6.1 mmol/L)
Postprandial plasma glucose
<180 mg/dLb (<10 mmol/L)
<140 mg/dL (<7.8 mmol/L)
ADA plasm a glucose and HbA1c goals for type 1 DM by age groupc
Values by age (years)
Plasma glucose goal
A 1C
Before meals bedtime/overnight

Toddlers and preschoolers (06)
100180 (5.610 mmol/L) 110200 (6.111.1 mmol/L)
7.5% to 8.5% (<0.085; <69 mmol/mol Hb)
School age (612)
90180 (510 mmol/L)
100180 (5.610 mmol/L)
<8% (<0.080; <64 mmol/mol Hb)
90150 (58.3 mmol/L)
<7.5% (<0.075; <58 mmol/mol Hb)
Adolescents and young adults (1319) 90130 (57.2 mmol/L)
ADA, American Diabetes Association; ACE, American College of Endocrinology; AACE, American Association of Clinical Endocrinologists.
aAssay should be National Glycohemoglobin Standardization Program (NGSP)certified measurement and Diabetes Control and Complications
Trial (DCCT) standardized. More stringent glycemic control may be appropriate if accomplished w ithout significant hypoglycemia or adverse
effects. Less stringent HbA 1c goals may be appropriate in patients w ith a history of severe hypoglycemia, limited life expectancy, advanced
microvascular/macrovascular complications or comorbidities, at-risk elderly, dementia, or in younger children.
b Postprandial glucose measurements should be made 12 hours after the beginning of the meal, generally the time of peak levels in patients
w ith diabetes.
c Vulnerability to hypoglycemia and relatively low risk of complication prior to puberty considered. Adolescents and young adults may have
adult goals if w ithout developmental and psychological issues, and if w ithout excessive hypoglycemia.
See reference 8.
Initial Evaluation of Diabetes Mellitus

25/88
7/1/2014
On initial evaluation, a thorough medical history and identification of specific type of diabetes, including
duration of diabetes, characteristics of onset (e.g., DKA or asymptomatic), dietary and weight history, education
history, medication history including current and past medications for DM, current regimen including
medications, diet, physical activity, and adherence, should be performed. Hospitalization history, hypoglycemia
(frequency, cause, timing), and diabetes-related complications should be documented. Laboratory evaluation
should include at a minimum an A1C, lipid profile, liver function tests, thyroid-stimulating hormone level, serum
creatinine and electrolytes, and a urine analysis for microalbuminuria. In type 1 DM, consider screening for
celiac disease by measuring tissue transglutaminase or antiendomysial antibodies. The physical examination
and pertinent data should include all vital signs, weight and/or BMI, blood pressure assessment, thyroid
palpation, cardiovascular and carotid auscultation, skin integrity, assessment for acanthosis nigricans, and a
foot examination, including screening for impaired sensation detection with a 10-g force monofilament.5
Monitoring for Complications

The ADA recommends initiation of complications monitoring at the time of diagnosis of DM.8 Current
recommendations continue to advocate yearly dilated eye examinations in type 2 DM, and an initial dilated eye
examination in the first 3 to 5 years in type 1 DM, and then yearly thereafter. Less frequent testing (every 2 to 3
years) can be implemented on the advice of an eye care specialist. The blood pressure should be assessed at
each visit. The feet should be examined at each visit for distal pulses, skin integrity, calluses, and deformities,
and yearly screening should be done for loss of protective sensation with a distal polyneuropathy tool, such as
the 10-g force Semmes-Weinstein monofilament. A urine test for microalbumin to screen for nephropathy once
yearly from diagnosis is appropriate in type 2 DM, and initiated 5 years after diagnosis if the patient has type 1
DM. Yearly testing for lipid abnormalities, and more frequently if needed to achieve lipid goals, is
recommended. It is generally accepted that a yearly thyroid-stimulating hormone level may be appropriate in
type 1 DM, LADA, and select type 2 DM patients.5
Self-Monitored Blood Glucose and Continuous Glucose Monitoring

The advent of SMBG in the early 1980s revolutionized the treatment of DM, enabling patients to know their BG
concentration at any moment easily and relatively inexpensively. At its core, SMBG is a tool to provide structure
for a change and/or safety: change, in that the patient has an opportunity to intervene when a SMBG value is
obtained, and safety, as hypoglycemia and hyperglycemia need to be avoided and/or identified and treated. In
general, SMBG frequency should match how complicated the regimen is for glycemic control and minimally
allow testing to avoid hypoglycemia.
Frequent SMBG is necessary to achieve near-normal BG concentrations if hypoglycemic agents are used.
Assessment for hypoglycemia and hyperglycemia, adjustment of prandial doses of insulin, administration of
corrective doses of insulin, change in diet and exercise, and checking accuracy of continuous glucose monitors
are but a few of the reasons a patient may need SMBG at a given time. This is particularly true in patients with
type 1 DM, as most will be intensively managed with insulin. The more intense the pharmacologic regimen is,
the more intense the SMBG needs to be (before meals, at bedtime, occasionally after meals, and middle of
sleep cycle in patients on multiple insulin injections or pump therapy whether type 1 or type 2 DM). The optimal
frequency of SMBG for patients with type 2 DM on oral agents is unresolved.26 Frequency of monitoring in type
2 DM should be sufficient to facilitate reaching glucose goals and to test for hypoglycemia. The role of SMBG in
improving glycemic control in type 2 DM patients is controversial, but has shown to reduce the HbA1c 0.4%
(0.004; 4 mmol/mol Hb) to no improvement. What is clear is that patients must be empowered to change their
therapeutic regimen (lifestyle and medications) in response to test results, or no meaningful glycemic
improvement is likely to be effected.5
26/88
7/1/2014
Alternate site testing may improve adherence to SMBG recommendations, but only SMBG meters that can sip
blood onto the strip will accommodate such testing. Alternate site glucose testing is performed on the palm,
forearm, or the thigh. These areas tend to have less nerve endings and may be more comfortable for a patient,
but several cautions must be observed. Interstitial glucose readings identified with alternative site testing will lag
behind fingertip capillary blood, as the capillary flow/density is often less in the alternate testing sites when
compared with that in the fingertip. Alternate site testing is discouraged in any situation where immediate action
will be needed based on the glucose reading, such as testing for hypoglycemia or in patients with hypoglycemia
unawareness, wide fluctuations in SMBG, or when the BG is known to be fluctuating, such as postprandially.
Choosing a meter for your patient depends most importantly on his or her dexterity, eye acuity, strip cost, and
features that may be important to him or her. Demonstrate to and then have the patient confirm the monitoring
technique to minimize problems. Each meter has specifications on hematocrit, elevation, whole blood versus
plasma, and heat/cold tolerance. In addition, acetaminophen, ascorbate, dopamine, mannitol, and sugar-based
products may alter testing results. Consult the manufacturer materials for specifics.
Continuous glucose monitoring (CGM) may be useful in select patients. CGM measures interstitial glucose,
which lags behind capillary SMBG, and the same cautions as alternate site testing should be followed. CGM
can be useful in patients with frequent hypoglycemia or hypoglycemic unawareness, nocturnal hypoglycemia,
and for identification of fluctuating glucose patterns and/or previously unknown problems in patients with higher
or lower than expected HbA1c results. CGM still needs to be calibrated after insertion of a new sensor and
minimally every 12 hours with SMBG readings, alarms need to be properly set, and a new sensor must be
placed every 3 to 7 days. The ADA currently recommends that CGM can be considered in type 1 DM adults
25 years of age, and those <25 years of age, if adherent to its use, and in others with the above issues
noted.5
Nonpharmacologic Therapy
Diet
Medical nutrition therapy is recommended for all persons with DM and, along with activity, is a cornerstone of
treatment.5 Paramount for all medical nutrition therapy is the attainment of optimal metabolic outcomes and the
prevention and treatment of complications. It is imperative that patients understand the connection between
carbohydrate intake, medications, and glucose control. For individuals with type 1 DM, the focus is on
physiologically regulating insulin administration with a balanced diet to achieve and maintain a healthy body
weight. A healthy meal plan that is moderate in carbohydrates and low in saturated fat (<7% of total calories),
with a focus on balanced meals delivering all of the essential vitamins and minerals, is recommended in DM.
The amount (grams) and type (via the glycemic index, though controversial) of carbohydrates, whether
accounted for by exchanges or carbohydrate counting, should be considered. All foods can be fit into a healthy
meal plan, and the days of recommending no sweets are in the past. If a healthy weight and normal glucose
goals can be maintained, there is no reason to deny food choices. Overweight/obese patients with type 2 DM
often require caloric restriction to promote weight loss, and portion size and frequency are often issues. The
specific diet appears to be less important than if the patient will adhere to the diet, although low-fat diet for CVD
or avoiding a high-protein diet in nephropathy may be appropriate. Rather than a set diabetic diet, advocate a
diet using foods that are within the financial reach and cultural milieu of the patient. Discourage bedtime and
between-meal snacks, set realistic goals for changes based on what the patient can/will change, and follow up
to see how and if those changes occurred.27
Activity
In general, most patients with DM can benefit from increased activity.28 Aerobic exercise improves insulin
sensitivity and modestly improves glycemic control in the majority of individuals, and reduces cardiovascular
27/88
7/1/2014
risk factors, contributes to weight loss or maintenance, and improves well-being. The patient should choose an
activity that he or she is likely to continue. Start exercise slowly in previously sedentary patients. It remains
unclear which asymptomatic patients should be screened for CVD prior to the beginning of an exercise
regimen. Patients with long-standing disease (age >35 years, or >25 years old with DM 10 years), patients
with multiple cardiovascular risk factors, presence of microvascular disease (especially renal disease), and
patients with previous evidence of atherosclerotic disease should have a cardiovascular evaluation, probably
including an electrocardiogram, with further workup related to CVD risk. In addition, several complications
(uncontrolled hypertension, autonomic neuropathy, insensate feet, and retinopathy) may require restrictions on
the activities recommended. Physical activity goals include at least 150 min/wk of moderate (50% to 70%
maximal heart rate) intensity exercise spread over at least 3 days a week with no more than 2 days between
activity. In addition, resistance/strength training, in patients without retinal contraindications, is recommended to
be added into this exercise regimen at least two times a week.5
Pharmacologic Therapy
From the late 1970s to 1995, only two options for pharmacologic treatment were 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
agents, injectables, and insulins have been introduced in the United States.
The Look Action for Health in Diabetes (Look AHEAD) trial recently reported that no decrease in cardiovascular
outcomes from intensive lifestyle changes in type 2 DM subjects was noted after 10 years of follow-up. In
addition, intensive lifestyle was not able to obtain intensive glycemic control in the majority of subjects,
reiterating the need for early diabetes medication use in conjunction with diet and exercise interventions.
Currently, nine classes of oral agents are approved for the treatment of type 2 diabetes: -glucosidase
inhibitors, biguanides, meglitinides, peroxisome proliferatoractivated receptor (PPAR-) agonists (which are
also commonly identified as thiazolidinediones [TZDs] or glitazones), DPP-4 inhibitors, dopamine agonists, bile
acid sequestrants, sodium-glucose cotransporter 2 inhibitors, and sulfonylureas. Oral antidiabetic agents are
often grouped according to their glucose-lowering mechanism of action. Biguanides and TZDs are often
categorized as insulin sensitizers due to their ability to reduce insulin resistance. Sulfonylureas and meglitinides
are often categorized as insulin secretagogues because they enhance endogenous insulin release. Three
injectable classes, including insulin, GLP-1 receptor agonists, and amylinomimetics, are also available.
Drug Class Information

Insulin
Pharmacology
Insulin is an anabolic and anticatabolic hormone. It plays major roles in protein, carbohydrate, and fat
metabolism. Endogenously produced insulin is cleaved from the larger proinsulin peptide in the cell to the
active peptide of insulin and inactive C-peptide. All commercially available insulin preparations contain only the
active insulin peptide.
Characteristics
Characteristics that are commonly used to categorize insulin preparations include source, strength, onset, and
duration of action. Additionally, insulin may be characterized as analog, defined as insulin preparations that
had amino acids within the insulin molecule modified and/or modifiers added to impart particular
physiochemical and pharmacokinetic advantages. Table 57-8 summarizes available insulin preparations.
Table 57-8 Available Injectable and Insulin Preparations
Room
28/88
7/1/2014
Generic Nam e
Manufacturer Analoga Adm inistration Options
Tem perature b
Expiration
Rapid-acting Insulins
Humalog (insulin lispro)
Lilly
Yes
Insulin pen 3 mL, vial, or 3-mL pen cartridge
28 days
NovoLog (insulin aspart)
Novo Nordisk
Yes
28 days
Apidra (insulin glulisine)
Sanofi-Aventis Yes
28 days
Short-acting Insulins
Humulin R (regular) available in U-100 and Lilly
U-500
No
U-100, 10-mL vial U-500, 20-mL vial
28 days
Novolin R (regular)
Novo Nordisk
No
10-mL vial
30 days
Humulin N
Lilly
No
Vial, 3-mL prefilled pen
Vial: 28 days; pen:

14 days
Novolin N
Novo Nordisk
No
Vial
30 days
Long-acting Insulins
Lantus (insulin glargine)
Sanofi-Aventis Yes
Vial, 3-mL pen, 3-mL pen cartridge
28 days
Levemir (insulin detemir)
Novo Nordisk
Yes
42 days
Lilly
Yes
Vial, prefilled pen
Vial: 28 days; pen:

10 days
Novolog Mix 70/30 (70% aspart protamine Novo Nordisk

suspension, 30% aspart)
Yes
Vial: 28 days;
others: 14 days
Humalog Mix 50/50 (50% neutral

protamine lispro/50% lispro)
Lilly
Yes
Vial, 3-mL pen
Vial: 28 days; pen:

10 days
Humulin 70/30
Lilly
No
Vial: 28 days; pen:

10 days
Novolin 70/30
Novo Nordisk
No
Vial
30 days
Byetta (exenatide)
Amylin/BMS
No
5- and 10-mcg pen, 60 injections (doses)/pen
30 days 25C
(77F)
Victoza (liraglutide)
Novo Nordisk
Yes
3-mL pen, delivers 0.6-, 1.2-, or 1.8-mg dose
30 days
Bydureon (exenatide)
Amylin/BMS
No
2-mg vial w ith separate diluent, single-use system
30 days 25C
(77F)
Amylin
Yes
1.5-mL pen: delivers 15-, 30-, 45-, or 60-mcg dose; 30 days

2.7-mL pen: delivers 60- or 120-mcg dose
Intermediate-acting Insulins
NPH
Premixed Insulins
Prem ixed insulin analogs
Humalog Mix 75/25 (75% neutral
protamine lispro, 25% lispro)
NPHregular Com binations
Other Injectables
Glucagon-like peptide-1 agonists (GLP-1
agonists)
Am ylinom im etic
Symlin (pramlintide)
aAll diabetes injectables 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 1530C (5986F). All products are good until expiration date on product if unopened and stored correctly.
U-100 and U-500, 100 and 500 units/mL, respectively, are the strengths of injectable insulin currently available
in the United States. U-500 regular insulin is available for individuals who may require large doses of insulin to
control their diabetes. In the United States, all other insulin preparations are available only in U-100 strength.
For some patients with type 1 diabetes who require extremely low doses of insulin, dilution of U-100 insulin to
obtain accurate insulin doses may be necessary. Diluents, instructions on dilution, and empty bottles can be
obtained from the manufacturers for dilution.
Historically, insulin came from either beef or pork sources. Manufacturers in the United States have
discontinued production of beef and pork source insulin preparations as of December 2003, and now
exclusively use recombinant DNA technology to manufacture insulin. Eli Lilly and Sanofi-Aventis currently use a
nondisease-producing strain of Escherichia coli for synthesis of insulin, whereas Novo Nordisk uses
29/88
7/1/2014
Saccharomyces cerevisiae, or bakers yeast, for synthesis.

Purity of insulin refers to the amount of proinsulin and other impurities present in a given insulin product. Prior
to 1980, most insulin contained enough impurities (300 to 10,000 ppm) to cause local reactions on injection, as
well as systemic adverse effects from antibody production. Modern technology has provided less expensive
techniques to purify insulin. As a result, all insulin products contain 10 ppm of proinsulin, with purified
preparations (all recombinant DNA human insulin and insulin analogs) containing <1 ppm of proinsulin.
Regular crystalline insulin naturally self-associates into a hexameric (six insulin molecules) structure when
injected subcutaneously. Before absorption through a blood capillary can occur, the hexamer must dissociate
first to dimers, and then to monomers. This principle is the premise for additives such as protamine and zinc
described below, and modification of amino acids for insulin analogs. Lispro, aspart, and glulisine insulin
preparations dissociate rapidly to monomers; thus, absorption is rapid. Lispro (B-28 lysine and B-29 proline
human insulin; monomeric) insulin with two amino acids transposed, aspart (B-28 aspartic acid human insulin;
monomeric and dimeric) insulin with replacement of one amino acid, and glulisine (B-3 lysine and B-29 glutamic
acid) are rapidly absorbed, peak faster, and have shorter durations of action when compared with regular
insulin. Proteins tend to be insoluble near their isoelectric point, and glargine insulin uses this to prolong
absorption. In comparison to human insulin, with an isoelectric point of 5.4, the analog glargine insulin (A-21
glycine, B-30a-arginine, B-30a L-arginine, and B-30b L-arginine human insulin) has an isoelectric point of 6.8.
In the bottle, glargine is buffered to a pH of 4, a level at which it is completely soluble, resulting in a clear
colorless solution. When injected into the neutral pH of the body, it rapidly forms microprecipitates that slowly
dissolve into monomers and dimers that are then subsequently absorbed. The result is a long-acting,
approximately 24-hour duration insulin analog. Detemir, in contrast, attaches a C14 fatty acid (a 14-carbon
fatty acid) at the B-29 position and removes the B-30 amino acid. This allows the fatty acid side chain to bind to
interstitial albumin at the SQ injection site. Also, the formulation allows stronger hexamer self-associations,
which prolong absorption. Once detemir dissociates from the interstitial albumin, it is free to enter a capillary,
where it is again bound to albumin, which can further prolong action. It then travels to a site of action and
interacts, after dissociation from albumin, with insulin receptors.
Insulin analogs are modified human insulin molecules, and safety is paramount for FDA approval. Key factors
that should be considered in the approval process include local injection reactions, antigenicity, efficacy
compared with human insulin, insulin receptor binding affinity, and insulin-like growth factor 1receptor affinity
(which is compared with that of human insulin to determine mitogenic potential).
Pharmacokinetics
Subcutaneous injection kinetics is dependent on onset, peak, and duration of action, and is summarized in
Table 57-9. Absorption of insulin from a subcutaneous depot is dependent on several factors, including source
of insulin, concentration of insulin, additives to the insulin preparations (e.g., zinc, protamine), blood flow to the
area (rubbing of injection area, increased skin temperature, and exercise in muscles near the injection site may
enhance absorption), and injection site. Regular or neutral protamine Hagedorn (NPH) insulin is commonly
injected in (from most rapid to slowest absorption): abdominal fat, posterior upper arms, lateral thigh area, and
superior buttocks area. Insulin analogs, unlike regular or NPH insulin, appear to retain their kinetic profile at all
sites of injection. U-500 regular insulin has a delayed onset and peak, and a longer duration of action when
compared with U-100 regular insulin; the pharmacokinetic profile of U-500 is more similar to NPH.
Table 57-9 Pharmacokinetics of Various Insulins Administered Subcutaneously
Type of Insulin
Onset
Peak (Hours)
Duration (Hours)
Maxim um Duration (Hours)
Appearance
Rapid Acting
Aspart
1530 minutes
12
35
56
Clear
Lispro
1530 minutes
12
34
46
Clear
Glulisine
1530 minutes
12
34
56
Clear
30/88
7/1/2014
Short Acting
Regular
0.51 hours
23
46
68
Clear
Intermediate Acting
NPH
24 hours
48
812
1418
Cloudy
Detemir
2 hours
1424
24
Clear
Glargine
45 hours
2224
24
Clear
Long Acting
aGlargine is considered flat pharmacokinetically, and detemir has a slight peak, but both have exhibited peak effects during comparative
testing, and these peak effects may necessitate changing therapy in a minority of type 1 DM patients.
Addition of protamine (NPH, NPL, and aspart protamine suspension) or excess zinc (historically lente or
ultralente insulin) will delay onset, peak, and duration of the insulins effect. Variability in absorption,
inconsistent suspension of the insulin by the patient or healthcare provider when drawing up a dose, and
inherent insulin action based on the pharmacokinetics of the products may all contribute to a labile glucose
response. NPH insulin and all suspension-based insulin preparations should be inverted or rolled gently at
least 10 times to fully suspend the insulin prior to each use.
As detemir insulin has a unique mechanism to prolong absorption, it should not be surprising that the
pharmacokinetics is unique. Detemir insulin reported less intrapatient variability between injections when
compared with NPH or glargine insulin. This may be advantageous when variability in the insulin level may
make a large difference in glycemic excursions, as in type 1 DM. It should be noted that at low dose (0.2
unit/kg) the duration of action is approximately 14 to 16 hours, while at doses above 0.3 unit/kg, it is close to 24
hours. In type 1 DM, 30% to 50% of patients may require twice-daily use of detemir insulin to cover 24-hour
basal insulin needs, but this is unlikely to be an issue in type 2 DM patients, as they tend to use more units per
day to attain glycemic goals. Direct comparative data between glargine insulin and detemir insulin are difficult to
interpret, as detemir insulin was allowed to be dosed twice daily. Equivalent glycemic control was attained with
either insulin. It is possible that glargine insulin in a minority of type 1 DM patients may require twice-daily
dosing, but this is poorly documented in the literature.
The half-life of an IV injection of regular insulin is about 9 minutes. Thus, the effective duration of action of a
single IV injection is short, and changes in IV insulin rates will reach steady state in approximately 45 minutes.
IV pharmacokinetics of other soluble insulin preparations (lispro, aspart, glulisine, and even glargine) is similar
to IV regular insulin, but they have no advantages over IV regular insulin and are more expensive. For
completeness, aspart, lispro, and glulisine are FDA approved for IV use.
Insulin is degraded in the liver, muscle, and kidney. Liver deactivation is 20% to 50% in a single passage.
Approximately 15% to 20% of insulin metabolism occurs in the kidney. This may partially explain the lower
insulin dosage requirements in patients with end-stage renal disease.
Currently, insulin must be injected to retain its glycemic lowering properties. Alternative absorption pathways,
including pulmonary, topical, GI, and even nasal, are being explored. The first inhalation insulin (Exubera) was
discontinued due to poor sales and subsequent reports of lung cancer. Technosphere inhaled insulin (Afrezza)
was rejected by the FDA due to concerns regarding the redesign of their delivery device. Additional trials are
underway to assess the safety of the redesigned delivery device in patients with type 1 and type 2 DM. The
onset of action is similar to IV insulin, which is unique.
Microvascular Complications
Insulin has been shown to be as efficacious as any oral agent for treating DM. The United Kingdom Prospective
Diabetes Study (UKPDS), which used sulfonylureas or insulin, showed equal efficacy in lowering the risk of
microvascular events in newly diagnosed type 2 DM.24 Similarly, in type 1 DM, the DCCT showed efficacy in
31/88
7/1/2014
reducing microvascular complications.23

Macrovascular Complications
The connection between high insulin levels (hyperinsulinemia), insulin resistance, and cardiovascular events
incorrectly leads some clinicians to believe that insulin therapy may cause macrovascular complications.
Endogenous hyperinsulinemia in the setting of insulin resistance has been linked to increased cardiovascular
events; however, this is not the case with hyperinsulinemia due to exogenous injectable insulin preparations.
The UKPDS and DCCT found no differences in macrovascular outcomes with intensive insulin therapy. One
study, the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction study,29 reported
reductions in mortality with insulin therapy. This group assessed the effect of an insulinglucose infusion in
type 2 DM patients who had experienced an acute myocardial infarction (MI). Those randomized to insulin
infusion followed by intensive insulin therapy lowered their absolute mortality risk by 11% over a mean follow-up
period of approximately 3 years. This was most evident in subjects who were insulin-nave or had a low
cardiovascular risk prior to the acute MI.29 The importance of glycemic control in hospitalized patients is
covered later in the chapter.
Adverse Effects
The most common adverse effects reported with insulin are hypoglycemia and weight gain. Hypoglycemia is
more common in patients on intensive insulin therapy regimens versus those on less-intensive regimens. Also,
patients with type 1 DM tend to have more hypoglycemic events compared with type 2 DM patients. In the
UKPDS study, performed over 10 years, the percentage of diabetic patients who needed assistance (thirdparty or hospitalization) due to a hypoglycemic reaction was 2.3%. The UKPDS reported a rate of 36.5% for risk
of any hypoglycemic event, including mild, self-treated events. In the DCCT, tighter control produced a risk
three times higher for severe hypoglycemia compared with conventional therapy. Moreover, insulin was
associated with 14% of emergency hospitalizations in older Americans using nationally representative public
health surveillance data.30 Glycemic goals should incorporate hypoglycemic risk versus the benefit of lowering
the glucose when HbA1c levels are near normal, especially in type 1 DM.
Hypoglycemia
Minimization of risk for patients on insulin should include education about the signs and symptoms of
hypoglycemia, proper treatment of hypoglycemia, and BG monitoring. BG monitoring is essential for those on
insulin, and is particularly of value in patients with hypoglycemia unawareness. Patients with hypoglycemia
unawareness do not experience the normal sympathetic symptoms of hypoglycemia (tachycardia,
tremulousness, and, often, sweating). Initial hypoglycemia symptoms are neuroglycopenic in nature (confusion,
agitation, loss of consciousness, and/or progression to coma). Patients with hypoglycemia unawareness should
at least temporarily raise their glycemic goals (requiring a reduction in insulin dose) and check their BG level
prior to any activities that may be dangerous with a low blood sugar (e.g., driving and certain sports, among
others). Proper treatment of hypoglycemia dictates ingestion of carbohydrates, with glucose being preferred.
Unconsciousness is an indication for either IV glucose or glucagon injection, which increases glycogenolysis in
the liver. Glucagon use would be appropriate in any situation in which the patient does not have or cannot have
ready IV access for glucose administration. Education for reconstitution and injection of glucagon is
recommended for close friends and family of a patient who has recurrent neuroglycopenic events. The patient
and close contacts should be informed that it can take 10 to 15 minutes for the injection to start raising glucose
levels, and patients often vomit during this time. Proper positioning to avoid aspiration should be emphasized.
Weight gain is predominantly from increased truncal fat, and tends to be related to daily dose and plasma
insulin levels present. It is undesirable in most type 2 DM patients, but may be seen as beneficial in
underweight patients with type 1 DM. Weight gain appears to be related to intensive insulin therapy, and can
32/88
7/1/2014
be somewhat minimized by physiologic replacement of insulin.

Two forms of lipodystrophy, although much less common today in people with diabetes, still occur.
Lipohypertrophy is caused by many injections into the same injection site. Due to insulins anabolic actions, a
raised fat mass is present at the injection site with resultant variable insulin absorption. Lipoatrophy, in
contrast, is thought to be due to insulin antibodies or allergic-type reactions with destruction of fat at the site of
injection. In both cases, injection away from the site with more purified insulin is recommended, although
reports of lipoatrophy have been reported with most insulin preparations. Anecdotal evidence has shown that
specially formulated cromolyn may help to stabilize the allergic type of reaction.
One large study using administrative data found an association between insulin glargine and cancer. However,
several other large database studies and meta-analysis have shown no such association. Glargine in vitro has
a higher affinity for IGF-1 than regular human insulin, which could theoretically explain the increased risk of
cancer, yet in vivo the metabolite of glargine is mostly present. The metabolite has similar affinity for IGF-1 as
regular insulin. However, in the observational retrospective study, confounding by indication, selection, or
detection bias in older patients may have played a greater role in the detection of cancer than the insulin
glargine therapy. Supporting this premise, when glargine was used in intensive insulin therapy regimens in
healthier populations, no such association was seen. Recently, the prospective, randomized Outcome
Reduction with Initial Glargine Intervention trial reported no difference in cancer risk or cardiovascular events
with low-dose insulin glargine use over approximately 6 years.31 These data are not definitive, but encouraging.
DrugDrug Interactions
There are no significant drugdrug interactions with injected insulin, although other medications that may affect
glucose control can be considered. Detemir does not have albumin binding interactions, as it occupies only a
small percent of albumin binding sites. Table 57-10 lists common medications known to affect BG levels.
Table 57-10 Medications that may Affect Glycemic Control
Drug
Effect on Glucose
Mechanism /Com m ent
Angiotensin-converting enzyme Slight reduction

inhibitors
Improves insulin sensitivity
Alcohol
Reduction
Reduces hepatic glucose production
-Interferon
Increase
Decreases insulin sensitivity/induces counterregulatory hormones
Atypical antipsychotics
Increase
Decrease insulin sensitivity; w eight gain
Calcineurin inhibitors
Increase
Decrease insulin secretion
Diazoxide
Increase
Decreases insulin secretion, decreases peripheral glucose use
Diuretics (thiazides)
Increase
May increase insulin resistance and/or decrease insulin secretion, K+ change may
Glucocorticoids
Increase
Impairs insulin action
Fluoroquinolones
Increase/decrease
Unclear, potential drug interaction w ith sulfonylureas or change in insulin secretion
Nicotinic acid
Increase
Impairs insulin action, increases insulin resistance
Oral contraceptives
Increase
Unclear
Pentamidine
Decrease, and then

increase
Toxic to cells; initial release of stored insulin, and then depletion
Phenytoin
Increase
Decreases insulin secretion
Protease inhibitors (PI)
Increase
Worsen insulin resistance/decrease first-phase insulin release or increase

lipotoxicity. Dependent on PI
-Blockers
May increase
Decreases insulin secretion
Ranolazine
Decrease
Improves oxidative glucose disposal
Salicylates
Decrease
Inhibition of IB kinase- (IKK-) (only high doses, e.g., 46 g/day)
Sympathomimetics
Slight increase
Increased glycogenolysis and gluconeogenesis
be in part responsible
aThis list is not inclusive of all medications reported to cause glucose changes.
33/88
7/1/2014
Dosing and Administration
The dose of insulin for any person with altered glucose metabolism must be individualized. In type 1 DM, the
average daily requirement for insulin is 0.5 to 0.6 unit/kg, with approximately 50% being delivered as basal
insulin, and the remaining 50% dedicated to meal coverage. During the honeymoon phase it may fall to 0.1 to
0.4 unit/kg. During acute illness or with ketosis or states of relative insulin resistance, higher dosages are
warranted. In type 2 DM a higher dosage is required for those patients with significant insulin resistance.
Dosages vary widely depending on underlying insulin resistance and concomitant oral insulin sensitizer use.
Strategies on how to initiate and monitor insulin therapy will be described later in Therapeutics below.
U-500 regular insulin is reserved for use in patients with extreme insulin resistance and most often is given two
or three times a day. Caution must be used, however, in order to avoid errors in prescribing and dispensing U500. In the inpatient setting, the prescription of U-500 is often written in volume (mL) and administered using a
tuberculin syringe. In an individual prescribed 50 units three times a day before meals, this prescription would
be written as follows: U-500 regular insulin, inject 50 units (0.1 mL) subcutaneously three times daily before
meals. In outpatients, however, it is often easier for patients to use U-100 insulin syringes. One unit of U-500
insulin drawn up using the markings of a U-100 equals 5 units of insulin. The same prescription as described
above would be written as follows: U-500 regular insulin: inject 50 units (10 units as measured by the unit
markings of a U-100 syringe) subcutaneously three times daily before meals.
Storage
It is recommended that unopened injectable insulin be refrigerated (2C to 8C [36F to 46F]) prior to use.
The manufacturers expiration date printed on the insulin is used for unopened, refrigerated insulin. Once the
insulin is in use, the manufacturer-recommended expiration dates will vary based on the insulin and delivery
device. Table 57-8 outlines manufacturer-recommended expiration dates for room temperature (15C to 30C
[59F to 86F]) insulin. For financial reasons, patients may attempt to use insulin preparations longer than their
expiration dates, but careful attention must be paid to monitoring for glycemic control deterioration and signs of
insulin decay (clumping, precipitates, discoloration, etc.) if this is attempted.
Glucagon-Like Peptide-1 Agonists

Exenatide
Pharmacology
Exendin 4 is a 39amino acid peptide isolated from the saliva of the Gila monster (Heloderma suspectum) and
shares 53% amino acid sequence with human GLP-1. Exenatide is the synthetic version of naturally occurring
exendin 4. Exenatide (Byetta, Bydureon) has been shown to bind to GLP-1 receptors in many parts of the body
including the brain and pancreas but is more resistant to DPP-4 degradation than endogenous GLP-1.
Exenatide and GLP-1 have common glucoregulatory actions. The GLP-1 receptor activity of exenatide is
pharmacologic, however, and is approximately three to four times more than the normal peak physiologic GLP1 activity. Exenatide enhances insulin secretion in a glucose-dependent manner, suppressing inappropriately
high postprandial glucagon secretion resulting in decreased hepatic glucose production. It increases satiety,
slows gastric emptying, and promotes weight loss.
Pharmacokinetics
There are two formulations of exenatide: exenatide injected twice daily (Byetta) and extended-release
exenatide injected once weekly (Bydureon).
The concentration of twice-daily exenatide is detectable in plasma within 10 to 15 minutes after subcutaneous
injection, and the drug has a tmax of 2 hours and a plasma half life of 3.3 to 4 hours. Plasma concentrations
34/88
7/1/2014
increase in a dose-dependent manner and concentrations are detectable for up to 10 hours postinjection,
although pharmacodynamically, effects last for approximately 6 hours.
Extended-release once-weekly exenatide has a prolonged duration of action due to the exenatide being
contained in a suspension of microspheres and gradually released over time. Following a single dose,
exenatide is released from the microspheres over approximately 10 weeks. After initiation of once-weekly
injections of 2 mg exenatide suspension, there is a gradual increase in plasma exenatide concentration over 6
to 7 weeks, after which steady state is achieved.
Bioavailability of exenatide after injection in the abdomen, upper arm, or the thigh is similar. Elimination of
exenatide is primarily by glomerular filtration with subsequent proteolytic degradation. When exenatide is
administered to subjects with worsening degrees of renal insufficiency, there is a progressive prolongation of
the half-life, and in dialysis patients, plasma clearance of exenatide is markedly reduced. The incidence of GI
side effects appears to be increased in individuals with impaired renal function, possibly due to higher plasma
levels; thus, caution is advised.
No significant differences in exenatide pharmacokinetics have been observed with obesity, race, gender, or
advancing age.
Efficacy
The average HbA1c reduction is approximately 0.9% (0.009; 10 mmol/mol Hb) with twice-daily exenatide, similar
to oral agents, but HbA1c lowering is dependent on baseline values. Some patients will have greater or lesser
reduction in HbA1c . Similar HbA1c reduction is seen in patients on oral agents. Once-weekly extended-release
exenatide resulted in significantly greater changes from baseline compared with twice-daily exenatide in HbA1c
(1.6% vs. 0.9% [0.016 vs. 0.009; 18 mmol/mol Hb vs. 10 mmol/mol Hb) and FPG (35 mg/dL vs. 12
mg/dL [1.9 mmol/L vs. 0.7 mmol/L]).32
Exenatide significantly decreases postprandial glucose excursions, but has only a modest effect on FPG
values. If a patient has significant elevations in FPG levels, these should be corrected with other agents and
then exenatide added later. It is recommended to lower the sulfonylurea dose only if GLP-1 agonists are
started with near-normal glucose levels. Sulfonylureas release insulin in a nonglucose-dependent fashion and
can cause hypoglycemia.
Exenatide may aid some patients efforts to lose weight. The average weight loss in controlled trials of twicedaily exenatide was 1 to 2 kg over 30 weeks, without dietary advice being given to the patients. Long-term,
open-label follow-up on 10 mcg twice a day shows continued and sustained weight loss for at least 3 years.
Approximately 84% of patients on exenatide lost some weight. Exenatide, through decreasing appetite and
slowing gastric emptying, may reduce the number of calories a patient eats at a meal. If a patient does not
decrease calorie intake, no weight loss is likely to occur, as exenatide does not increase caloric expenditure.
Exenatide reduces the HbA1c level, which has been shown to be related to the risk of microvascular
complications.
No randomized clinical trials have examined the effect of exenatide on long-term cardiovascular outcomes.
However, improvements in several cardiovascular risk factors have been reported. In an open-label study of
exenatide 10 mcg twice a day, triglycerides (37 10 mg/dL [0.42 0.11 mmol/L]) decreased, and HDL
cholesterol (+4.5 0.4 mg/dL [0.12 0.01 mmol/L]) increased. Once-weekly extended-release exenatide
resulted in greater reduction in total cholesterol and LDL cholesterol compared with twice-daily exenatide.33
35/88
7/1/2014
Nonsignificant reductions in systolic and diastolic blood pressure have been observed; a significant reduction
was seen in subjects with above-normal systolic blood pressure. The greatest improvement in cardiovascular
risk factors was, in general, seen in subjects who had the greatest weight loss.
Adverse Effects
The most common adverse effects associated with exenatide are GI. Nausea is more likely with twice-daily
exenatide (>35%) compared with once-weekly extended-release exenatide (14%). Vomiting or diarrhea occurs
in approximately 10% of patients on twice-daily exenatide. As these adverse effects appear to be dose related,
the patient on twice-a-day exenatide should be started on 5 mcg twice a day and titrated to 10 mcg twice a day
only if the adverse effects have resolved. When the patient is increased to the 10 mcg twice a day dose, these
adverse effects may recur for a short period of time. GI adverse effects appear to decrease over time.
However, approximately 1 in 20 patients on twice-daily exenatide have prolonged problems with side effects,
possibly requiring discontinuation or transition to once-weekly extended-release exenatide.
Many episodes of nausea are better characterized as stomach fullness. Patients should be instructed to eat
slowly and stop eating when full, or risk nausea/vomiting. Weight loss does not appear to be related to adverse
effects, but rather to a reduction in calories consumed. Exenatide provides glucose-dependent insulin
secretion; thus, hypoglycemic rates when combined with metformin or a TZD are not substantially increased.
However, when combined with a sulfonylurea or insulin, hypoglycemia may occur. Although exenatide reduces
glucagon when the glucose is high, there is no suppression of counterregulatory hormones during
hypoglycemia. Exenatide antibodies can occur, but generally decrease over time and usually do not affect
glycemic control. In approximately 5% of patients, titers may increase over time, potentially resulting in a
deterioration of glycemic control.
Exenatide has been associated with cases of acute pancreatitis, but this has not been shown to be causal.
Further study is needed, however, and several important points should be noted: (a) patients with type 2 DM
often have risk factors for pancreatitis such as gallstones, hypertriglyceridemia, obesity, and concomitant
medication use; (b) GLP-1 agonists could mask initial signs of pancreatitis, including nausea, vomiting, and
abdominal pain; and (c) large database studies have not linked exenatide to a higher rate of acute pancreatitis.
In a patient with a history of pancreatitis, the benefits of using exenatide must be weighed against potential
risks. If a patient with abdominal pain, nausea, and/or vomiting presents, it is best to discontinue exenatide
temporarily and confirm that the symptoms are not a sign of a more serious underlying problem. Exenatide
given twice daily does not change the risk of thyroid C-cell tumors in rats and does not have a black box
warning; no increased risk of C-cell tumors has been reported in humans. Extended-release exenatide has a
black box warning in regards to thyroid C-cell tumors due to rat data. The difference appears to be that the
extended release continually stimulates the GLP-1 receptor on the thyroid of rodents, increasing the risk of
thyroid C-cell tumors. No tumors have been reported in humans.
There have been reports of injection site reactions with extended-release once-weekly exenatide. Nodule
injection site reactions are not painful and are often not visible, but can be felt at the injection site, which may
have been injected 2 to 4 weeks prior. These nodules are an aggregation of the microspheres subcutaneously,
not an immune reaction, and they may last 6 to 8 weeks. Injection site erythema, which can be severe in some
cases, is related to exenatide antibody status (potentially worse if very high titers) or may be due to the
platform, as this reaction is well described with the poly(D,L-lactide-co-glycolide) microsphere material.
Drug Interactions
Exenatide delays gastric emptying; if the patient has gastroparesis, exenatide is not recommended. Exenatide
can also delay the absorption of other medications. Examples of medications that may be effected include oral
pain medications and antibiotics dependent on concentration-dependent efficacy. If rapid absorption of the
medication is necessary, it is best to take the mediation 1 hour before, or at least 3 hours after, the injections of
36/88
7/1/2014
twice-daily exenatide. There have been postmarketing reports of increased INR in patients on warfarin on
exenatide, sometimes associated with bleeding. It is advised that INR be monitored frequently until stable on
initiation of exenatide.
Dosing of twice-daily exenatide (Byetta) should begin with 5 mcg twice a day, and titrated to 10 mcg twice a day
in 1 month or when tolerability allows and if warranted for glycemic control. Twice-daily exenatide should be
injected subcutaneously 0 to 60 minutes before the morning and evening meals. If the patient does not eat
breakfast, he or she may take the first injection of the day at lunch. The peak effect of twice-daily exenatide is
at approximately 2 hours, so anecdotally the patient may get better appetite suppression if injected an hour
prior to the meal.
The dosing of extended-release exenatide (Bydureon) is 2 mg suspension injected subcutaneously every 7
days, at any time of day, with or without meals. Extended-release exenatide is injected immediately after the
powder is suspended in the diluent. The process of extended-release once-weekly exenatide injections is more
complex than using the twice-daily exenatide pen. Patients must be instructed on self-administration.
Exenatide may be injected in abdomen, thigh, or upper arm region, but patients are advised to use a different
injection site when injecting into the same region.
Storage and dosage availability information can be found in Table 57-8.
Liraglutide
Pharmacology
Liraglutide (Victoza) is a GLP-1 receptor agonist that has 97% amino acid sequence homology to endogenous
GLP-1. The only alteration is an arginine substituted for lysine at position 34. A C-16 fatty acid (palmitic acid) is
attached at position 26 (with a glutamic amino acid spacer to optimize GLP-1 receptor interaction) so that
liraglutide can bind noncovalently to albumin, prolonging the half-life.
Liraglutide enhances glucose-dependent insulin secretion while suppressing inappropriately high glucagon
secretion in the presence of elevated glucose concentrations, resulting in a reduction in hepatic glucose
production. Liraglutide reduces food intake, which may result in weight loss, and slows gastric emptying so that
the rate of glucose appearance into the plasma better matches the glucose disposition. During hypoglycemia,
liraglutide does not stimulate insulin secretion and does not inhibit the release of the counterregulatory
hormone glucagon.
Pharmacokinetics
After injection of liraglutide, there is self-association into a heptameric structure, binding to albumin first in the
interstitial space, then in the blood, and then in the interstitial space around the GLP-1 receptor that prolongs
the half-life. In healthy individuals, the half-life is 13 hours, making it suitable for daily administration. Injection
into the abdomen, upper arm, and thigh gives clinically similar pharmacokinetics. Maximum concentrations are
reached approximately 8 to 12 hours after injection, with steady state reached after approximately 3 days.
Liraglutide is extensively plasma protein bound (mostly to albumin as previously stated) with an elimination halflife of 10 to 18 hours. The absolute bioavailability is approximately 50%.
The metabolism of liraglutide appears to be by degradation, similar to other large proteins, and several small
minor metabolites (total of 3% to 5% of the dose) may be found. The DPP-4 enzyme in vitro has been shown to
slowly metabolize liraglutide, and this may be the case in vivo as well.
The pharmacokinetics of liraglutide does not appear to be affected by age, race, and gender. Severe renal or
mild to severe hepatic impairment may actually lower the AUC by approximately 25%, although the clinical
37/88
7/1/2014
significance of this is not known.

Efficacy
The average HbA1c reduction is approximately 1.1% (0.0011; 12 mmol/mol Hb) with liraglutide. Similar to other
agents, the reduction in HbA1c is dependent on the baseline values. Liraglutide lowers FPG level by
approximately 25 to 40 mg/dL (1.4 to 2.2 mmol/L), and postprandial plasma glucose levels are reduced
similarly. Due to the longer half-life, liraglutide can suppress glucagon overnight, which improves the FPG.
Similar to exenatide, liraglutide-treated patients may lose weight. The average weight loss in controlled trials
was 1 to 3 kg over 26 weeks, and weight loss achieved appeared to be sustained through 2 years. Liraglutide,
through decreasing appetite and slowing gastric emptying, may reduce the number of calories a patient eats at
a meal.
Liraglutide reduces the HbA1c level, which has been shown to be related to the risk of microvascular
complications.
There are no published clinical trials examining the effect of liraglutide on long-term cardiovascular outcomes;
however, no signal of cardiovascular harm was noted on FDA approval.
Adverse Effects
The most common adverse effects associated with liraglutide are GI. Nausea occurs in 11% to 29% of subjects
on 1.2 mg, and 14% to 40% of subjects on 1.8 mg daily. Vomiting occurs in approximately 5% of subjects, and
diarrhea occurs in approximately 8% to 15% of patients placed on liraglutide. GI adverse effects appear to
decrease over time, but approximately 5% to 10% of subjects withdrew due to GI side effects. As these adverse
effects appear to be dose related, the patient should be titrated from 0.6 to 1.2 mg, and to 1.8 mg as tolerated.
Randomized trials did not allow for individualized titration, and likely had worse tolerability that can be obtained
clinically by individualization of titration.
Many episodes of nausea would be better characterized as stomach fullness. To minimize GI side effects,
patients should be instructed to eat slowly and stop eating when full, or risk nausea/vomiting. Liraglutide
provides glucose-dependent insulin secretion, and hypoglycemic rates when combined with metformin a TZD
are not substantially increased, but when combined with a sulfonylurea or insulin, significant hypoglycemia may
occur. When combined with a sulfonylurea, the rates of hypoglycemia were similar between addition of
liraglutide and that of glargine insulin. Liraglutide antibodies can occur (4% to 13%), but the rates are generally
low and do not affect glycemic control or risk of side effects.
Liraglutide has been associated with the serious adverse event of acute pancreatitis, but causality has not
been proven. Further study is needed, but type 2 DM patients have many risk factors for pancreatitis and the
common GI side effects of GLP-1 agonists could mask initial signs of pancreatitis. If a patient with abdominal
pain, nausea, and/or vomiting presents, it is best to discontinue liraglutide temporarily and if symptoms persist,
evaluate for other potential causes, including pancreatitis. Clinicians must weigh the benefits of liraglutide
against the potential risks in a patient with a history of pancreatitis.
A boxed warning about thyroid C-cell tumors (as with extended-release exenatide) is listed in the package
insert of liraglutide. Rodent models reported a higher risk of C-cell tumors of the thyroid, including medullary
thyroid carcinoma. Rodents may not be the ideal model to study this effect as they express a high number of
GLP-1 receptors on thyroid C-cells, whereas in humans the expression of GLP-1 receptors in the thyroid is
minimal. Rodents also have a higher baseline prevalence of C-cell tumors compared with humans. In addition,
38/88
7/1/2014
calcitonin, a marker used to screen for C-cell tumors, may increase by a nonclinically significant amount in
select patients. No signal for C-cell tumors in humans or nonhuman primates has been noted thus far. As
clinical use increases, however, this will continue to be examined. Currently no specific additional monitoring of
patients is recommended. Nonetheless, liraglutide is contraindicated in patients with a personal or family history
of medullary thyroid cancer, and in those with multiple endocrine neoplasia syndromes.
Drug Interactions
Liraglutide delays gastric emptying; thus, it can delay the absorption of other medications. Examples of
medications that may be effected include oral pain medications and antibiotics dependent on threshold levels
for efficacy. If rapid absorption of the medication is necessary, it is best to take the mediation 1 hour before, or
at least 3 hours after, the injection. Liraglutide may worsen gastroparesis and clinically it may not be prudent to
use in this patient population.
The dosing of liraglutide should begin with 0.6 mg daily for 1 week, and then increased to 1.2 mg daily for 1
week. Patients may be maintained on the 1.2-mg dose, or increased to the maximum dose of 1.8 mg daily after
1 week. The 0.6-mg dose is considered a titration dose, and does not reduce the HbA1c substantially in the
majority of patients. This titration is recommended to improve GI tolerability. Titration should be individualized
based on side effects and clinical response. Liraglutide is dosed once daily, and may be given independent of
meals. As with exenatide, a reduction in insulin secretagogues and insulin may be necessary if the patient is
near glycemic goal or hypoglycemia occurs.
Storage and dosage availability information can be found in Table 57-8.
Amylinomimetic
Pramlintide
Pharmacology
Pramlintide (Symlin) is an antihyperglycemic agent used in patients currently treated with insulin. Pramlintide is
a synthetic analog of amylin (amylinomimetic), a neurohormone cosecreted from the cells with insulin. Amylin
is very low or absent in type 1 DM, and lower than normal in type 2 DM patients requiring insulin therapy.
Pramlintide is provided as a 37amino acid polypeptide, which differs in amino acid sequence from human
amylin by replacement positions 25 (alanine), 28 (serine), and 29 (serine) with proline. Pramlintide suppresses
inappropriately high postprandial glucagon secretion, increases satiety, which may result in weight loss, and
slows gastric emptying so that the rate of glucose appearance into the plasma better matches the glucose
disposition.
Pharmacokinetics
The absolute bioavailability of pramlintide after subcutaneous injection is 30% to 40%. The tmax is
approximately 20 minutes, but the Cmax is dose dependent. The t1/2 is approximately 45 minutes; thus, the
pharmacodynamic duration of action is about 3 to 4 hours. Pramlintide does not extensively bind to albumin,
and should not have significant binding interactions. Metabolism is primarily by the kidneys, and one active
metabolite (2-37 pramlintide) has a similar half-life as the parent compound. No accumulation has been seen in
renal insufficiency, but caution is advised. Injection into the arm may increase exposure and variability of
absorption, so injection into the abdomen or thigh is recommended. Moderate to severe renal insufficiency
does not affect exposure.
Efficacy
39/88
7/1/2014
The average HbA1c reduction is approximately 0.6% (0.006; 7 mmol/mol Hb) with pramlintide, although
optimization of the insulin and pramlintide doses may result in further drops in HbA1c . If the 120-mcg dose is
used in type 2 DM patients on insulin, it may also result in 1.5-kg weight loss. In type 1 DM patients, the
average reduction in HbA1c was 0.4% to 0.5% (0.004 to 0.005; 5 to 6 mmol/mol Hb). Prandial pramlintide added
versus rapid-acting insulin in type 2 DM subjects uncontrolled on basal insulin reported similar efficacy, but with
no weight gain, compared with 5-kg weight gain with rapid-acting insulin. Pramlintide decreases prandial
glucose excursions, but has little effect on the FPG concentration. When pramlintide is injected before the
meal, gastric emptying may delay absorption of mealtime nutrients, necessitating delay of rapid-acting insulin.
This may be overcome by injecting the mealtime insulin at the conclusion of the meal, or whenever the BG
starts to rise. The average weight loss in controlled trials was 1 to 2 kg, without dietary advice being given to
the patients. Pramlintide, through decreasing appetite, may reduce the number of calories a patient eats at a
meal.
Pramlintide reduces the HbA1c level, which has been shown to be related to the risk of microvascular
complications.
No published clinical trials have examined the effect of pramlintide on cardiovascular outcomes.
Adverse Effects
The most common adverse effects associated with pramlintide are GI in nature. Nausea occurs in 20% of type
2 DM patients, and vomiting or anorexia occurs in approximately 10% of type 1 or type 2 DM patients. Nausea
is more common in type 1 DM, occurring in 40% to 50% of patients. The higher rates in type 1 DM related to GI
adverse effects appear to decrease over time and are dose related; thus, starting at a low dose and slowly
titrating as tolerated is recommended. Pramlintide alone does not cause hypoglycemia, but it is indicated for
use in patients on insulin; thus, hypoglycemia can occur. The risk of severe hypoglycemia early in therapy is
higher in type 1 DM than in type 2 DM patients. A twofold increase in severe hypoglycemic reactions in type 1
DM patients has been reported.
Drug Interactions
Pramlintide delays gastric emptying; thus, it can delay the absorption of other medications. Examples of
medications that may be effected include oral pain medications and antibiotics dependent on threshold levels
for efficacy. If rapid absorption of the medication is necessary, it is best to take the mediation 1 hour before, or
at least 3 hours after, the injection of pramlintide.
Pramlintide dosing varies in type 1 and type 2 DM. It is imperative that the prandial insulin dose, if used, be
reduced 30% to 50% when pramlintide is started to minimize severe hypoglycemic reactions or delayed until
postprandial glucose levels rise. Basal insulin may need to be adjusted only if the FPG is close to normal. In
type 2 DM, the starting dose is 60 mcg prior to meals, and may be titrated to the maximally recommended 120mcg dose as tolerated and warranted based on postprandial plasma glucose concentrations. At least one
clinical trial started at the 120-mcg dose without significantly more intolerability. In type 1 DM, dosing starts at
15 mcg prior to meals, and can be titrated up in 15-mcg increments to a maximum of 60 mcg prior to each meal
if tolerated and warranted. Snacks may or may not need to be covered with pramlintide (recommended if 250
kcal [1,046 kJ] or 30 g of carbohydrate is eaten). Storage information can be found in Table 57-8.
Sulfonylureas
40/88
7/1/2014
Pharmacology
The primary mechanism of action of sulfonylureas is enhancement of insulin secretion. Sulfonylureas bind to a
specific sulfonylurea receptor (SUR) on pancreatic cells. Binding closes an adenosine triphosphate
dependent K+ channel, leading to decreased potassium efflux and subsequent depolarization of the membrane.
Voltage-dependent Ca2+ channels open and allow an inward flux of Ca2+. Increases in intracellular Ca2+ bind to
calmodulin on insulin secretory granules, causing translocation of secretory granules of insulin to the cell
surface and resultant exocytosis of the granule of insulin. Elevated secretion of insulin from the pancreas
travels via the portal vein and subsequently suppresses hepatic glucose production.
Classification
Sulfonylureas are classified as first-generation and second-generation agents. The classification scheme is
largely derived from differences in relative potency, potential for selective side effects, and differences in
binding to serum proteins (i.e., risk for protein-binding displacement drug interactions). First-generation agents
consist of acetohexamide, chlorpropamide, tolazamide, and tolbutamide. Each of these agents is lower in
potency relative to the second-generation drugs: glimepiride, glipizide, and glyburide (Table 57-11). It is
important to recognize that all sulfonylureas are equally effective at lowering BG when administered in
equipotent doses.
Table 57-11 Oral Agents for the Treatment of Type 2 Diabetes Mellitus
Recom m ended Starting
Dosage
Drug Nam e a
Brand
Nam e
Usual/Maxim al
Other
Dose
Dose
Nonelderly
Elderly
Acetohexamide (Y) Dymelor
250, 500 mg
250 mg/day
125250
mg/day
1,500 mg/day
Metabolized in liver; metabolite potency

equal to parent compound; renally
eliminated
Chlorpropamide (Y) Diabinese
100, 250 mg
250 mg/day
100 mg/day
500 mg/day
Metabolized in liver; also excreted

unchanged renally
Tolazamide (Y)
Tolinase
100, 250, 500

mg
100250
mg/day
100 mg/day
1,000 mg/day
Metabolized in liver; metabolite less active

than parent compound; renally eliminated
Tolbutamide (Y)
Orinase
250, 500 mg
1,0002,000
mg/day
5001,000
mg/day
3,000 mg/day
Metabolized in liver to inactive metabolites

that are renally excreted
Glipizide (Y)
Glucotrol
5, 10 mg
5 mg/day
2.55 mg/day 40 mg/day
Glipizide (Y)
Glucotrol
XL
2.5, 5, 10, 20 mg 5 mg/day
Slow -release form; do not cut tablet
Glyburide (Y)
DiaBeta,
Micronase
1.25, 2.5, 5 mg
5 mg/day
1.252.5
mg/day
Metabolized in liver; elimination one half

renal, one half feces. tw o active
metabolites
Glyburide,
micronized (Y)
Glynase
1.5, 3, 6 mg
3 mg/day
Better absorption from micronized

preparation
Glimepiride (Y)
Amaryl
1, 2, 4 mg
12 mg/day
Nateglinide (Y)
Starlix
60, 120 mg
120 mg/day
w ith meals
120 mg/day
w ith meals
Metabolized by cytochrome P450 (CYP450)

2C9 and 3A4 to w eakly active metabolites;
renally eliminated
Repaglinide (N)
Prandin
0.05, 1, 2 mg
0.51 mg/day 0.51 mg/day 16 mg/day

w ith meals
w ith meals
Sulfonylureas
20 mg/day
Short-acting
insulin
secretagogues
120 mg three
times a day
Caution w ith gemfibrozil or trimethoprim

potential hypoglycemia
Biguanides
Metformin (Y)
Glucophage 500, 850, 1,000 500 mg tw ice Assess renal 2,550 mg/day
mg
a day
function
No metabolism; renally secreted and

excreted
Metformin ER (Y)
Glucophage 500, 750, 1,000 5001,000 mg Assess renal 2,550 mg/day

XR
mg
w ith evening function
meal
Take full dose w ith evening meal or may

split dose; may consider trial if intolerant to
immediate release
41/88
7/1/2014
Metformin solution Riomet
500 mg/5 mL
500 mg daily
Assess renal 2,000 mg/day

function
Metformin is indicated in children 10 years

old
Metabolized by CYP2C8 and 3A4; tw o
active metabolites have longer half-lives
than parent compound
Thiazolidinediones
Pioglitazone (Y)
Actos
15, 30, 45 mg
15 mg/day
15 mg/day
45 mg/day
Rosiglitazone (N)
Avandia
2, 4, 8 mg
24 mg/day
2 mg/day
8 mg/day or 4 Limited availability. Continuation of therapy

mg tw ice a day or unable to take pioglitazone.
Clinician/patient sign that know n risk of MI
Acarbose (Y)
Precose
25, 50, 100 mg
25 mg one to 25 mg one to
three times a three times a
day
day
25100 mg
three times a
day
Eliminated in bile. Slow titration key for

tolerability. With meals
Miglitol (N)
Glyset
25, 50, 100 mg
25 mg one to 25 mg one to
three times a three times a
day
day
25100 mg
three times a
day
Eliminated renally
-Glucosidase
inhibitors
Dipeptidyl peptidase-4 inhibitors (DPP-4

inhibitors)
Sitagliptin (N)
Januvia
100, 50, 25 mg
100 mg daily
25100 mg
100 mg daily
daily based on
renal function
50 mg daily if estimated creatinine

clearance >30 to <50 mL/min (>0.50 to
<0.83 mL/s); 25 mg if creatinine clearance
<30 mL/min (<0.50 mL/s)
Saxagliptin (N)
Onglyza
2.5, 5 mg
5 mg daily
2.55 mg daily 5 mg daily

based on
renal function
2.5 mg daily if creatinine clearance <50

mL/min (<0.83 mL/s) or if on strong
inhibitors of CYP3A4/5
Linagliptin (N)
Tradjenta
5 mg
5 mg daily
5 mg daily
5 mg daily
Not substantially eliminated by renal, found

in feces. Do not use w ith strong inducer of
CYP3A4/p-glycoprotein
Alogliptin (N)
Nesina
25, 12.5, 6.25

mg
25 mg daily
25 mg
25 mg
75% eliminated unchanged in urine. 12.5

mg CrCl <60 mL/min (<1 mL/s), 6.25 mg
<3015 mL/min (<0.500.25 mL/s)
Bile acid
sequestrants
Colesevelam (N)
Welchol
625-mg
6 tablets
6 tablets 3.75 g/day
tablet
daily or
daily or
three
three
tablets
tablets
tw ice a
tw ice a
day
day
1.875 g
1.875 g
tw ice a
tw ice a
day or
day or
3.75 g
3.75 g
daily
daily
1.875- and
3.75-g oral
suspension
Constipation may occur. Take w ith meal.

Drugdrug absorption interactions present,
may increase triglycerides; contraindicated
if TG>500 mg/dL (>5.65 mmol/L)
Dopamine agonist
Bromocriptine
mesylate (N)
Cycloset
0.8-mg tablets
1.64.8 mg
daily
1.64.8 mg
daily
4.8 mg daily
Take w ithin 2 hours of rising w ith food.

Significant nausea, other side effects, and
drugdrug, drugdisease interactions may
occur
aGeneric version available? Y, yes; N, no.
Pharmacokinetics
42/88
7/1/2014
All sulfonylureas are metabolized in the liver, some to active and others to inactive metabolites. Glyburide
metabolites are active, whereas glipizide and glimepiride do not have active metabolites. Cytochrome P450
(CYP450) 2C9 is involved with the hepatic metabolism of the majority of sulfonylureas. Agents with active
metabolites or parent drug that are renally excreted require dosage adjustment or use with caution in patients
with compromised renal function. The half-life of the sulfonylurea also relates directly to the risk for
hypoglycemia. The hypoglycemic potential is therefore higher with chlorpropamide and glyburide. The long
duration of effect of chlorpropamide may be particularly problematic in elderly individuals, whose renal function
declines with age, and therefore it has great potential for accumulation, resulting in severe and protracted
hypoglycemia. Individuals at high risk for hypoglycemia (e.g., elderly individuals and those with renal
insufficiency or advanced liver disease) should be started at a very low dose of a sulfonylurea with a short halflife. Hypoglycemia on low-dose sulfonylureas may dictate a therapy without the risk of hypoglycemia.
Efficacy
As mentioned earlier, when given in equipotent doses, all sulfonylureas are equally effective at lowering BG.
On average, HbA1c will fall 1.5% to 2% (0.015 to 0.020; 17 to 22 mmol/mol Hb) in drug-nave patients, with FPG
reductions of 60 to 70 mg/dL (3.3 to 3.9 mmol/L), but is dependent on baseline values and duration of
diabetes. A majority of patients will not reach glycemic goals with sulfonylurea monotherapy. Patients with
inadequate control on a sulfonylurea usually fall into two groups: those with low C-peptide levels and high
(>250 mg/dL [>13.9 mmol/L]) FPG levels. These patients are often primary failures on sulfonylureas (<30
mg/dL [<1.7 mmol/L] drop of FPG) and have significant glucose toxicity or LADA. The other group is those with
a good initial response (>30 mg/dL [>1.7 mmol/L] drop of FPG), but which is insufficient to reach their glycemic
goals. Over 75% of patients fall into the second group. Factors that portend a positive response include newly
diagnosed patients with no indicators of type 1 DM, high fasting C-peptide levels, and moderate fasting
hyperglycemia (<250 mg/dL [<13.9 mmol/L]).
Sulfonylureas showed a reduction of microvascular complications in type 2 DM patients in the UKPDS.24 A more
in-depth discussion follows later in the chapter.
The UKPDS reported no significant benefit or harm in newly diagnosed type 2 DM patients given sulfonylureas
over 10 years. The University Group Diabetes Program study documented higher rates of coronary artery
disease in type 2 patients given tolbutamide, when compared with patients given insulin or placebo, although
this study has been widely criticized.34 Some sulfonylureas bind to the SUR-2A receptor that is found in cardiac
tissue. Binding to the SUR-2A receptor has been implicated in blocking ischemic preconditioning via K+ channel
closure in the heart. Ischemic preconditioning is the premise that prior ischemia in cardiac tissue can provide
greater tolerance of subsequent ischemia. Thus, patients with heart disease potentially have one
compensatory mechanism to protect the heart from ischemia blocked. Conclusions are controversial, but
alternative treatments are available if questioned.
Adverse Effects
The most common side effect of sulfonylureas is hypoglycemia. The pretreatment FPG is a strong predictor of
hypoglycemic potential. The lower the FPG is on initiation, the higher the potential for hypoglycemia. Also, in
addition to the high-risk individuals outlined in Pharmacokinetics below, those who skip meals, exercise
vigorously, or lose substantial amounts of weight are also more likely to experience hypoglycemia.
Hyponatremia (serum sodium <129 mEq/L [129 mmol/L]) is reportedly associated with tolbutamide, but it is most
common with chlorpropamide and occurs in as many as 5% of individuals treated. An increase in antidiuretic
43/88
7/1/2014
hormone secretion is the mechanism for hyponatremia. Risk factors include age >60 years, female gender, and
concomitant use of thiazide diuretics.
Weight gain is common with sulfonylureas. In essence, patients who are no longer glycosuric and who do not
reduce caloric intake with improvement of BG will store excess calories. Other notable, although much less
common, adverse effects of sulfonylureas are skin rash, hemolytic anemia, GI upset, and cholestasis.
Disulfiram-type reactions and flushing have been reported with tolbutamide and chlorpropamide when alcohol
is consumed.
Drug Interactions
Several drugs are thought to interact with sulfonylureas, most likely through the CYP450 system or altered
renal excretion. Protein-binding changes should occur shortly after the interacting medication is given, as the
concentration of free (thus active) sulfonylurea will acutely increase. First-generation sulfonylureas, which bind
to proteins ionically, are more likely to cause drugdrug interactions than second-generation sulfonylureas,
which bind nonionically. The clinical importance of protein-binding interactions has been questioned, as the
majority of these drug interactions have been found to be truly due to hepatic metabolism. Drugs that are
inducers or inhibitors of CYP450 2C9 should be monitored carefully when used with a sulfonylurea.35
Additionally, other drugs known to alter BG should be considered (Table 57-10).
The usual starting dose and maximum dose of sulfonylureas are summarized in Table 57-11. Lower dosages
are recommended for most agents in elderly patients and those with compromised renal or hepatic function.
The dosage can be titrated as soon as every 2 weeks based on FPG values (use a longer interval with
chlorpropamide) to achieve glycemic goals. This is possible due to the rapid increase of insulin secretion in
response to the sulfonylurea. Of note, immediate-release glipizides maximal dose is 40 mg/day, but its maximal
effective dose is about 10 to 15 mg/day. The maximal effective dose of sulfonylureas tends to be about 60% to
75% of their stated maximum dose.
Short-Acting Insulin Secretagogues
Pharmacology
Although the binding site is adjacent to the binding site of sulfonylureas, nateglinide and repaglinide stimulate
insulin secretion from the cells of the pancreas, similarly to sulfonylureas. Both repaglinide (a benzoic acid
derivative) and nateglinide (a phenylalanine amino acid derivative) require the presence of glucose to stimulate
insulin secretion. As glucose levels diminish to normal, stimulated insulin secretion diminishes.
Pharmacokinetics
Both nateglinide and repaglinide are rapid-acting insulin secretagogues that are rapidly absorbed (0.5 to 1
hour) and have a short half-life (1 to 1.5 hours). Nateglinide is highly protein bound, primarily to albumin, but
also to 1-acid glycoprotein. It is predominantly metabolized by CYP2C9 (70%) and CYP3A4 (30%) to less
active metabolites. Glucuronide conjugation then allows rapid renal elimination. No dosage adjustment is
needed in moderate to severe renal insufficiency. Repaglinide is highly protein bound, and is mainly
metabolized by oxidative metabolism and glucuronidation. The CYP3A4 and 2C8 systems have been shown to
be involved with metabolism. Approximately 90% of repaglinide is eliminated in the feces, with only 10% found
in the urine. Moderate to severe renal insufficiency does not appear to affect repaglinide, but moderate to
severe hepatic impairment may prolong exposure.
Efficacy
In monotherapy, both significantly reduce postprandial glucose excursions and reduce HbA1c levels.
44/88
7/1/2014
Repaglinide, dosed 4 mg three times a day, when compared with glyburide in diet-treated, drug-nave patients
reduced HbA1c levels less (1% vs. 2.4% [0.01 vs. 0.024; 11 mmol/mol Hb vs. 26 mmol/mol Hb], from baseline,
respectively). Nateglinide, dosed 120 mg three times a day, in a similar population reduced HbA1c values by
0.8% (0.008; 9 mmol/mol Hb). The lower efficacy of these agents versus sulfonylureas should be considered
when patients are >1% (>0.01; >11 mmol/mol Hb) above their HbA1c goal. These agents can be used to
provide increased insulin secretion during meals, when it is needed, in patients close to glycemic goals. Also, it
should be noted that addition of either agent to a sulfonylurea will not result in any improvement in glycemic
parameters.
Adverse Effects
Hypoglycemia is the main side effect noted with both agents. Hypoglycemic risk appears to be less versus
sulfonylureas. In part, this is due to the glucose-sensitive release of insulin. If the glucose concentration is
normal, less glucose-stimulated release of insulin will occur. In two separate studies, nateglinide rates of
hypoglycemia were 3% and repaglinide 15% versus glyburide and glipizide rates of 15% and 19%, respectively.
Weight gain of 2 to 3 kg has been noted with repaglinide, whereas weight gain with nateglinide appears to be
<1 kg.
Drug Interactions
Glycemic control and hypoglycemia should be closely monitored when glucuronidation inhibitors are given with
repaglinide. Gemfibrozil more than doubles the half-life of repaglinide and has resulted in prolonged
hypoglycemic reactions. It is a potent glucuronidation inhibitor and CYP2C8 inhibitor. Trimethoprim, a CYP2C8
inhibitor, increased repaglinide levels by 60%. Nateglinide appears to be a weak inhibitor of CYP2C9 based on
tolbutamide metabolism. Although no significant drugdrug interactions have been reported, caution should be
used with strong CYP2C9 and CYP3A4 inhibitors.
Nateglinide and repaglinide should be dosed prior to each meal (up to 30 minutes prior). The recommended
starting dose for repaglinide is 0.5 mg in subjects with HbA1c <8% (<0.08; <64 mmol/mol Hb) or treatment-nave
patients, increased weekly to a total maximum daily dose of 16 mg (see Table 57-11). The maximal effective
dose of repaglinide is likely 2 mg with each meal, as a dose of 1 mg prior to each meal provides approximately
90% of the maximal glucose-lowering effect. Nateglinide should be dosed at 120 mg prior to meals, and does
not require titration. A 60-mg dose is available, but the HbA1c decrement is small (0.3% to 0.5% [0.003 to
0.005; 3 to 6 mmol/mol Hb]). If a meal is skipped, the medication can be skipped, and meals extremely low in
carbohydrate content may not need a dose. Both agents may be used in patients with renal insufficiency, and
may fit into therapy in patients in need of an insulin secretagogue but having hypoglycemia to sulfonylureas,
moderate to severe renal insufficiency, and well-controlled diabetes, but with erratic meal schedules.
Biguanides
Pharmacology
Metformin is the only biguanide available in the United States. It has been used clinically for more than 50
years, and has been approved in the United States since 1995. Metformin enhances insulin sensitivity of mainly
hepatic but also peripheral (muscle) tissues. This allows for an increased uptake of glucose into these insulinsensitive tissues. All the mechanisms of how metformin accomplishes glucose reduction are still being
investigated, although adenosine 5-monophosphateactivated protein kinase activity, tyrosine kinase activity
enhancement, increased adenosine 5-monophosphate, and partial inhibition of the mitochondrial respiratory
chain are involved. Metformin has no direct effect on the cells, although insulin levels are reduced, reflecting
increases in insulin sensitivity.
45/88
7/1/2014
Pharmacokinetics
Metformin has approximately 50% to 60% oral bioavailability, low lipid solubility, and a volume of distribution
that approximates body water. It is not metabolized and does not bind to plasma proteins. Metformin is
eliminated by renal tubular secretion and glomerular filtration. The average plasma half-life of metformin is 6
hours, although pharmacodynamically, metformins antihyperglycemic effects last more than 24 hours. Red
blood cells are a second compartment of distribution for metformin, delivering an effective half-life of 17 hours.
Efficacy
Metformin consistently reduces HbA1c levels by 1.5% to 2% (0.015 to 0.020; 17 to 22 mmol/mol Hb) and FPG
levels by 60 to 80 mg/dL (3.3 to 4.4 mmol/L) in drug-nave patients, and retains the ability to reduce FPG levels
when they are extremely high (>300 mg/dL [>16.7 mmol/L]). The sulfonylureas ability to stimulate insulin
release from cells at extremely high glucose levels is often impaired, a concept commonly referred to as
glucose toxicity. Metformin also has positive effects on several components of the insulin resistance syndrome.
It decreases plasma triglycerides and LDL-C by approximately 8% to 15%, in addition to increasing HDL-C very
modestly (2%). Metformin reduces levels of PAI-1 and causes a modest reduction in weight (2 to 3 kg). In
preliminary findings, metformin may also lower the risk of pancreatic, colon, and breast cancer in type 2 DM
patients. Metformin, potentially through multiple mechanisms including adenosine 5-monophosphateactivated
protein kinase activity, may act as a growth inhibitor in some cancers and help to kill cancer stem cells which
are resistant to chemotherapy, and liver kinase B1, which is an upstream kinase of adenosine 5monophosphateactivated protein kinase. More controlled studies are needed.
Metformin (n = 342) was compared with intensive glucose control with insulin or sulfonylureas in the UKPDS. No
significant differences were seen between therapies with regard to reducing microvascular complications, but
the power of the study is questionable.36
Metformin reduced macrovascular complications in obese subjects in the UKPDS.36 It significantly reduced allcause mortality and risk of stroke versus intensive treatment with sulfonylureas or insulin. Metformin also
reduced diabetes-related death and MIs versus the conventional treatment arm of the UKPDS. It should be
noted that the UKPDS had very few people on lipid-lowering therapy, antihypertensives, or aspirin. Metformin is
logical in overweight/obese patients, if tolerated and not contraindicated, as it is the only oral antihyperglycemic
medication potentially proven to reduce the risk of total mortality and is generic.
Adverse Effects
Metformin causes GI side effects, including abdominal discomfort, stomach upset, and/or diarrhea, in
approximately 30% of patients. Anorexia and stomach fullness is likely part of the reason loss of weight is noted
with metformin. These side effects are usually mild and can be minimized by slow titration. GI side effects also
tend to be transient, lessening in severity over several weeks. If encountered, make sure patients are taking
metformin with or right after meals, and reduce the dose to a point at which no GI side effects are encountered.
Increases in the dose may be tried again in several weeks. Anecdotally, extended-release metformin
(Glucophage XR) may lessen some of the GI side effects. Metallic taste, interference with vitamin B12
absorption, and hypoglycemia during intense exercise have been documented, but are clinically uncommon.
Metformin therapy rarely (3 to 9 cases per 100,000 patient-years) causes lactic acidosis. Metformin partially
blocks the mitochondrial respiratory chain. In addition, any disease state that may increase lactic acid
production or decrease lactic acid removal may predispose to lactic acidosis. Tissue hypoperfusion, such as
that due to congestive heart failure, severe lung disease, hypoxic states, shock, or septicemia, via increased
46/88
7/1/2014
production of lactic acid, and severe liver disease or alcohol, via reduced removal of lactic acid in the liver, all
increase the risk of lactic acidosis. The clinical presentation of lactic acidosis is often nonspecific flu-like
symptoms; thus, the diagnosis is usually made by laboratory confirmation of high lactic acid levels and acidosis.
Metformin use in renal insufficiency, defined as a serum creatinine of 1.4 mg/dL (124 mol/L) in women and 1.5
mg/dL (133 mol/L) in men or greater, is contraindicated, as it is renally eliminated. Elderly patients, who often
have reduced muscle mass, should have their glomerular filtration rate estimated by a 24-hour urine creatinine
collection. If the estimated glomerular filtration rate is less than 60 mL/min (1 mL/s), metformin use should be
carefully evaluated. Recent evidence has reported that metformin may be fairly safe in moderate renal
insufficiency. Metformin use can be modified based on the estimated glomerular filtration rate, at <60, <45 to
30, and <30 mL/min/1.73 m2 (<0.58, <0.43 to 0.29, and <0.29 mL/s/m2); corresponding actions are to
monitor renal function every 3 to 6 months, then limit dose to 50% of maximal dose, and then stop metformin,
respectively. Due to the risk of acute renal failure during IV dye procedures, metformin therapy should be
withheld starting the day of the procedure and resumed in 2 to 3 days, after normal renal function has been
documented.
Drug Interactions
Cimetidine competes for renal tubular secretion of metformin and concomitant administration leads to higher
metformin serum concentrations. At least one case report of lactic acidosis with metformin therapy implicates
cimetidine. Theoretically other cationic drugs may interact, but none have been reported to date.
Immediate-release metformin is usually dosed 500 mg twice a day with the largest meals to minimize GI side
effects. Metformin may be increased by 500 mg as tolerated until glycemic goals or 2,500 mg/day is achieved
(see Table 57-11). Metformin 850 mg may be dosed daily, and then increased every 1 to 2 weeks to the
maximum dose of 850 mg three times a day (2,550 mg/day). Approximately 80% of the glycemic-lowering effect
may be seen at 1,500 mg, and 2,000 mg/day is the maximal effective dose.
Extended-release metformin can be initiated at 500 mg a day with the evening meal and titrated by 500 mg as
tolerated to a single evening dose of 2,000 mg/day. Extended-release metformin 750-mg tablets may be
titrated as tolerated to the maximum dose of 2,250 mg/day, although, as stated above, 1,500 mg/day provides
the majority of the glycemic-lowering effect. Twice-daily to three-times-a-day dosing of extended-release
metformin may help to minimize GI side effects and improve glycemic control, but will not change the glycemic
reduction.
Thiazolidinediones
Pharmacology
TZDs are also referred to as glitazones. Pioglitazone (Actos) and rosiglitazone (Avandia) are the two currently
approved TZDs for the treatment of type 2 DM (see Table 57-11). TZDs work by binding to the PPAR-, which
are primarily located on fat cells and vascular cells. The concentration of these receptors in the muscle is very
low, but improvement in mitochondrial function through changes in lipotoxicity, glucotoxicity, and possibly
binding of proteins outside the mitochondrial membrane may occur. TZDs enhance insulin sensitivity at muscle,
liver, and fat tissues indirectly. They cause preadipocytes to differentiate into mature fat cells in subcutaneous
fat stores. Small fat cells are more sensitive to insulin and more able to store FFAs. The result is a flux of FFAs
out of the plasma, visceral fat, and liver into subcutaneous fat, a less insulin-resistant storage tissue. Muscle
intracellular fat products, which contribute to insulin resistance, also decline. TZDs also affect adipokines (e.g.,
angiotensinogen, tissue necrosis factor-, interleukin 6, PAI-1), which can positively affect insulin sensitivity,
endothelial function, and inflammation. Of particular note, adiponectin is reduced with obesity and/or diabetes,
but is increased with TZD therapy, which improves endothelial function and insulin sensitivity, and has a potent
47/88
7/1/2014
antiinflammatory effect. Lastly, TZDs appear to improve mitochondrial function through a reduction in FFAs.
Cyclin-dependent kinase 5 has also recently been purposed as an important activator of PPAR-.
Pharmacokinetics
Pioglitazone and rosiglitazone are well absorbed with or without food. Both are highly (>99%) bound to albumin.
Pioglitazone is primarily metabolized by CYP2C8, to a lesser extent by CYP3A4 (17%), and by
hydroxylation/oxidation. The majority of pioglitazone is eliminated in the feces with 15% to 30% appearing in
urine as metabolites. Two active metabolites (M-III and M-IV) are present. Rosiglitazone is metabolized by
CYP2C8, and to a lesser extent by CYP2C9, and also by N-demethylation and hydroxylation. Two thirds is
found in urine and one third in feces. The half-lives of pioglitazone and rosiglitazone are 3 to 7 and 3 to 4
hours, respectively. The two active metabolites of pioglitazone, with longer half-lives, deliver the majority of
activity at steady state. Pioglitazone requires no dosage adjustment in moderate to severe renal disease for
pharmacokinetic reasons. Interestingly, with pioglitazone the AUC in women is 20% to 60% higher, which is not
seen with rosiglitazone, but no dosage adjustment is recommended. Both medications have a duration of
antihyperglycemic action of over 24 hours.
Efficacy
Pioglitazone and rosiglitazone reduce HbA1c values 1% to 1.5% (0.010 to 0.015; 11 to 17 mmol/mol Hb) and
reduce FPG levels by 60 to 70 mg/dL (3.3 to 3.9 mmol/L) at maximal doses. Glycemic-lowering onset is slow,
and maximal glycemic-lowering effects may not be seen until 3 to 4 months of therapy. It is important to inform
patients of this fact and that they should not stop therapy even if minimal glucose lowering is initially
encountered. The efficacy of both drugs is dependent on sufficient insulinemia. If there is insufficient
endogenous insulin production (-cell function) or exogenous insulin delivery via injections, neither will lower
glucose concentrations efficiently. Interestingly, patients who are more obese or who gain weight on either
medication tend to have a larger reduction in HbA1c values. Pioglitazone consistently decreases plasma
triglyceride levels by 10% to 20%, whereas rosiglitazone tends to have a neutral effect. LDL-C concentrations
tend to increase with rosiglitazone 5% to 15%, but do not significantly increase with pioglitazone. Both appear
to convert small, dense LDL particles, which have been shown to be highly atherogenic, to large, fluffy LDL
particles that are less dense. Large, fluffy LDL particles may be less atherogenic, but any increase in LDL must
be of concern. Both drugs increase HDL, although pioglitazone may raise it more than rosiglitazone. TZDs also
affect several components of the insulin resistance syndrome. PAI-1 levels are decreased, and many other
adipocytokines are affected, endothelial function improves, and blood pressure may decrease slightly.
TZDs reduce HbA1c levels, which have been shown to be related to the risk of microvascular complications.
Macrovascular complications with TZDs are controversial. In PROactive, the prospective pioglitazone clinical
trial in macrovascular events, pioglitazone 45 mg was added to standard therapy in patients who had
experienced a macrovascular event or had peripheral vascular disease.37 The two groups were well matched at
baseline and the reported average observation time period was about 3 years. The primary end point
(reduction in death, MI, stroke, acute coronary syndrome, coronary revascularization, leg amputation, and leg
revascularization) was reduced 10% (P = 0.095). The main secondary end point (all-cause mortality, nonfatal
MI, or stroke) was reduced 16% (P = 0.027). The seemingly dichotomous results relate to the inclusion of leg
revascularization as a primary end point, which were increased in the pioglitazone group. Reasons for the
increase are speculative, but may relate to more testing/inspection due to peripheral edema. Also of note, the
pioglitazone group had 209 nonadjudicated admissions for heart failure occur versus 153 in the placebo group
(P = 0.007), although fatal heart failure was not increased. Several published meta-analyses of rosiglitazone
48/88
7/1/2014
reported higher MI rates with rosiglitazone, but none have reported a higher risk of mortality. A hazard ratio
(HR) of 1.43 (95% confidence interval [CI], 1.03 to 1.98; P = 0.03) for the risk of an MI with rosiglitazone versus
other oral agents was reported.38
A prospective, multicenter, open-label noninferiority trial in 4,447 patients of rosiglitazone added to background
metformin or sulfonylurea versus the active comparator metformin + sulfonylurea was recently reported
(Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes
[RECORD]). Rosiglitazone was noninferior to the comparator for all CV outcomes except for heart failure. A
nonsignificant increase in risk for MI (HR, 1.14; 95% CI, 0.80 to 1.63) as well as a nonsignificant reduction in
stroke (HR, 0.72; 95% CI, 0.49 to 1.05) was reported. On subset analysis, previous ischemic heart disease
trended toward a higher risk (HR, 1.26; CI, 0.95 to 1.68; P = 0.055).39 Most studies with rosiglitazone trend
toward, but do not reach, statistically significant increases in ischemic events. The FDA has placed
rosiglitazone under a strict risk evaluation and mitigation program, limiting access to patients and prescribers
who acknowledge and consent to knowing its macrovascular risks.
Adverse Effects
Troglitazone, the first TZD approved, caused idiosyncratic hepatotoxicity and had deaths from liver failure,
which prompted removal from the U.S. market. Newer TZDs do not have the same propensity, but have had
postmarketing reports of liver injury. Patients with abnormal alanine aminotransferase (ALT) levels should be
started with caution, and if the ALT is >3 times the upper limit of normal, especially if the total bilirubin is also >2
times the upper limit of normal, the medication should be discontinued. Pioglitazone has been shown in one
well-designed trial to reduce hepatic steatosis, which may improve abnormal ALT levels in many patients with
diabetes.
Retention of fluid leads to many different possible side effects with TZDs. The etiology of the fluid retention has
not been fully elucidated, but appears to include peripheral vasodilation and/or improved insulin sensitization at
the kidney with a resultant increase in renal sodium and water retention. A reduction in plasma hemoglobin (2%
to 4%), attributed to a 10% increase in plasma volume, may result in a dilutional anemia that does not require
treatment. Peripheral edema is also commonly (4% to 5% in monotherapy or combination therapy) reported.
When a TZD is used in combination with insulin, the incidence of edema (15%) is increased. TZDs are
contraindicated in patients with New York Heart Association Class III and IV heart failure, and great caution
should be exercised when given to patients with Class I and II heart failure or other underlying cardiac disease,
as pulmonary edema and heart failure have been reported. Edema tends to be dose related and if not severe,
a reduction in the dose as well as use of diuretics, anecdotally hydrochlorothiazide with triamterene, amiloride,
or spironolactone instead of loop diuretics, will allow the continuation of therapy in the majority of patients.
Rarely, TZDs have been reported to worsen macular edema of the eye.
Weight gain, which is also dose related, can be seen with both rosiglitazone and pioglitazone. Mechanistically,
both fluid retention and fat accumulation play a part in explaining the weight gain. TZDs, besides stimulating fat
cell differentiation, also reduce leptin levels, which stimulate appetite and food intake. Average weight gain
varies, but a 1.5- to 4-kg weight gain is not uncommon. Rarely, a patient will gain large amounts of weight in a
short period of time, and this may necessitate discontinuation of therapy. Weight gain positively predicts a
larger HbA1c reduction, but must be balanced with the well-documented effects of long-term weight gain.
TZDs have also been associated with an increased fracture rate in the upper and lower limbs in women and
men, although women appear to have a higher risk. These fractures are not osteoporitic in the classic sense,
and do not occur in common osteoporosis fracture sites such as spine or hip. Most occur in wrists, forearms,
ankles, or feet. Versus comparative diabetes therapy, TZDs may increase the risk of a fracture by 25%. The
underlying pathophysiology is speculative, but may relate to TZD effects on the pluripotent stem cell and
shunting of new cells to fat instead of osteocytes as well as altering osteoblasts/osteoclasts. It would be prudent
49/88
7/1/2014
to consider a patients risk factors for fractures if a TZD is being considered as antidiabetic therapy.
The risk of bladder cancer is slightly increased with pioglitazone, and likely rosiglitazone. Bladder tumors have
been noted in rodent models using TZDs. An ongoing 10-year observational study reported an excess of 3 in
10,000 patient-years (from 7 to 10 in 10,000) risk of bladder cancer with pioglitazone at 5 years. Excess risk
appears to be mostly in men and smokers, and is dose and duration associated. Mechanisms are speculative,
but may involve microcrystals of the drug in the bladder that cause chronic irritation.
As a caution, premenopausal anovulatory patients may resume ovulation on TZDs. Adequate pregnancy and
contraception precautions should be explained to all women capable of becoming pregnant, as both agents are
pregnancy category C.
Drug Interactions
Significant drug interactions that can cause clinical sequelae have not been noted with either medication.
Neither pioglitazone nor rosiglitazone appears to be an inhibitor or inducer of CYP3A4/2C8 or
CYP2C8/CYP2C9, respectively, although drugs that are strong inhibitors or inducers of these pathways (e.g.,
gemfibrozil or rifampin) may increase or decrease levels of active drug significantly. The package insert
recommends limiting the dose of pioglitazone to 15 mg in combination with gemfibrozil.
The recommended starting dosages of pioglitazone and of rosiglitazone are 15 to 30 mg once daily and 2 to 4
mg once daily, respectively. Dosages may be increased slowly based on therapeutic goals and side effects.
The maximum dose and maximum effective dose of pioglitazone is 45 mg, and rosiglitazone is 8 mg once daily,
although 4 mg twice a day may reduce HbA1c by 0.2% to 0.3% (0.002 to 0.003; 2 to 3 mmol/mol Hb) more
versus 8 mg once daily.
Rosiglitazones availability is limited for now, and an active risk evaluation and mitigation program has been
implemented due to the risk of ischemic events. Patients and prescribers must sign up through the rosiglitazone
website in order to receive the medication from a central mail-order pharmacy, as local pharmacies no longer
carry rosiglitazone. Patients and prescribers must agree either that it is continuation of therapy and the risks
versus benefits are known to both or that it is a new prescription and that the patient has been fully informed of
the risk, including MI, and of the alternatives available, including pioglitazone. Pioglitazone is not included in this
particular risk evaluation and mitigation program.
-Glucosidase Inhibitors
Pharmacology
Currently, there are two -glucosidase inhibitors available in the United States: acarbose (Precose) and miglitol
(Glyset). -Glucosidase inhibitors competitively inhibit enzymes (maltase, isomaltase, sucrase, and
glucoamylase) in the small intestine, delaying the breakdown of sucrose and complex carbohydrates. They do
not cause any malabsorption of these nutrients. The net effect from this action is to reduce the postprandial BG
rise. GLP-1 may also be increased. Distal intestinal degradation of undigested carbohydrate by the gut flora
results in gas (CO2 and methane) and production of short-chain fatty acids, which may stimulate GLP-1 release
from intestinal L cells.
Pharmacokinetics
The mechanism of action of -glucosidase inhibitors is limited to the luminal side of the intestine. Some
metabolites of acarbose are systemically absorbed and renally excreted, whereas the majority of miglitol is
absorbed and renally excreted unchanged.
Efficacy
50/88
7/1/2014
Postprandial glucose concentrations are reduced (40 to 50 mg/dL [2.2 to 2.8 mmol/L]), while fasting glucose
levels are relatively unchanged (10% reduction). Efficacy on glycemic control is modest (average reductions in
HbA1c of 0.3% to 1% [0.003 to 0.010; 3 to 11 mmol/mol Hb]), affecting primarily postprandial glycemic
excursions. Thus, patients near target HbA1c levels with near-normal FPG levels, but high postprandial levels,
may be candidates for therapy.
-Glucosidase inhibitors modestly reduce HbA1c levels, which has been shown to be related to the risk of
microvascular complications.
The STOP-NIDDM study, in subjects with IGT, reported a significant reduction in the risk of cardiovascular
events, although the total number of events was very small.40,41 No large cardiovascular study confirming these
preliminary results has been done in prediabetes or diabetes patients.
Adverse Effects
The GI side effects, such as flatulence, bloating, abdominal discomfort, and diarrhea, are very common and
greatly limit the use of -glucosidase inhibitors. Mechanistically, these side effects are caused by distal
intestinal degradation of undigested carbohydrate by the microflora, which results in gas (CO2 and methane)
production. Microflora convert the carbohydrate to short-chain fatty acids that are mostly absorbed; thus, there
is not a large calorie loss. -Glucosidase inhibitors should be initiated at a low dose and titrated slowly to
reduce GI intolerance. Beano, an -glucosidase enzyme, may help to decrease GI side effects, but may
decrease efficacy slightly, and it is better to decrease carbohydrate or the dose of the -glucosidase inhibitor.
If a patient develops hypoglycemia within several hours of ingesting an -glucosidase inhibitor, oral glucose is
advised because the drug will inhibit the breakdown of more complex sugar molecules. Milk, with lactose sugar,
may be used as an alternative when no glucose is available, as acarbose only slightly (10%) inhibits lactase.
Fructose may also work, if the others are not available.
Rarely, elevated serum aminotransferase levels have been reported with the highest doses of acarbose. It
appeared to be dose and weight related, and is the premise for the weight-based maximum doses.
Dosing for both miglitol and acarbose are similar. Initiate with a very low dose (25 mg with one meal a day);
increase very gradually (over several months) to a maximum of 50 mg three times a day for patients 60 kg or
100 mg three times a day for patients >60 kg (see Table 57-11). Titration speed should be varied based on GI
side effects to the target dose. Both -glucosidase inhibitors should be taken with the first bite of the meal so
that drug may be present to inhibit enzyme activity. Only patients consuming a diet high in complex
carbohydrates will have significant reductions in glucose levels. -Glucosidase inhibitors are contraindicated in
patients with short-bowel syndrome or inflammatory bowel disease, and neither should be administered in
patients with serum creatinine >2 mg/dL (>177 mol/L), as this population has not been studied.
Dipeptidyl Peptidase-4 Inhibitors
Sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina) are DPP-4 inhibitors
currently approved in the United States.
Pharmacology
DPP-4 inhibitors prolong the half-life of endogenously produced GLP-1 and GIP that normally is only minutes.
GIP levels are normal in type 2 DM, and may contribute a minor amount of insulin secretion but have no effect
51/88
7/1/2014
on glucagon. However, levels of GLP-1 are deficient in type 2 DM. As these agents block nearly 100% of the
DPP-4 enzyme activity for at least 12 hours, normal physiologic, nondiabetic GLP-1 levels are achieved. DPP-4
inhibitors significantly reduce the inappropriately elevated glucagon postprandially, although not back to
nondiabetic levels, and improve insulin response to hyperglycemia. This results in reduction of glucose levels
without increase in hypoglycemia when used as monotherapy. These drugs do not alter gastric emptying and
do not have significant satiety effects. DPP-4 inhibitors also appear to be weight neutral.
Pharmacokinetics
Sitagliptin has rapid absorption, with a tmax of approximately 1.5 hours. Absolute bioavailability after oral intake
is approximately 87%. Only 40% is bound to plasma proteins; the volume of distribution is approximately 200 L.
The t1/2 of sitagliptin is approximately 12 hours. Seventy-nine percent of the dose of sitagliptin is excreted
unchanged in the urine by active tubular secretion; however, the organic anion transporter 3 or p-glycoprotein
transport may be involved as well. Sitagliptin exposure is increased by approximately 2.3-, 3.8-, and 4.5-fold
relative to healthy subjects for patients with moderate renal insufficiency (creatinine clearance [CLcr] 30 to <50
mL/min [0.50 to <0.83 mL/s]), severe renal insufficiency (CLcr <30 mL/min [<0.50 mL/s]), and ESRD (on
dialysis), respectively. This is not a safety or adverse reaction issue; however, reduction of the dose based on
renal function is appropriate, as only 100% of the enzyme can be inhibited, and long-term exposure to higher
levels in humans has not been extensively studied. Pharmacodynamically, DPP-4 inhibition appeared to mirror
directly the plasma concentration of sitagliptin. Doses of 50 mg produce at least 80% inhibition of DPP-4
enzyme activity at 12 hours, and those of 100 mg produce 80% inhibition of DPP-4 enzyme activity at 24 hours.
Food has no effect on absorption kinetics of sitagliptin. Hepatic impairment, age, gender, or race has no effect
on the pharmacokinetics of sitagliptin.
When saxagliptin is administered with a high-fat meal, the tmax increases about 20 minutes and the AUC
increases about 27%. However, this is not clinically significant and saxagliptin may be given with or without
meals. The oral bioavailability of saxagliptin is approximately 67%. Distribution is similar to the body water
compartment. There is negligible protein binding, and one active metabolite, 5-hydroxy saxagliptin, is half as
potent a DPP-4 inhibitor as the parent compound, and contributes to activity. Metabolism is by the CYP3A4/5
system, and strong inhibitors or inducers will have an effect on activity. The half-lives of saxagliptin and its
active metabolite are 2.5 and 3.1 hours, respectively. Approximately 25% of the dose is found in feces
representing unabsorbed drug and bile excretion. Females have 25% more exposure to 5-hydroxy saxagliptin,
and exposure is increased 25% to 50% in elderly, likely due to renal clearance. The majority (75%) of
saxagliptin and 5-hydroxy saxagliptin is renally eliminated, and some renal excretion is seen. In moderate (CLcr
30 to 50 mL/min [0.50 to 0.83 mL/s]) or severe (CLcr <30 mL/min [<0.50 mL/s]) renal impairment, saxagliptin
and its active metabolite exposure are increased 2.1- and 4.5-fold, respectively.
The peak plasma concentrations of linagliptin occur at approximately 1.5 hours after oral administration of a
single 5-mg dose to healthy subjects. The half-life of linagliptin is approximately 12 hours. The absolute
bioavailability of linagliptin is approximately 30%. A high-fat meal reduces Cmax by 15% and increases AUC by
4%. However, this effect is not clinically relevant and linagliptin may be taken with or without food. Linagliptin
distributes extensively in tissues and at high concentrations. Seventy percent to 80% is bound to plasma
proteins while 20% to 30% is unbound in plasma. Plasma binding is not altered in patients who have renal or
hepatic impairment. Following oral administration, metabolism is minimal and about 90% of linagliptin is
excreted unchanged. Renal excretion is less than 5% of the administered dose and is not affected by
decreased renal function.
Alogliptin has a bioavailability of approximately 100% and can be administered with or without food. It is only
20% bound to plasma proteins and approximately 75% of the dose is found unchanged in the urine. Less than
52/88
7/1/2014
1% is metabolized to an active metabolite, and <6% to an inactive metabolite.

Efficacy
The average reduction in HbA1c is approximately 0.7% to 1% (0.007 to 0.010; 8 to 11 mmol/mol Hb) at
maximum dose. The decrease in HbA1c at different baseline values is very small. As these drugs are well
tolerated, adjustment in the dose due to adverse effects is unlikely. They tend to have a shallow dose
response curve.
Microvascular and Macrovascular Complications
HbA1c levels are reduced, which has been related to a reduction in microvascular complications, but no
outcome data are available to date.
Significant drugdrug interactions with sitagliptin are unlikely. Sitagliptin is metabolized approximately 20% by
CYP450 3A4 with some CYP450 2C8 involvement, but is neither an inhibitor nor an inducer of any CYP450
enzyme system. It is a p-glycoprotein substrate, but had negligible effects on digoxin and cyclosporine A,
increasing the AUC by only 30%.
Saxagliptin is metabolized by CYP3A4/5, and is a p-glycoprotein substrate, but is neither an inhibitor nor an
inducer. Rifampin, an inducer, can decrease active levels by 50%. However, moderate to strong inhibitors or
inducers of CYP3A4/5, such as diltiazem or ketoconazole, can increase the AUC of saxagliptin by approximately
twofold, with a corresponding decrease in the formation of the active metabolite 5-hydroxy saxagliptin. In such
situations, it is recommended that the dose of saxagliptin be limited to 2.5 mg daily.
Linagliptin is a weak to moderate inhibitor of CYP3A4, and a p-glycoprotein substrate. Thus, efficacy of
linagliptin may be reduced when administered in combination with inducers of p-glycoprotein and CYP3A4 (e.g.,
with rifampin). If patients require the use of such drugs, the use of alternative treatments is recommended. No
other significant drug interactions have been reported.
No significant drugdrug interactions with alogliptin have been noted to date.
Adverse Effects
DPP-4 inhibitors are very well tolerated, are weight neutral, and do not cause GI side effects. Mild
hypoglycemia may occur, but in monotherapy or in combination with medications that have a low incidence of
hypoglycemia, DPP-4 inhibitors do not increase the risk of hypoglycemia. Headache and nasopharyngitis,
potentially related to the drug, may be slightly more common with DPP-4 inhibitors, but no significant increases
in peripheral edema, hypertension, or cardiac outcomes have been noted to date.
Urticaria and/or facial edema may be seen in approximately 1% of patients, and discontinuation is warranted.
Rare cases of Stevens-Johnson syndrome have been reported.
In regard to long-term safety, DPP-4 enzymes metabolize a wide variety of peptides (PYY, neuropeptide Y,
growth hormonereleasing hormone, vasoactive intestinal polypeptide, and others), potentially affecting other
regulatory systems. DPP-4 (also known as CD26) plays an important role for T-cell activation. Theoretically the
inhibition of DPP-4 could be associated with adverse immunologic reactions. Saxagliptin results in a doserelated reduction in absolute lymphocyte count in up to 0.5% to 1.5% of patients. In most, recurrence is not
observed with reexposure. However, it may recur with rechallenge in some patients. The clinical relevance is
not known, but if prolonged infection is encountered, it is logical to measure lymphocyte counts and consider
discontinuation.
53/88
7/1/2014
Sitagliptin is dosed orally at 100 mg daily unless renal insufficiency is present. The 50-mg dose is
recommended if the CLcr is 30 to <50 mL/min (0.50 to <0.83 mL/s), or 25 mg if <30 mL/min (<0.50 mL/s).
Saxagliptin is dosed orally 5 mg daily, unless the CLcr is <50 mL/min (<0.83 mL/s), or strong CYP3A4/5
inhibitors are used; then the recommended daily dose is 2.5 mg. Linagliptin is available only in one dose: 5 mg
daily, and does not require dose adjustment in renal insufficiency or related to concomitant drug therapy.
Alogliptin, similar to sitagliptin, has a two-step dosing adjustment in renal insufficiency. Alogliptin 25 mg daily
should be decreased to 12.5 mg when the CrCl <60 mL/min (<1 mL/s), and 6.25 mg when <30 mL/min (<0.50
mL/s). Because of their excellent tolerability profile and flat doseresponse curve, these drugs should be
maximally dosed, unless noted above.
Bile Acid Sequestrants
Currently, the only bile acid sequestrant approved for the treatment of type 2 DM is colesevelam (Welchol).
Pharmacology
Colesevelam is a bile acid sequestrant that acts in the intestinal lumen to bind bile acid, decreasing the bile
acid pool for reabsorption. Whether colesevelams mechanism of action to lower plasma glucose levels is in the
intestinal lumen, a systemic effect due to the intestinal lumen effect or some combination of these two is
unknown. Possible mechanisms include effects on the farnesoid X and TGR5 receptors within the intestine as
well as effects on farnesoid X receptor within the liver. There is evidence that colesevelam may affect the
secretion of GLP-1 and GIP. See also Chapter 11.
Pharmacokinetics
Colesevelam is not absorbed from the intestinal lumen; thus, there is no absorption, distribution, or metabolism.
Efficacy
HbA1c reductions from baseline (8% [0.08; 64 mmol/mol Hb]) were approximately 0.4% (0.004; 5 mmol/mol
Hb) when a dose of 3.8 g/day was added to stable metformin, sulfonylureas, or insulin. The FPG was modestly
reduced about 5 to 10 mg/dL (0.3 to 0.6 mmol/L). Colesevelam also reduces LDL-C cholesterol in patients with
type 2 DM. A 12% to 16% reduction in LDL-C was reported from baseline LDL-C concentrations of 105 mg/dL
(2.72 mmol/L). Triglycerides increased when combined with sulfonylureas or insulin, but not with metformin.
Colesevelam is weight neutral. Pediatric patients (10 to 17 years of age) have been studied for cholesterol
reduction, but not for type 2 DM.
Bile acid sequestrants modestly reduce HbA1c levels, which have been shown to be related to the risk of
microvascular complications.
Although colesevelam lowers plasma glucose and LDL-C, it has not been proven to prevent cardiovascular
morbidity or mortality.
There are multiple absorption-related drugdrug interactions with colesevelam. The most important include
levothyroxine, glyburide, and oral contraceptives. In addition, phenytoin, warfarin, digoxin, and fat-soluble
vitamins have postmarketing reports of altered absorption. It is recommended that medications suspected of an
interaction should be moved at least 4 hours prior to dosing the colesevelam. Colesevelam has also been
implicated in the malabsorption of fat-soluble vitamins (A, E, D, K). In addition to the obvious fat-soluble vitamin
supplementation, this may have implications for associated conditions. Other drugs that are very fat-soluble
54/88
7/1/2014
such as cyclosporine A, drugs that may be affected by a change in fat-soluble vitamin status such as warfarin
and vitamin K, or conditions that may be potentially worsened by fat-soluble vitamin status such as some
bleeding disorders or dermatologic conditions should be monitored.
Adverse Effects
The most common side effects are GI. Constipation (11%) and dyspepsia (8%) are more common with
colesevelam than placebo. Because of the constipating effects of colesevelam, it is not recommended in
patients with gastroparesis, bowel obstruction, or a history of major GI surgery. It also should not be used in
patients with significant swallowing or esophageal issues, as it may worsen the underlying condition or cause
obstruction. Colesevelam should be taken with a large amount of water to lower the risk of the above issues.
Hypoglycemia rates were low, although caution with insulin or sulfonylureas is prudent.
Colesevelam, similar to all bile acid sequestrants, may raise triglyceride levels. The increase in triglycerides is
proportional to baseline triglyceride levels, and colesevelam is contraindicated in patients with a triglyceride
>500 mg/dL (>5.65 mmol/L). Close monitoring is recommended if the baseline triglycerides >300 mg/dL (3.39
mmol/L). Colesevelam is contraindicated in patients with a history of triglyceridemia-induced pancreatitis, and
prudent clinical judgment should be used in any patient with a history of pancreatitis and elevated triglycerides.
Dosing for type 2 DM is six 625-mg tablets daily (total dose/day = 3.75 g), which may be split into three tablets
two times a day if desired. A 3.75-g oral suspension packet, dosed daily, or a 1.875-g oral suspension packet
dose twice daily is also available. Suspension packets must be diluted in a minimum of one half to one cup of
water. Take tablets and suspension with a large amount of water, if possible. All dosage forms should be
administered with meals as colesevelam binds to bile released during the meal.
Dopamine Agonists
Bromocriptine mesylate (Cycloset) is currently approved for the treatment of type 2 DM.
Pharmacology
Bromocriptine is a dopamine agonist, but the exact mechanism of how bromocriptine improves glycemic control
is unknown. Low hypothalamic dopamine levels, especially on waking, are augmented, which may decrease
sympathetic tone and output. These effects are speculated to improve hepatic insulin sensitivity.
Pharmacokinetics
Bioavailability is 65% to 95% after an orally administered dose; bioavailability may be increased 50% if given
with a meal. Peak plasma concentration is about 1 hour if taken without food, but with food it is 90 to 120
minutes. Bromocriptine is highly protein bound, and has a volume of distribution of 61 L. Only 7% reaches the
systemic circulation due to GI-based metabolism and first-pass metabolism. Bromocriptine is extensively
metabolized by the CYP3A4 pathway, and the majority (95%) is excreted in the bile. The half-life is
approximately 6 hours. Plasma exposure is increased in females by approximately 18% to 30%, but no dosage
adjustment is currently recommended.
Efficacy
In clinical trials, bromocriptine mesylate reduced HbA1c by 0.3% to 0.6% (0.003 to 0.006; 3 to 7 mmol/mol Hb)
from baseline.
Microvascular and Macrovascular Complications
There is no study examining microvascular disease. Macrovascular event reduction has not been proven. In
just over 3,000 subjects, bromocriptine decreased a composite cardiovascular outcome over 1 year. The
55/88
7/1/2014
composite outcome occurred in 37 (1.8%) bromocriptine-treated subjects versus 32 (3.2%) subjects not given
bromocriptine (HR 0.6 [95% two-sided CI, 0.35 to 0.96]).
Bromocriptine is extensively metabolized by CYP3A4 and strong inhibitors or inducers may change
bromocriptine levels. As bromocriptine is highly protein bound, it may increase the unbound fraction of other
highly protein-bound drugs. Several drugdrug and potential drugdisease interactions are present including
antipsychotics in psychotic disorders as they decrease dopamine activity, atypical antipsychotics as they may
decrease the effectiveness of bromocriptine, and ergot-based therapy for migraines as bromocriptine may
increase migraine and ergot-related nausea and vomiting. There are case reports of hypertension and
tachycardia when administered with sympathomimetic drugs in postpartum women, and bromocriptine should
not be given to this group of potential patients. The effectiveness in other disease states where dopamine
agonism may be indicated is unknown.
Adverse Effects
Adverse reactions leading to discontinuation occurred in 24% of bromocriptine patients compared with 9% in
the placebo comparator group. Nausea, rhinitis, headache, asthenia, dizziness, constipation, and sinusitis all
occurred in over 10% of subjects. Nausea occurred in 25% to 35% of patients, and vomiting, which tended to
be more common in women, occurred in 5% to 6% of patients. Nausea, vomiting, fatigue, headache, and
dizziness were common adverse events during the titration phase of phase 3 studies, and only 70% of
completors could be titrated to the maximum dose. Orthostatic hypotension or syncope occurred in 2.2% and
1.4%, and 0.6% and 0.8% in the bromocriptine and placebo groups, respectively. No predisposing factors were
identified, but caution should be exercised in patients with low, normal blood pressure. Somnolence was
reported in 4.3% of patients on bromocriptine, compared with 1.3% in the placebo, and response to the drug
should be ascertained prior to operating machinery or combining with other sedating medications. Psychiatric
disorders including hallucinations and pathologic gambling have been reported with other forms of
bromocriptine, but were not seen in phase III trials.
Bromocriptine is dosed with 0.8-mg tablets administered within 2 hours of waking from sleep daily with food.
From 0.8 mg daily, the dose may be increased weekly based on response by 0.8-mg tablet increments, to a
maximum of 4.8 mg daily (0.8 mg 6 tablets, although it is unclear if another commercial dose could be made
available). The minimal effective dose is 1.6 mg daily. It is recommended to be taken with food as this may
decrease nausea/vomiting.
Potential Future Medications

Many medications for the treatment of diabetes are currently in late-phase development. No guarantee of FDA
approval is given for any agent in development.
Insulin
Insulin degludec is a long-acting basal insulin that appears to be truly peakless. Hypoglycemia in clinical trials
has been slightly less to date versus insulin glargine with similar glycemic control.
Incretin Class Medications
Once-daily lixisenatide and several weekly GLP-1 receptor agonist medications are being developed. Closest
to market is albiglutide, but also in development is semaglutide.
Selective Sodium-Dependent Glucose Cotransporter-2 Inhibitors (SGLT-2 Inhibitors)
56/88
7/1/2014
SGLT-2 inhibitors work in the kidney to block the reabsorption of some glucose. Normally, all glucose is
reabsorbed back into the systemic circulation from the kidney at normal glucose levels: about 10% through the
SGLT-1 receptor, and 90% through the SGLT-2 receptor. Early data have shown approximately 50 to 80 g of
glucose per day may be allowed to pass into the urine with SGLT-2 inhibition. This lowers systemic glucose and
allows weight loss. Glucose levels may be lowered in both type 1 and type 2 DM by this mechanism of action.
Safety data have shown a slightly higher rate of genitourinary yeast infections. SGLT-1 is involved with glucose
absorption in the gut, and inhibition of SGLT-1 has been historically thought to cause GI toxicity, but this is
unclear and dual inhibitors may be marketed. Canagliflozin (Invokana) is currently the farthest in development,
but several are being developed. Dapagliflozin has been rejected by the FDA several times due to concerns
about cancer.
Pivotal Trials
Diabetes Control and Complications Trial
Much of the last century in diabetes care was dominated by the debate over whether glycemic control
actually was causative in complications of DM. Animal studies and some human studies suggested that the
worse the glycemia, the greater the risk of complications. But the glucose hypothesis was not ultimately
accepted as proven until the publication of the DCCT in 1993.23 In this study, 1,441 patients with type 1 DM
were divided into two groups: those without complications (726 subjects, primary prevention) and those with
early microvascular complications (715 subjects, secondary prevention). These two groups were then again
divided into two groups: one randomized to receive conventional therapy (one or two shots of insulin daily and
infrequent SMBG with no attempt to change therapy based on home BG readings) and the other to receive
intensive therapy (>3 injections of insulin daily or insulin pump, with frequent SMBG and alteration of insulin
therapy based on SMBG results, plus frequent contact with a health professional). After 6.5 years, mean followup with a difference in HbA1c between the two groups being 2% (0.02; 22 mmol/mol Hb) (9% vs. 7% [0.09
vs. 0.07; 75 mmol/mol Hb vs. 53 mmol/mol Hb), retinopathy was decreased by 76% in the primary
prevention cohort, with retinopathy progression reduced 54% in the secondary prevention group. Neuropathy
was decreased by 60% in both groups combined. Microalbuminuria was decreased 39%, while
macroproteinuria was reduced 54% with intensive therapy. Hypoglycemia was more common and weight gain
greater with intensive therapy. A nonstatistically significant reduction in coronary events was seen in the
intensively treated group as compared with the conventional group. The DCCT revolutionized therapy of DM,
demanding that stricter glycemic control be the goal.
United Kingdom Prospective Diabetes Study
The UKPDS was a landmark study for the care of patients with type 2 DM, confirming the importance of
glycemic control for reducing the risk of microvascular complications.24 More than 5,000 patients with newly
diagnosed type 2 DM were entered into the study. Patients were followed for an average of 10 years. The
major portion of the study assessed conventional therapy (no drug therapy unless the patient was
symptomatic or had FPG >270 mg/dL [>15 mmol/L]), versus intensive therapy starting with either sulfonylureas
or insulin, aimed at keeping the FPG <108 mg/dL (6 mmol/L). A subset of obese patients was studied using
metformin as the primary therapeutic agent.
Significant findings from the study include the following:
1. Microvascular complications (predominantly the need for laser photocoagulation on retinal lesions) are
reduced by 25% when median HbA1c is 7% (0.07; 53 mmol/mol Hb) as compared with 7.9% (0.079; 63
mmol/mol Hb).24
57/88
7/1/2014
2. A continuous relationship exists between glycemia and microvascular complications, with a 35% reduction
in risk for each 1% decrement in HbA1c (0.01; 11 mmol/mol Hb). No glycemic threshold for microvascular
disease exists.42
3. Glycemic control has minimal effect on macrovascular disease risk. Excess macrovascular risk appears to
be related to conventional risk factors such as dyslipidemia and hypertension.43
4. Sulfonylureas and insulin therapy do not increase macrovascular disease risk.24
5. Metformin reduces macrovascular risk in obese patients.36
6. Vigorous blood pressure control reduces microvascular and macrovascular events.43 There was no
evidence for a threshold systolic blood pressure above 130 mm Hg for protection against complications. Blockers and angiotensin-converting enzyme (ACE) inhibitors appear to be equally efficacious.44
Long-Term Follow-up of DCCT (EDIC) and UKPDS
At the conclusion of the DCCT and UKPDS trials, willing subjects continued to be followed over time to
ascertain microvascular and macrovascular outcomes. In the follow-up of the DCCT, called the Epidemiology of
Diabetes Interventions and Complications (EDIC), several important points have been discovered. First, HbA1c
levels between conventional and intensive groups converged to an HbA1c of approximately 8% (0.08; 64
mmol/mol Hb). Despite similar HbA1c values, continued microvascular and new macrovascular benefit was seen.
Microvascular benefits were maintained for 10 to 15 years, and at 17 years of follow-up, a 57% (P = 0.02)
reduction in death, first occurrence of nonfatal MI, and stroke was seen between the conventional and intensive
groups.45,46
In the follow-up of the UKPDS, HbA1c (8% [0.08; 64 mmol/mol Hb]) converged and values were not
significantly different for the majority of the follow-up. After a mean follow-up of 8.5 years, a 24% (P = 0.001)
reduction in microvascular complications (during the UKPDS, 25% reduction was reported) and a significant
reduction in MI (15%; P = 0.014) and all-cause mortality (13%; P = 0.007) in the intensively treated group
versus the conventional group were reported.47 Early glycemic control may have long-standing benefits to
patients over several decades, despite later glycemic control deterioration. This concept is being called
metabolic memory or the legacy effect. These studies lay the framework for why early intensive glycemic control
is important not only for short-term but also for long-term prevention of complications.
ACCORD, ADVANCE, and VADT
The Action to Control Cardiovascular Risk in Diabetes (ACCORD),48 Action in Diabetes and Vascular
Disease (ADVANCE),49 and Veterans Affairs Diabetes Trial (VADT)50 were three trials that reported on the
effects of glycemic control and macrovascular disease risk.
ACCORD randomized 10,251 high CVD risk subjects (CVD event or significant risk) with type 2 DM to intensive
glycemic control (goal HbA1c <6% [<0.06; <42 mmol/mol Hb]) or standard glycemic control (HbA1c 7% to 7.9%
[0.07 to 0.079; 53 to 63 mmol/mol Hb]). Multiple oral agents and/or insulin were allowed to achieve glycemic
goals. Baseline HbA1c level was 8.1% (0.081; 65 mmol/mol Hb), and the intensive glycemic group achieved a
HbA1c of 6.4% (0.064; 46 mmol/mol Hb), whereas standard glycemic control achieved a HbA1c of 7.5% (0.075;
58 mmol/mol Hb) when the study stopped after a mean follow-up period of 3.5 years. The study was stopped
after an interim analysis reported an increased rate of mortality in the intensive arm (1.41%/y vs. 1.14%/y; HR,
58/88
7/1/2014
1.22; 95% CI, 1.01 to 1.46). Interestingly, the primary end point (myocardial, stroke, or cardiovascular death)
was trending down due to a lower risk of nonfatal MI in the intensive therapy group. In addition, on subset
analysis, individuals with a baseline HbA1c <8% (<0.08; <64 mmol/mol Hb) or no previous CVD had a significant
reduction in the primary outcome. Increased mortality, though substantially increased in the intensive group,
could not be associated with a specific medication, hypoglycemia (higher in intensive group), lipid levels, or
weight gain. The dichotomous results have been hard to explain, although the ACCORD investigators reported
that in the intensive group, it was subjects who could not attain intensive glycemic control goals who were at
higher risk, not subjects who did achieve the goal. A 20% higher risk of death for each 1% (0.01; 11 mmol/mol
Hb) above an HbA1c of 6% (0.06; 42 mmol/mol Hb) was reported.
ADVANCE randomized 11,140 subjects to intensive (6.5% HbA1c [0.065; 48 mmol/mol Hb]) or standard
therapy (investigator-driven goals). Extended-release gliclazide, a sulfonylurea available outside of the United
States, was used as first-line therapy in the intensive group versus no gliclazide in the standard therapy group,
although multiple other agents were needed in both groups. A baseline HbA1c was only 7.5% (0.075; 58
mmol/mol Hb), and at the end of therapy, the intensive group versus standard group HbA1c was 6.5% versus
7.2% (0.065 vs. 0.072; 48 mmol/mol Hb vs. 55 mmol/mol Hb). ADVANCE reported a significant reduction in
renal events, including new or worsening nephropathy (HR, 0.79; 95% CI, 0.66 to 0.93), but no difference in
major macrovascular events (HR, 0.94; 95% CI, 0.84 to 1.06) with intensive versus standard therapy.
VADT randomized 1,791 subjects to intensive glycemic control (HbA1c goal <6% [<0.06; <42 mmol/mol Hb], and
action required of >6.5% [>0.065; >48 mmol/mol Hb]) versus nonintensive glycemic control (investigator
determined). At entry, the HbA1c was the highest of the three trials (9.4% [0.094; 79 mmol/mol Hb]). Multiple
medications including insulin were used to achieve glycemic control. The intensive group achieved an HbA1c of
6.9% versus 8.5% (0.069 vs. 0.085; 52 mmol/mol Hb vs. 69 mmol/mol Hb) in the investigator-determined group.
The primary end point of nonfatal MI, nonfatal stroke, CVD death, hospitalization for heart failure, and
revascularization was not significantly different (HR, 0.88; 95% CI, 0.74 to 1.05) and mortality was unchanged.
These three trials should be viewed as confirmatory that short term (3 to 5 years) of intensive glycemic control
does not positively affect the risk of macrovascular risk in type 2 DM. ACCORD reported that a subset of
subjects who could not achieve intensive glycemic control may be at higher risk of death, but identifying these
patients and implementing this recommendation into clinical practice may prove to be challenging. As
previously mentioned in Long-Term Followup of DCCT (EDIC) and UKPDS above, reduction of macrovascular
events from improved glycemic control may take over a decade to come to fruition.
Therapeutics
Knowledge of the patients quantitative and qualitative meal patterns, activity levels, pharmacokinetics of
insulin preparations and other injectables, and pharmacology of oral and antidiabetic agents for type 2 DM is
essential to individualize the treatment plan an optimize BG control while minimizing risks for hypoglycemia and
other adverse effects of pharmacologic therapies.
All patients with type 1 DM require insulin. However, how that insulin is delivered to the patient is a 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 insulin available) were given. Modifications of insulin led to longer-acting insulin suspensions
and the use by many patients of one or two injections of longer-acting insulin each day. Because selfmonitored BG and HbA1c testing were not available at that time, patients and practitioners had no idea how well
59/88
7/1/2014
their patients BG concentrations were controlled, other than a vague sense from an indirect method,
measurement of glucose in the urine. While the renal threshold for glucose is relatively predictable in young
healthy subjects, it is highly variable in older patients and patients with renal disease. The advent of SMBG and
HbA1c testing in the 1980s revolutionized the care of diabetes, enabling patients and practitioners to directly
access BG for assessment, and enabling the patient to make instantaneous changes in the insulin regimen if
need be. Modern diabetes management would be impossible without these two tools.
Contemporary management of type 1 DM attempts to match carbohydrate intake with glucose-lowering
processes, most commonly insulin, as well as with exercise. The goal is to allow the patient to live as normal a
life as possible. Understanding the principles of glucose input and glucose egress from the blood allows the
practitioner and the patient great latitude in the management of type 1 DM.
Normal secretion of insulin can be divided into a relatively constant background level of insulin (basal) during
the fasting and postabsorptive period, with prandial spikes of insulin after eating (bolus) (Fig. 57-6).51 Insulin
sensitivity and insulin secretion are not constant throughout the day, however, which renders the concept of
stable basal insulin requirements to be inaccurate. However, in most clinical situations, attempting to emulate
normal secretion of insulin is a useful paradigm for understanding and applying insulin treatment for the
management of type 1 DM. The other basic principle to consider is that the timing of insulin onset, peak, and
duration of effect must match meal patterns and exercise schedules to achieve near-normal BG values
throughout the day.
60/88
7/1/2014
Relationship between insulin and glucose over the course of a day and how various insulin and amylinomimetic
regimens could be given. (A, aspart; CSII, continuous subcutaneous insulin infusion; D, detemir; G, glargine;
GLU, glulisine; L, lispro; P, pramlintide; N, NPH; R, regular.)
Historically, the complexity of insulin regimens was related to the number of injections of insulin administered
per day. This was a reasonable classification; however, a single injection of any insulin preparation daily will in
no way mimic normal physiology, and therefore is unacceptable. Similarly, two injections of any insulin daily will
fail to replicate normal patterns of insulin release.
Injection regimens that begin to approximate physiologic insulin release start with split-mixed injections
consisting of a morning dose of an intermediate-acting insulin such as NPH and a bolus rapid-acting insulin or
regular insulin before breakfast, and again before the evening meal. The presumption is made that the morning
intermediate-acting insulin gives basal insulin for the day and covers the midday meal, the morning bolus
insulin covers breakfast, the evening intermediate-acting insulin gives basal insulin for the rest of the day, and
the evening bolus insulin covers the evening meal. If patients are very compulsive about consistency of timing
of their injections and meals and intake of carbohydrate, such a strategy may be acceptable. However, the vast
majority of patients are not sufficiently predictable in their schedule and food intake to allow tightglucose
control with such an approach.
61/88
7/1/2014
A modification that can be made to the above regimen is the movement of the evening NPH to bedtime (now
three total injections per day) because the fasting glucose in the morning is too high or there is hypoglycemia
in the early hours of sleep. This approach improves glycemic control and may reduce hypoglycemia sufficiently
for those patients who decline or are unable to follow more intense regimens. However, most patients with type
1 DM need a more intense approach that also allows greater flexibility in their lifestyle.
The basalbolus concept attempts to replicate normal insulin physiology with a combination of intermediateor long-acting insulin to provide the basal component, and rapid-acting insulin to provide the bolus or premeal
component. Various long-acting insulins have been used to provide the basal insulin component, including
once- or twice-daily NPH, detemir, or glargine. Insulin glargine and insulin detemir are the most feasible basal
insulins for most patients with type 1 DM.
The bolus or prandial insulin component can be regular insulin, insulin lispro, insulin aspart, or insulin glulisine
injected before meals. The rapid onset of action and short time course of rapid-acting insulin analogs more
closely replicate normal physiology than does regular insulin. The patient varies the amount of before meal
rapid-acting insulin injected, depending on the preprandial BG level, the anticipated activity (upcoming exercise
may reduce insulin requirement), and anticipated carbohydrate intake. Many patients start with a prescribed
dose of insulin before meals that they vary by use of an adjusted scale insulin or correction factor to
normalize a high premeal plasma glucose reading. Patients on more advanced regimens later may adjust the
amount of mealtime insulin based on anticipated carbohydrate intake.
A correction factor can be calculated as a starting point to estimate the approximate plasma glucoselowering
effect of 1 unit of short-acting insulin in mg/dL. For regular insulin, one may use a factor of 1,500 (a
corresponding factor for calculation of glucose in SI units would require multiplying by 0.0555) divided by the
total daily insulin dose in number of units that the patient currently uses. For rapid-acting insulin analogs, a
factor of 1,700 is more often used when calculating the correction factor. For example, if a patient is currently
taking 40 units of basal insulin and 12 units of rapid-acting insulin at each of three meals, the total daily insulin
dose equals 76 units. Using this calculation 1,700 divided by 76 equals 22; thus, each unit of rapid-acting
insulin analog will lower the plasma glucose approximately 22 mg/dL (1.2 mmol/L). Review of follow-up BG data
permits better individualization of the correction factor.
Carbohydrate counting is a very effective tool for determining the amount of rapid-acting insulin that should be
injected preprandially in people with type 1 DM. Instead of using a prescribed or preset dose of rapid-acting
insulin before meals, patients can self-adjust their premeal dose based on the estimated grams of
carbohydrates that will be consumed. Although general algorithms for carbohydrate counting give rough
guidelines, each patient will have to adjust the preprandial insulin dosage based on his or her own individual
response to different food items.
One method of calculating how much carbohydrate (grams) 1 unit of rapid-acting insulin will cover is to use 500
divided by the total daily dose of insulin in number of units. Therefore, using the example above with a total
daily insulin dose of 76 units, we would use 500 divided by 76, which estimates that 1 unit of rapid-acting insulin
will cover approximately 7 g of carbohydrate. Review of follow-up BG data before and 2 hours after meals will
enable more precise determination of an individuals insulin-to-carbohydrate ratio.
In type 1 DM, approximately 50% of total daily insulin replacement should be basal insulin, and the other 50%
will be bolus insulin, divided into doses before meals. If the patients ratio is not close to this recommendation, a
reassessment of the regimen should be implemented. Empirically, patients may be begun on 0.6 unit/kg/day
with basal insulin 50% of total dose and prandial insulin 20% of total dose prebreakfast, 15% prelunch, and
15% presupper. Type 1 DM patients generally require between 0.5 and 1 unit/kg/day. The need for significantly
higher amounts of insulin suggests the presence of insulin resistance or, less often, of insulin antibodies.
Intensive basalbolus multi-injection insulin therapy is recommended for all adult patients with type 1 DM at the
62/88
7/1/2014
time of diagnosis to reinforce the importance of glycemic control from the outset rather than change strategies
over time because of lack of control. Occasional patients with an extended honeymoon period may need less
intense therapy initially, but should later be converted to basalbolus therapy at the onset of glycemic lability.
For those patients who insist on only two injections daily, intermediate-acting insulin and a rapid-acting insulin
or regular insulin (starting at 0.6 unit/kg with two thirds in the morning, two thirds of the morning dose as
intermediate-acting insulin, and one half of evening dose as intermediate-acting insulin) is an option; however,
most often this approach will not be allowed as an aggressive glycemic control option due to increased risk of
hypoglycemia.
Insulin pump therapy (continuous subcutaneous insulin infusion [CSII], generally using a rapid-acting analog
insulin) is the most sophisticated form of insulin delivery. In a motivated patient, CSII may be more efficacious in
achieving excellent glycemic control than multiple-dose insulin injections. Extensive discussion of this mode of
therapy is beyond the scope of this text. Nevertheless, the basic principles for implementation are the same.
One advantage of pump therapy is that the basal insulin dose may be varied, related to changes in basal
insulin requirements throughout the day. In selected patients, this feature allows better glycemic control with
CSII. However, insulin pumps require even greater attention to detail and frequency of SMBG than does a
basalbolus regimen with four injections daily.52 In appropriately selected patients willing to pay sufficient
attention to detail of SMBG and insulin administration, CSII can be a very effective form of therapy. CSII is only
a tool for diabetes control, however. Thus, if the patient is not well controlled and/or unwilling to actively control
the diabetes on injections, it is unlikely that the patient will have superior control on a pump. CSII placement
and adjustment should be made by an experienced clinician, and only after a discussion with the patient about
the reality of CSII, addressing expectations, and proper training on the pump.
Regardless of the insulin regimen chosen, gross adjustments in the total insulin dose are made based on
HbA1c measurements and symptoms such as polyuria, polydipsia, and weight gain or loss. Finer insulin
adjustments are determined on the basis of the results of frequent BG monitoring, documentation of mealtime
carbohydrate intake, physical activity, and other factors that affect glycemic control.
All patients should have extensive education in the recognition and treatment of hypoglycemia. Many patients
experiencing hypoglycemia are tempted to overtreat episodes of hypoglycemia resulting in rebound
hyperglycemia afterwards. To minimize this, patients are advised to follow the rule of 15. If hypoglycemia is
identified (BG less than 70 mg/dL [3.9 mmol/L]), the patient is instructed to consume 15 g of simple
carbohydrate (8 oz [250 mL] orange juice or four glucose tablets) and then retest his or her BG 15 minutes
later. If BG is still less than 70 mg/dL (3.9 mmol/L), the patient may repeat the rule of 15 until his or her BG has
normalized.
At each visit, patients with type 1 DM should be questioned about hypoglycemia. The frequency of
hypoglycemia, particularly hypoglycemia requiring assistance of another person, a visit to an emergent or
urgent care facility, or hospitalization, should be recorded.
In type 1 DM, it is common for patients to develop hypoglycemia unawareness. Hypoglycemic unawareness may
result from progression of disease with autonomic neuropathy. The loss of warning signs of hypoglycemia is a
relative contraindication to intensive therapy. More commonly, type 1 DM patients have loss of warning signs
because of a presumed lower set point for release of counterregulatory hormones as a result of frequent
episodes of hypoglycemia (hypoglycemia begets hypoglycemia). In such situations, more normal
hypoglycemia awareness may be restored by reduction or redistribution of the insulin dose to eliminate
significant and/or frequent hypoglycemic episodes.
In children and pubescent adolescents, glycemic goals may need to be tempered with the risks of
hypoglycemia. Table 57-7 lists glycemic goals for different age groups of type 1 DM patients. Therefore, it is
63/88
7/1/2014
not unreasonable to use less intense management until the patient is postpubertal, if age-specific goals can be
maintained.5
Occasional patients develop antibodies to injected insulin, but the significance of the antibodies is usually
minimal. Human insulin therapy has not totally eliminated insulin allergies. In most patients local reactions will
dissipate over time. If mild reactions at the site of injection occur, reassess the insulin injected. Many times the
patient is injecting cold insulin, which may cause compensatory local vasodilation around the injection site in
response to the injected cold liquid. Anecdotally, a different type or source of insulin could be tried. If the
allergic reaction does not improve or is systemic, insulin desensitization can be carried out. Protocols for
desensitization are available from major insulin manufacturers.
While more common in the animal insulin era, lipohypertrophy is still seen in some patients with long-standing
type 1 DM. Some patients give their insulin injections in the same site repeatedly to minimize discomfort; over
time this can result in lipohypertrophy. Lipohypertrophy can sometimes be visualized on physical examination
and also can be identified by palpation of injection sites. Because insulin absorption from an area of
lipohypertrophy is unpredictable, it is mandatory to avoid insulin injections into these areas.
There are several common errors in the management of patients with type 1 DM that can cause erratic glucose
fluctuations:
1. Failure to take into account action of insulin: The timing of meals and/or physical activity must be
planned around the peaks of insulin action accordingly.
2. Choice of insulin injection sites: There is variability of insulin absorption from site to site such that
random selection of insulin injection sites may cause wide glucose swings. The most consistent absorption
of insulin is from the abdominal wall. Patients are encouraged to take all their injections in the abdomen. If
the patient is unable or unwilling to follow this advice, then systematic site rotation is the next preferable
option. The patient should always give the insulin injection in the same region of the body the same time of
the day each day. For instance, the arms are always used every morning. Needless to say, the patient
should not inject in a limb and then go out and exercise that limb, which could cause increased blood flow
and insulin absorption.
3. Overinsulinization: The answer to all high BG is not necessarily more insulin. Hyperglycemia could be
due to too little insulin or it could be due to rebounding from a previous low glucose and treating it with
excessive amounts of carbohydrate. Fastidious BG testing, particularly during the night (or selected use of
CGM), can assist in sorting this out. Many clinicians do not adequately differentiate type 1 DM from type 2
DM when choosing doses of insulin. Patients with type 1 DM are insulin deficient but have normal insulin
sensitivity. Patients with type 2 DM have varying degrees of insulin resistance. Therefore, a small change in
the dose of insulin for a patient with type 1 DM can have a dramatic effect on glucose concentrations,
whereas in patients with type 2 DM and insulin resistance a change in dose many times that amount of
insulin has little effect on glucose concentrations. Large changes in insulin dose in patients with type 1 DM
are not usually indicated unless the patients BG control is very poor. Widely erratic BGs and/or weight gain
may be due to too high a dose of insulin.
4. Injection technique and BG monitoring: When in doubt, always reevaluate the patients technique for
insulin dosing, insulin injection, and BG testing. Sometimes simple errors result in unpredictable glycemic
control.
64/88
7/1/2014
Type 1 DM patients who continue to have erratic postprandial control despite implementation of the above
strategies may be appropriate for treatment with pramlintide (Symlin). Pramlintide is not recommended to be
mixed with insulin; therefore, the patient will need to take an additional injection at each meal. With initiation of
pramlintide the doses of prandial insulin (rapid-acting analog or regular insulin) should be reduced by 30% to
50%, to prevent hypoglycemia. Pramlintide should be titrated based on GI adverse effects and postprandial
glycemic goals. Injecting pramlintide prior to the meal and the rapid-acting insulin at the time of or after the
meal may better match the appearance of the food with the postprandial increase in glucose due to delayed
gastric emptying. The patient must be cognizant of the risk of hypoglycemia, GI side effects, and how to reduce
both.
Islet cell and whole pancreas transplantation is occasionally used in patients who require immunosuppressive
therapy for other reasons, such as renal transplants.53 Many patients are able to stop insulin and/or only
require insulin secretion support therapy with sulfonylureas or GLP-1 agonists. However, within 2 years as
many 80% or more will need to reinitiate some form of insulin therapy.
Pharmacotherapy for type 2 DM has changed dramatically in the last few years with the addition of several
new drug classes and recommendations to achieve more stringent glycemic control. Symptomatic patients may
initially require treatment with insulin or combination oral therapy to reduce glucose toxicity (which may reduce
-cell insulin secretion and worsen insulin resistance). Patients with HbA1c 7% (0.07; 53 mmol/mol Hb) or
less are usually treated with therapeutic lifestyle measures and an agent that will not cause hypoglycemia.
Those with HbA1c >7% but <8.5% (>0.07 but <0.085; >53 but <69 mmol/mol Hb) could be initially treated with
single oral agents, or combination therapy. Patients with higher initial HbA1c may benefit from initial therapy with
two oral
agents, or insulin. This section addresses management of hyperglycemia; however, this needs to be
balanced within a multifactorial risk reduction framework of blood pressure reduction, dyslipidemia and
antiplatelet therapy, and smoking cessation. All therapeutic decisions should consider the needs and
preferences of the patient, if feasible. Individualization of therapy is necessary for success.
Depending on patient motivation and adherence to therapeutic lifestyle changes, most patients with HbA1c
greater than 9% to 10% (0.09 to 0.10; 75 to 86 mmol/mol Hb) will likely require therapy with two or more oral
agents to reach glycemic goals. Treatment of type 2 DM often necessitates use of multiple therapeutic agents
(combination therapy), to obtain glycemic goals.
The best oral therapy regimen for patients with type 2 DM is widely debated. Based on the results of the
UKPDS and safety record, obese patients (>120% ideal body weight) without contraindications should be
started on metformin titrated to 2,000 mg/day.5,54 Near-normal-weight patients may be better treated with
insulin secretagogues, although metformin will work in this population. Metformin is the only oral
antihyperglycemic agent to ever report a reduction in total mortality. Despite this, long-term durability of HbA1c
reduction, due to the inability to stop progressive -cell failure, is suboptimal with metformin, and patients over
several years will often need additional therapy. An insulin secretagogue, such as a sulfonylurea, is often
added second, although it has clearly been shown that sulfonylureas do not produce durable HbA1c reductions
in the majority of patients. Better choices to sustain HbA1c reductions would be a TZD or GLP-1 agonist, but
each has limitations as well. Goal-oriented therapy is what we currently strive for, meaning the intervention
should be in relation to the distance from the glycemic goal. When initial therapy is no longer keeping the
patient at goal, if the HbA1c is close to goal, one additional agent may be appropriate. If >1% to 1.5% (>0.01 to
0.015; >11 to 16 mmol/mol Hb) above goal, it is unlikely any one oral agent will result in reaching the glycemic
goal, and multiple oral agents or insulin therapy may be appropriate. TZDs may be substituted in situations in
which a patient is intolerant of, or has a contraindication to, metformin, understanding that TZDs should be
65/88
7/1/2014
used with caution in heart failure. Figure 57-7 is a consensus algorithm by the ADA and the European
Association for the Study of Diabetes.54 No algorithm can substitute for good clinical judgment, and algorithms
for glycemic control start with the premise that the clinician will identify medication contraindications, adverse
reactions, and comorbidities that may be advantageous or harmful if the medication was taken.
Position Statement on the Treatment of Type 2 Diabetes Mellitus: American Diabetes Association and
European Association for the Study of Diabetes. (Adapted from reference 54.)
We should also treat type 2 DM by matching therapy to the suspected underlying problem. Consider some
simple questions to guide therapy: (a) How long has the patient had diabetes? The longer a patient has had
diabetes, the more insulinopenic he or she likely is and the more likely that insulin therapy will be needed. (b)
Fasting, postprandial, or both plasma glucose readings poorly controlled? Some drugs address postprandial
glucose excursions better, whereas some address FPG better. (c) How far do we have to go to goal and what is
the goal? Each oral agent has limits on HbA1c reduction, and the reduction is baseline HbA1c dependent. (d)
Adverse effect profile? Contraindications, hypoglycemia potential, and tolerability are based on the current
status of the patient. (e) Comorbidities? CVD, dementia, life expectancy, depression, osteoporosis, and other
conditions where select medications may be poor choices and additionally those comorbidities may drive our
HbA1c goal. Based on the ADVANCE, ACCORD, and VADT trials, a HbA1c goal may now be above 7% (0.07;
53 mmol/mol Hb) if certain comorbidities are present. See Figure 57-8 for HbA1c individualization based on
comorbidities from the Texas Diabetes Council. Drugs such as metformin, TZDs, sulfonylureas, repaglinide,
liraglutide, extended-release exenatide, intermediate-acting insulins given at bedtime, and basal insulins control
FPG more effectively. Exenatide, DPP-4 inhibitors, -glucosidase inhibitors, nateglinide, and regular and rapidacting insulin better control postprandial glucose excursions. We can also guide therapy based on the risk of
hypoglycemia. Metformin, TZDs, liraglutide, exenatide, DPP-4 inhibitors, and -glucosidase inhibitors have a
low risk of hypoglycemia. Combining these agents will allow aggressive targeting of near-normal HbA1c levels
while minimizing hypoglycemia and weight gain. Combining these agents early in the diagnosis of type 2 DM is
logical to potentially realize the microvascular and macrovascular reduction seen in the long-term follow-up of
UKPDS.
A1C goals. See www.texasdiabetescouncil.org for current algorithms. (Reprinted with permission from the
Texas Diabetes Council.)
Preserving -cell function, thus arresting the progressive nature of type 2 DM, could be paradigm changing,
but to date medications have only shown to slow, not arrest, progression. In the UKPDS, insulin, metformin, or
sulfonylureas did not halt -cell failure. TZDs (out to 5 years with rosiglitazone) and GLP-1 agonists (open-label
exenatide has shown durable HbA1c reduction to 3 years and liraglutide to 2 years) may potentially slow -cell
failure. Pathophysiologically treating type 2 DM for potential -cell preservation is possible, but unproven. It
appears unlikely any one drug class will arrest -cell failure, necessitating combination therapy. TZD and GLP1 agonist combination is logical as TZDs reduce apoptosis of cells and GLP-1 agonists augment pancreatic
function through insulin secretion in a glucose-dependent manner and reduction of inappropriate glucagon, but
long-term data are lacking. -Cell function is heavily damaged by the time type 2 DM is diagnosed, and it is
possible that -cell failure is inevitable by type 2 DM diagnosis. HbA1c reduction is dependent on baseline
values, with higher reductions seen with higher values, but, again, therapy should be goal oriented. Triple
therapy is often with metformin, a sulfonylurea, and a TZD or DPP-4 inhibitor, but a logical alternative is to use
metformin, a TZD, and a GLP-1 agonist, which can lower glucose levels and increase satiety, reducing the
weight gain potential of a TZD, and still has a low risk of hypoglycemia. A DPP-4 inhibitor may be an alternative,
although without weight loss potential, if an injectable product is not preferred. If the HbA1c is >8.5% to 9%
(>0.085 to 0.09; >69 to 75 mmol/mol Hb) on multiple therapies, insulin therapy should be considered.
66/88
7/1/2014
Sulfonylureas are often stopped when insulin is added and insulin sensitizers continued. This may be beneficial
to decrease hypoglycemia, but continuing the sulfonylurea is permissible until multiple daily injections are
started, at which time it should definitely be discontinued. Combination therapy with a TZD and insulin should
be closely monitored for excessive weight gain and edema.
Virtually all patients with type 2 DM ultimately become relatively insulinopenic and will require insulin therapy.
Insulin therapy for type 2 DM has changed dramatically in the last few years. Specifically, patients are often
transitioned to insulin by using a bedtime injection of an intermediate- or long-acting insulin, and using oral
agents primarily for control during the day. This strategy leads to less hyperinsulinemia during the day and is
associated with less weight gain and has equal efficacy and a lower risk of hypoglycemia for up to 3 years when
compared with starting prandial insulin or split-mix twice-daily insulin.55 Because most patients are insulin
resistant, insulin sensitizers are commonly used with insulin therapy. Patients with type 2 DM are usually well
buffered against hypoglycemia. Patients should be monitored for hypoglycemia by asking about nocturnal
sweating, nightmares (both indicative of nocturnal hypoglycemia), palpitations, tremulousness, and
neuroglycopenic symptoms, as well as SMBG. When bedtime insulin plus daytime oral medications fail to
achieve glycemic goals, a conventional multiple daily dose insulin regimen while continuing the insulin
sensitizers is often tried. This may mean adding an injection of bolus insulin with the largest meal of the day for
a total of two injections. If this is unsuccessful, a bolus injection can be given with the second largest meal of
the day, for a total of three injections. After this, the standard basalbolus model is followed. Alternatively,
patients may be switched to split-mix insulin such as 70/30 mix insulin, Humalog Mix 75/25, or Novolog Mix
70/30. These are often given twice daily before the first and third meals (see Type 1 Diabetes Mellitus under
Therapeutics above for longer explanation), but if inadequate control is seen, a third dose of mix insulin may be
given with the third meal of the day. This allows for better prandial coverage, but can also increase the risk of
hypoglycemia.56 Use of GLP-1 agonists or pramlintide for prandial coverage can be considered. GLP-1
agonists, based on chosen drug, can be dosed weekly, daily, or twice daily, whereas pramlintide can be given
before each meal. Concerns and problems with insulin administration as addressed in Type 1 Diabetes Mellitus
under Therapeutics above generally relate to the therapy of type 2 DM. However, patients with type 2 DM
rarely have hypoglycemia unawareness. Also, the variability of insulin resistance means that insulin doses may
range from 0.7 to 2.5 units/kg or more. Figure 57-9 is an algorithm for insulin therapy options in type 2
diabetes developed by the Texas Diabetes Council. This algorithm gives most options for insulin therapy, but
the choice of regimen should be individualized based on the discussion with the patient.
Insulin algorithm for type 2 DM in children and adults. See www.texasdiabetescouncil.org for current algorithms.
(Reprinted with permission from the Texas Diabetes Council.)
The availability of short-acting insulin secretagogues, rapid-acting insulin analogs, exenatide, DPP-4 inhibitors,
and -glucosidase inhibitors, all of which target postprandial glycemia, has reminded practitioners that glycemic
control is a function of fasting, preprandial, and postprandial glycemic excursions. Many clinicians and patients
neglect monitoring postprandial glucose. However, postprandial glycemic excursions proportionally contribute
more than the FPG to the HbA1c percentage when the HbA1c nears goals, and thus will need to be targeted for
optimal glycemic control in many patients. It remains controversial whether targeting after-meal glucose
excursions will have more of an effect on complications risk than more conventional strategies.
Special Populations
Children and Adolescents with Type 2 DM
Type 2 DM is increasing in adolescence.1,6 Obesity and physical inactivity seem to be particular culprits in the
pathogenesis of this disease. Given the many years that the patient will have to live with diabetes, and recent
67/88
7/1/2014
evidence that the time frame after diagnosis for microvascular complications may mimic that of older adults,
extraordinary efforts should be expended on lifestyle modification measures in an attempt to normalize glucose
levels. Failing that strategy, the only labeled oral agent for use in children (10 to 16 years of age) is metformin,
although sulfonylureas are also commonly used in therapy. TZDs and DPP-4 inhibitors have not been
adequately studied in children, but studies to ascertain safety and efficacy are currently under way. GLP-1
agonist therapy, as it potentially helps the child to lose weight, is attractive, but the long-term effects of this
therapeutic modality are unknown. Insulin therapy continues to be the standard therapy after metformin and a
sulfonylurea. In adolescent females, the possibility of future pregnancy should be considered in the prescription
of any drug regimen. Screening and recommendations for treatment of hypertension, dyslipidemia,
nephropathy, retinopathy, hypothyroidism, and celiac disease are available.6
Elderly Patients with DM
Elderly patients with newly diagnosed DM (almost always type 2 DM) present a different therapeutic challenge.
Consideration of the risks of hypoglycemia, the extent of comorbidities including severe microvascular disease,
CVD, dexterity, self-care and social situations, falls risk, mental status, and the probable life span should help
determine glycemic goals. If extensive comorbidities, hypoglycemic unawareness, unstable CVD, dementia,
high falls risk, or similar diagnosis is made, the clinician may adjust the glycemic goal. Avoidance of
hypoglycemia, especially severe hypoglycemia, as well as elevated glucose levels that may exacerbate the
comorbidities is necessary (Fig. 57-8). It should also be remembered that elderly may have an altered
presentation of hypoglycemia, as they lose adrenergic symptoms due to loss of autonomic nerve function as
they age. This may raise the rise of neuroglycopenic symptoms shortly after identification of hypoglycemia. If
the patient is newly diagnosed and does not have the above problems, a goal HbA1c <7% (<0.07; <53
mmol/mol Hb) is justified. If the person has significant comorbidities as mentioned above, then a goal <8%
(<0.08; <64 mmol/mol Hb) may be reasonable, and if the person has end-stage illness, glycemic control
should limit symptomatic (polyuria/polydipsia) or mental status issues. If oral agents will work, DPP-4 inhibitors,
shorter-acting insulin secretagogues, low-dose sulfonylureas (preferably not long-acting ones), or glucosidase inhibitors may be used. The risk for lactic acidosis, which increases with older age and the agerelated decline in renal function, makes metformin therapy difficult, but lower doses may be used if not
contraindicated. In a patient in whom weight gain or loss may not be unwelcome, TZDs or GLP-1 agonists,
respectively, may be considered, but falls risk and fracture risk must be considered with TZDs. DPP-4 inhibitors
or -glucosidase inhibitors are oral medications that may be advantageous due to a low risk of hypoglycemia.
Simple insulin regimens such as an injection of basal insulin daily may be appropriate for glycemic control in
elderly patients, especially if tight glycemic control is not the goal. The Texas Diabetes Council publishes an
algorithm; see www.tdctoolkit.org.
Sidebar: Clinical Controversy...
Treatment of Type 2 DM in Older Adults

The U.S. population continues to age. The ACCORD,48 ADVANCE,49 and VADT 50 had older individuals who
were in their 60s at enrollment. As stated earlier in the chapter, all improved glycemic control but did not reduce
the risk of CVD over 3 to 5 years, although more people died in the ACCORD, resulting in termination of the
study. ADVANCE reported improvement in nephropathy outcomes, and this did not differ by age, but otherwise
these neutral studies did not report improved microvascular outcomes. In addition, one Japanese study had
subjects with a mean age of 72 years, and a 6-year follow-up, but changes in glycemia were minimal, thus
showing no benefit.57 This is unfortunate, as up to one in three people in this age category may have type 2
DM. Diabetes in older adults is complicated by clinical and functional heterogeneity. Patients may be relatively
healthy, free-living adults all the way to the other end of the spectrum with assistive living, multiple
comorbidities, and cognitive issues. Based on this, what is the optimal medication therapy for this group of
68/88
7/1/2014
individuals?
Critical evaluation of most medications in populations over 65 years of age is severely lacking. Many clinicians
have decided that insulin, especially basal insulin, is a reasonable choice in this age group, and that minimal
orals (maybe metformin if not contraindicated) are reasonable. Yet, in the new ADA guidelines and clinical
practice recommendations, a patient-centered approach is stated. It is unlikely that most patients would choose
basal insulin as their initial intervention if asked. Also, the cost for basal insulin is not minimal, and one must
ask if it is truly more cost-effective than many other interventions. Severe hypoglycemia must be avoided in this
population, as it has been associated with a higher risk of death for more than 1 year after the incident. Any of
the agents can avoid severe hypoglycemia if used properly, but the risk factors for hypoglycemia are: use of
insulin or insulin secretagogues, duration of diabetes, antecedent hypoglycemia, erratic meals, exercise, and
renal insufficiency. In addition, self-care, visual acuity, and dexterity issues may be of concern in patients.
Medications that do not cause hypoglycemia may be advantageous. Metformin, if not contraindicated,
continues to be an excellent first choice. As metformin may be used in Stage III CKD, with a reduced dose, this
may be a reasonable choice. Second-choice agents such as DPP-4 inhibitors, if close to the chosen HbA1c
goal, or a GLP-1 receptor agonist, if farther from the chosen goal, may be warranted. Each has its own issues,
as both may be cost prohibitive and GLP-1 receptor agonists may be inappropriate for patients with GI issues
or gastroparesis, or normal-weight to underweight patients. -Glucosidase inhibitors, if close to goal and
constipation is an issue, may be helped by these agents, although GI tolerability is problematic.
As the care for people with diabetes improves, it is imperative that issues concerning older adults continue to
be addressed. It is important for our society that optimal therapy in older adults be properly addressed, as this
population will continue to grow, and currently there is no consensus. Several organizations have
recommendations in regards to older adults,58,59 but recommendations on optimal pharmacotherapy are not
included.
Gestational DM and Pregnancy with Preexisting Diabetes
GDM is diagnosed as previously described. The adverse outcomes associated with GDM include birth defects,
increased rates of miscarriage, necessity of cesarean section delivery, neonatal hypoglycemia,
preeclampsia/eclampsia, preterm delivery, shoulder dystocia/birth injury, and hyperbilirubinemia. Dietary
therapy to minimize wide fluctuations in BG is of paramount importance.5,8 Intensive educational efforts are
usually necessary. Pregnant women without DM maintain plasma glucose concentrations between 50 and 130
mg/dL (2.8 and 7.2 mmol/L). Normoglycemia is the goal, and failure to maintain this despite dietary
interventions often will necessitate medication use. Goals during therapy are minimally a preprandial goal of
90 mg/dL (5 mmol/L), and either 1-hour postprandial plasma glucose levels 120 mg/dL (6.7 mmol/L) or 2hour postprandial plasma glucose levels 110 mg/dL (6.1 mmol/L), and avoidance of ketones as much as
possible. In patients who have preexisting type 1 or type 2 DM and become pregnant, premeal, bedtime, and
overnight glucose should be 60 to 90 mg/dL (3.3 to 5 mmol/L), with a peak postprandial of 100 to 120 mg/dL
(5.6 to 6.7 mmol/L). HbA1c during pregnancy should be less than 6% (<0.06; <42 mmol/mol Hb), but frequent
SMBG is the method of choice for monitoring glycemic control. Titration of insulin and switching to more
complicated regimens is guided by SMBG results. Use of basal insulins other than NPH is still debated, but with
the ease of use of detemir or glargine insulin, their use in GDM is increasing. In addition, pump therapy for the
duration of the pregnancy is often instituted, as it can obtain excellent glycemic control and is quickly
adjustable. Both metformin and glyburide have been studied as alternatives to insulin therapy. Glyburide was
not detected in the cord serum of any infant in one study, whereas metformin crosses the placenta. Further
study is needed prior to routinely recommending them in GDM. Patients with GDM should be evaluated 6 weeks
after delivery to ensure that normal glucose tolerance has returned. Because these patients lifetime risk for the
development of type 2 DM is >50%, periodic assessment after that is warranted.
69/88
7/1/2014
Sidebar: Clinical Controversy...
Oral Agents in Pregnancy

The use of oral antidiabetic agents for the management of gestational diabetes or type 2 DM during pregnancy
is controversial. For those patients who fail to maintain optimal glycemic control during pregnancy with diet and
lifestyle modification, traditionally the next step has been to proceed with insulin therapy. More recently,
however, some clinicians have begun using oral agents including sulfonylureas and/or metformin in patients
with GDM or type 2 DM during pregnancy.
A randomized, open-label, controlled trial evaluated the efficacy of glyburide compared with insulin initiated
after 11 weeks gestation.60 The control of BG compared with insulin therapy was similar, with less
hypoglycemia in the glyburide group. There was not any evidence of significant difference in complications,
including cord serum insulin concentrations, incidence of macrosomia (birth weight 4,000 g), cesarean
delivery, or neonatal hypoglycemia between regimens. Glyburide was not detected in the cord serum of any
infant. However, this study limited enrollment to beyond 11 weeks gestation; therefore, no conclusions can be
made regarding teratogenicity from using glyburide in the first trimester.
A more recent retrospective cohort study of 10,682 women with GDM who required medical therapy, however,
revealed that babies born to women with GDM who were managed on glyburide were more likely to be
macrosomic and to be admitted to the intensive care unit compared with those treated with insulin therapy.61
Metformin has also been used in the management of GDM and type 2 DM in pregnancy, and also in polycystic
ovarian syndrome to prevent miscarriage. Early studies dating back to the 1980s did not show any differences
in perinatal mortality, maternal hypoglycemia, lactic acidosis, or congenital anomalies.62,63
However, a more recent cohort study investigating the effects of metformin, sulfonylureas, and insulin in
pregnant women with diabetes found a significantly higher rate of preeclampsia in women treated with
metformin compared with women treated with sulfonylurea or insulin (32% metformin vs. 7% sulfonylureas vs.
10% insulin). The perinatal mortality was also significantly increased in women treated with metformin in the
third trimester compared with women not treated with metformin (11.6% vs. 1.3%).64
In contrast, another study of 751 women with GDM randomly assigned subjects at 20 to 33 weeks of gestation
to open treatment with metformin (with supplemental insulin if required) or insulin. This study did not find any
increased rate of preeclampsia or other perinatal complications compared with insulin.65
Subsequently there have also been meta-analyses that also revealed no differences in maternal or neonatal
outcomes with the use of glyburide or metformin compared with the use of insulin in women with GDM.66,67
The current guidelines of the ADA continue to suggest insulin therapy as the preferred treatment for managing
women with gestational diabetes or type 2 DM in pregnancy who fail to achieve optimal control with diet/lifestyle
modification alone.68 Moreover, neither metformin nor glyburide has formal FDA approval for the management
of diabetes in pregnancy.
The use of oral antidiabetic agents in pregnancy is becoming more common, but nevertheless remains
controversial. Clinicians who prescribe oral agents to manage their patients with diabetes during pregnancy
must consider the potential benefits (avoidance of injections, decreased cost, and patient preference) against
the potential risk (unknown safety, inconsistent effect on the pregnancy outcomes, and potential liability due to
using nonFDA-approved therapy).
Special Situations
Sick Days
70/88
7/1/2014
Acute self-limited illness rarely presents a major problem for patients with type 2 DM, but can be a significant
challenge for insulinopenic type 1 DM patients.69 While caloric intake generally declines, insulin sensitivity also
decreases, meaning that it may take greater amounts of insulin to control BG concentrations. Patients need to
be adept at frequent SMBG, checking urine ketones, use of short-acting insulin, and understanding that sugar
intake in this situation is not detrimental but may be necessary to balance the glucose levels when extra insulin
is needed during illness. Plan to maintain a meal plan containing 120 to 150 g of carbohydrates per day. We
encourage patients to continue their usual insulin regimen and to use supplemental rapid-acting insulin based
on SMBG results, with additional insulin given if ketonuria develops. Ketone testing should be in type 1 DM
patients prone to ketonuria, if two consecutive plasma glucose readings are above 250 mg/dL (13.9 mmol/L),
or if vomiting occurs, as it is a possible sign of ketosis. Sugar and electrolyte solutions, can be used to maintain
hydration, to provide needed electrolytes if there are significant GI or urinary losses, and to provide sugar to
keep the patient from developing hypoglycemia because of the extra insulin that is usually needed. If patients
with type 1 DM are consistently hyperglycemic, we suggest they abstain from sugary drinks and increase intake
of sugar-free liquids. In contrast, patients with type 2 DM may need to switch to sugar-free drinks if BG levels
are continually elevated. Most patients can be taught how to sufficiently manage sick days and avoid
hospitalization.
Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State
DKA and HHS are true diabetic emergencies.70 A comprehensive discussion of their treatment is beyond the
scope of this chapter. In patients with known diabetes, DKA is usually precipitated by insulin omission in type 1
DM, and intercurrent illness, particularly infection, in both type 1 and type 2 DM. However, patients with type 1
or type 2 DM (the latter being usually nonwhites or Hispanics) may present with DKA at initial presentation. It is
possible that some of the patients deemed to have type 2 DM actually have type 1 idiopathic DM. Patients with
DKA may be alert, stuporous, or comatose at presentation. The hallmark diagnostic laboratory values for DKA
include hyperglycemia, anion gap acidosis, and large ketonemia or ketonuria. Diagnostic criteria for HHS are
similar with the exception of significantly higher plasma glucose, elevated effective serum osmolality, and little to
no ketonuria or ketonemia when compared with DKA. HHS typically evolves over several days to weeks,
whereas DKA evolves much quickly. Afflicted patients will have either fluid deficits of several liters or sodium
and potassium deficits of several hundred milliequivalents. Restoration of intravascular volume acutely with
normal saline, followed by hypotonic saline to replace free water, potassium supplements, and constant
infusion of insulin restore the patients metabolic status relatively quickly. A flow sheet is often helpful in
tracking the fluid and insulin therapies and laboratory parameters in these patients. Bicarbonate administration
is generally not needed and may be harmful, especially in children. Treatment of the inciting medical condition
is also vital. Hourly bedside monitoring of glucose and frequent monitoring (every 2 to 4 hours) of potassium is
essential. Metabolic improvement is manifested by an increase in the serum bicarbonate or pH. Serum
phosphorus usually starts high and plummets to lower-than-normal levels, although replacing phosphorus,
while not unreasonable, is of questionable benefit in most patients. Fluid administration alone will reduce the
glucose concentration, so a decrement in glucose values does not necessarily mean that the patients
metabolic status is improving. Rare patients will require larger amounts of insulin than those usually given (5 to
10 units/h). We double the patients insulin dose if the serum bicarbonate has not improved after the first 4
hours of insulin therapy. Constant infusion of a fixed dose of insulin and the administration of IV glucose when
the BG level decreases to <250 mg/dL (<13.9 mmol/L) are preferable to titration of the insulin infusion based
on the glucose level. The latter strategy may delay clearance of the ketosis and prolong treatment. The insulin
infusion should be continued until the urine ketones clear and the anion gap closes. Long-acting insulin should
be given 1 to 3 hours prior to discontinuing the insulin infusion. Intramuscular regular insulin or subcutaneous
insulin lispro or aspart given every 1 to 2 hours can be utilized rather than an insulin infusion in patients without
hypoperfusion. Patients may develop hyperchloremic metabolic acidosis with treatment if they have been given
large volumes of normal saline in the course of their treatment. Such a situation does not require any specific
71/88
7/1/2014
treatment.
HHS usually occurs in older patients with type 2 DM, at times undiagnosed, or in younger patients with
prolonged hyperglycemia and dehydration or significant renal insufficiency. Large ketonemia is usually not
seen, as residual insulin secretion suppresses lipolysis. Infection or another medical illness is the usual
precipitant. Fluid deficits are usually greater and BG concentrations higher (at times >1,000 mg/dL [>55.5
mmol/L]) in these patients than in patients with DKA. BG levels should be lowered very gradually with hypotonic
fluids and low-dose insulin infusions (1 to 2 units/h). Rapid correction of the glucose levels, a drop greater than
75 to 100 mg/dL/h (4.2 to 5.6 mmol/L/h), is not recommended, as it can result in cerebral edema. This is
especially true for children with DKA. Mortality is high with the HHS.
Hospitalization for Intercurrent Medical Illness
Patients on oral agents may need transient therapy with insulin to achieve adequate glycemic control. In
patients requiring insulin, patients should receive scheduled doses of insulin with additional short-acting insulin.
Sliding-scale insulin is to be discouraged, as it is notorious for not controlling glucose and for sometimes
resulting in therapeutic misadventures, with wide amplitudes of glycemic excursions.71 In-hospital mortality is
increased in many hyperglycemic conditions. At least one study documented a reduction in mortality in type 2
diabetes patients with acute MIs72 who receive constant IV insulin during the acute phase of the event to
maintain near-normal glucose concentrations. Similar mortality results have been documented in some
intensive care unit settings using IV insulin and tight glucose control.72,73 The ADA and American Association of
Clinical Endocrinologists released a joint consensus statement on inpatient glycemic control stating that
glucose control measures should be implemented if the BG is 180 mg/dL (10 mmol/L), and maintained
between 140 and 180 mg/dL (7.8 and 10 mmol/L).74 The Normoglycemia in Intensive Care EvaluationSurvival
Using Glucose Algorithm Regulation trial, and several other negative trials, has resulted in this loosening of
inpatient glycemic goals. Critically ill patients had higher 90-day mortality when a goal of 81 to 108 mg/dL (4.5
to 6 mmol/L) was targeted than when BG of 180 mg/dL (10 mmol/L) (achieved 144 mg/dL [8 mmol/L]) was
targeted.75 For noncritically ill patients there are no established BG goals. Reasonable BG goals for these
patients are <140 mg/dL (<7.8 mmol/L) premeal and <180 mg/dL (<10 mmol/L) random.5 Many protocols for IV
insulin infusion are currently available, and implementation for an inpatient setting should use a wellestablished protocol. It is prudent to stop metformin in all patients who arrive in acute care settings until full
elucidation of the reason for presentation can be ascertained, as contraindications to metformin are prevalent
in hospitalized patients. Discharge planning is also important, as approximately one third of patients will have
newly diagnosed diabetes and another one third will likely have prediabetes, as determined by obtaining an
HbA1c on admission (best) or prior to discharge.
Perioperative Management
Surgical patients may experience worsening of glycemia for reasons similar to those listed above for
intercurrent medical illness. Therapy should be individualized based on the type of DM, nature of the surgical
procedure, previous therapy, and metabolic control prior to the procedure. Patients on oral agents may need
transient therapy with insulin to control BG. In patients requiring insulin, scheduled doses of insulin or
continuous insulin infusions are preferred. For patients who can eat soon after surgery, the time-honored
approach of giving one half of the usual morning NPH insulin dose with dextrose 5% in water IV is acceptable,
with resumption of scheduled insulin, perhaps at reduced doses, within the first day. Patients receiving
basal/bolus insulin therapy can continue receiving their usual dose of long-acting insulin while holding the
premeal bolus doses until the patient can tolerate meals. For patients requiring more prolonged periods without
oral nutrition and for major surgery, such as coronary artery bypass grafting and major abdominal surgery,
constant infusion of IV insulin is preferred. Use of IV insulin infusion has been shown to reduce deep sternal
wound infections in patients after coronary artery bypass grafting, although there is no need to start the
72/88
7/1/2014
infusion during or before the procedure. Metformin should be discontinued temporarily after any major surgery
until it is clear that the patient is hemodynamically stable and normal renal function is documented.
Reproductive-Age Women and Preconception Care for Women
An increasing prevalence of DM has been noted in reproductive-age women.5,76,77 Prepregnancy planning is
absolutely mandatory, as organogenesis is largely completed within 8 weeks, so good glycemic control should
be obtained prior to conception. Unfortunately, major congenital malformations due to poor glucose control
remain the leading cause of mortality and serious morbidity in infants of mothers with type 1 or type 2 DM. For
women with DM controlled by lifestyle measures alone, conversion to insulin as soon as the pregnancy is
confirmed is appropriate. Patients previously treated with insulin may need intensification of their regimen to
achieve therapeutic goals. Normal pregnancy is associated with a decrease in the BG concentration as it is
diverted to the fetus.
Human Immunodeficiency Virus (HIV) Patients and Diabetes
Patients living with HIV are at higher risk for the development of type 2 DM.78 This risk may be related to HIV
infection, concomitant infections such as hepatitis C, and concomitant medications often used to treat HIV or
comorbidities. Pentamidine, used for P. carinii pneumonia, is directly -cell toxic in some patients; hypoglycemia
may be followed by hyperglycemia. Megestrol, used as an appetite stimulant, can have glucocorticoid-like
effects in some patients. In addition, protease inhibitors, used to manage HIV, have been shown to potentially
worsen insulin sensitivity, decrease the ability of the cell to secrete insulin, and/or worsen lipotoxicity. Longterm stavudine may also increase the risk of diabetes. Redistribution of fat from medication or HIV infection,
with resultant increases in visceral fat and decreases in subcutaneous fat, is not uncommon. Metformin
continues to be the first-line therapy choice for HIV patients, as weight gain can be minimized, but additional
cautions must be noted. Stavudine, zidovudine, and didanosine may cause lactemia, especially on long-term
use, whereas abacavir, lamivudine, and tenofovir have less incidence of lactemia. It may be advisable to check
lactate levels in appropriate subjects prior to metformin use. If lactate levels are greater than two times normal,
alternative therapy should be considered. If excess visceral adiposity is noted, a TZD, which redistributes fat
back to subcutaneous adipose tissue and causes visceral fat apoptosis, may be considered. Significant drug
drug interactions may also be present (refer to specific diabetes drugs in Chap. 103).
Special Topics
Prevention of Diabetes Mellitus
Efforts to prevent type 1 DM with niacinamide, injected insulin, or oral insulin therapy have been
unsuccessful. Anti-CD3 and anti-CD20 monoclonal antibodies and a GAD vaccine have shown to delay, but not
stop, -cell destruction in type 1 DM. In addition, a 24amino acid sequence derived from human heat shock
protein 60 called DiaPep277 may slow loss of C-peptide secretion in type 1 DM. Future directions include
potential combination therapy trials. The Diabetes Prevention Program79 confirmed that modest weight loss in
association with exercise can have a dramatic impact on insulin sensitivity and the conversion from IGT to type
2 diabetes. In this study approximately 2,000 individuals with IGT were randomized to lifestyle changes (diet,
exercise, and weight loss) versus usual care. The study, which was originally planned to be ongoing for 5
years, was stopped early after 2.8 years. The usual care group developed diabetes at the rate of 11% each
year. The lifestyle arm developed diabetes at a rate of 5% per year, a 58% reduction in the risk of developing
diabetes.79 Surprisingly, a modest amount of diet and exercise yielded impressive results. The exercise
program in the lifestyle group was walking 30 minutes 5 days each week. The mean weight loss over the 2.8year study period was only 8 lb (3.6 kg). In the Diabetes Prevention Program79 discussed above, approximately
1,000 of the study patients were randomized to metformin therapy. Metformin therapy reduced the risk of
73/88
7/1/2014
developing type 2 DM by 31% compared with usual care and resulted in a 4-lb (1.8-kg) weight loss.
Interestingly, young and overweight individuals on metformin had a greater reduction in the risk of developing
diabetes than normal-weight and older study patients.79
All diabetes medications studied for the prevention of diabetes, when discontinued, do not appear to have
residual positive effects on -cell function. Thus, patients must continue the medication for continued
prevention, although the question arises if this is merely early treatment. Troglitazone, a TZD removed from
the market, was able to prevent the development of diabetes in women with a history of gestational diabetes.
Total preservation of -cell function was demonstrated over a 5-year period in women who had near-normal cell function at baseline and who initially responded to the drug.80 The preservation of -cell function was
observed for at least 8 months after the drug had been discontinued. The DREAM trial evaluated rosiglitazone
and/or ramipril treatment for the delay or prevention of type 2 DM in impaired glucose-tolerant subjects.81,82
Rosiglitazone 8 mg daily, over approximately 3 years, reduced the incidence of type 2 diabetes by 60%. In
addition, a 37% nonsignificant increase in cardiovascular events was reported. Ramipril 15 mg daily did not
significantly prevent the conversion to diabetes. It is possible that longer exposure could have made a
difference, but the study was stopped prematurely. In contrast, valsartan, an angiotensin receptor blocker
(ARB), administered for 5 years was recently reported to reduce the risk of progression from IGT to type 2 DM
by 14%. The ACT Now trial used pioglitazone 45 mg daily in an IGT population and found a 72% reduction in
the risk of development of diabetes over 2.4 years.83 It should be noted that no pharmacologic agents are
currently FDA approved or recommended for prevention of type 2 diabetes, although the ADA recommends
metformin in conjunction with lifestyle changes if the patient is younger, obese, has a family history of diabetes,
dyslipidemia, hypertension, or a HbA1c >6% (>0.06; >42 mmol/mol Hb).5 The next step is discussions with the
FDA to decide how and if medications to prevent diabetes can be approved for this indication.
Patient Education
It is not satisfactory to give patients with DM brief instructions with a few pamphlets and expect them to
manage their disease adequately.84 Diabetes education is a lifetime exercise. Successful treatment of DM
involves lifestyle changes for the patient (e.g., medical nutrition therapy, physical activity, SMBG and possibly
of urine for ketones, recognition of hyperglycemia and hypoglycemia, and taking prescribed medications). The
American Association of Diabetes Educators (AADE) has developed the AADE7 self-care behaviors of healthy
eating, being active, monitoring, taking medication, problem solving, reducing risk, and healthy coping, which is
a good starting framework for patient discussions. The patient must be involved in the decision-making process
and must learn as much about the disease and associated complications as possible. Emphasis should be
placed on the evidence that indicates that complications can be prevented or minimized with glycemic control
and management of risk factors for CVD. Recognition of the need for proper patient education to empower
them into self-care has generated programs for certification in diabetes education for pharmacists. Certified
diabetes educators (CDEs) must document their patient education hours and sit for a certification examination
that assesses the knowledge, tasks, and skills of an educator in order to become certified. An increasing
number of nurses, pharmacists, dietitians, and physicians are becoming CDEs to document to the public that
they meet a minimum standard for diabetes education, and to fulfill quality initiatives in meeting guidelines for
education recognition. Being a CDE does not guarantee reimbursement of services, and CDEs who are not
dietitians will often need to become part of a recognized program to obtain reimbursement. Currently the AADE
and ADA have accreditation programs.
Treatment of Concomitant Conditions and Complications

Retinopathy
Patients with established retinopathy should see an ophthalmologist or optometrist trained in diabetic eye
74/88
7/1/2014
disease. A dilated eye examination is required to fully evaluate diabetic eye disease. Early background
retinopathy may reverse with improved glycemic control and optimized blood pressure control. More advanced
retinopathy will not fully regress with improved glycemia, but caution should be taken on the expediency of
glycemia lowering, as aggressive reductions in glycemia may acutely worsen retinopathy. The pathophysiology
of retinopathy is better understood to involve inappropriate growth factor increase and microcirculation
ischemia. Bevacizumab, used off-label, and ranibizumab, recently FDA approved, are antivascular endothelial
growth factor monoclonal antibodies given by intravitreal injection. Although approved for macular edema, use
may also apply to other neovascular ocular conditions. A protein kinase C inhibitor has been studied, but
results have been modest. Laser photocoagulation has markedly improved sight preservation in diabetic
patients. People with diabetes also have a higher rate of cataracts and possibly open-angle glaucoma.
Neuropathy
Neuropathy in diabetes can generally be placed into three categories: peripheral neuropathy, autonomic
neuropathy, and focal neuropathy. Distal symmetrical peripheral neuropathy is the most common complication
seen in type 2 DM patients in outpatient clinics.85 Paresthesias, perceived hot or cold, numbness, or pain may
be the predominant symptom. The feet are involved far more often than the hands as it affects longer nerves
first and progresses proximally. Improved glycemic control is the primary treatment and may alleviate some of
the symptoms. If neuropathy is painful, symptomatic pain treatment is indicated, although it will not change the
course of the neuropathy nor has one medication been shown to be superior to another. Treatment may be
with low-dose tricyclic antidepressants, anticonvulsants (gabapentin, pregabalin, rarely carbamazepine),
duloxetine, venlafaxine, topical capsaicin, and various pain medications, including tramadol and nonsteroidal
antiinflammatory drugs. Duloxetine and pregabalin have FDA approval for this indication. The numb variant of
peripheral neuropathy is not treated with medication, but may lead to pressure areas on the foot and
subsequent ulcer in a subset of patients. Clinical manifestations of diabetic autonomic neuropathy include
resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile
dysfunction, sudomotor dysfunction (anhidrosis, heat intolerance, gustatory sweating, and/or dry skin),
impaired neurovascular function, and hypoglycemic autonomic failure. Gastroparesis can be a severe and
debilitating complication of DM. Improved glycemic control, discontinuation of medications that slow gastric
motility, and the use of metoclopramide (preferably for only a few weeks at a time) or low-dose erythromycin
may be helpful. Gastric pacemakers as therapeutic hardware are rarely used, though available. Cisapride,
removed from the market several years ago, is still available for compassionate use and domperidone,
available outside of the United States, may be useful. Orthostatic hypotension, after stopping antihypertensives
and liberalizing dietary sodium intake, may require pharmacologic management with mineralocorticoids or
adrenergic agonist agents. In severe cases, supine hypertension is extreme, mandating that the patient sleep
in a sitting or semirecumbent position. Patients with cardiac autonomic neuropathy are at a higher risk for silent
MI and sudden cardiac death. The hallmark of diabetic diarrhea is its nocturnal occurrence. Diabetic diarrhea
frequently responds to a 10- to 14-day course of an antibiotic such as doxycycline or metronidazole. In more
unresponsive cases, octreotide may be useful. Erectile dysfunction is common in diabetes, and initial treatment
should include a trial of one of the phosphodiesterase type 5 inhibitors prior to referral. People with diabetes
often require the highest doses of these medications to have an adequate response. Sudomotor dysfunction,
as earlier defined, results in loss of sweating and resultant dry, cracked skin. Use of hydrating creams and
ointments is needed. Hypoglycemic unawareness requires the patient to avoid hypoglycemia, as the body will
slowly increase the glycemic level at which it will signal the autonomic signals, although damage may severely
lessen the response. Focal neuropathies are uncommon, but occur more often in older, poorly controlled
diabetes patients. Diabetic amyotrophy, which is characterized by a proximal thigh muscle pain and weakness,
is one of the most debilitating. In addition, cranial nerve III, IV, and VI neuropathies, as well as Bells palsy, may
occur. The presentation can be quite dramatic, but the course is usually self-limited, and partial or full recovery
happens in a few weeks to months. Carpal tunnel syndrome, caused by radial nerve entrapment, is also more
75/88
7/1/2014
common in people with diabetes,

Microalbuminuria and Nephropathy
DM, particularly type 2 DM, is the biggest contributor statistically to the development of end-stage renal disease
in the United States.1,5 The ADA recommends a screening urinary analysis for albumin at diagnosis in persons
with type 2 DM. Precise onset of type 2 DM can rarely be ascertained, and patients will often present at
diagnosis with microvascular complications. In type 1 DM, microalbuminuria rarely occurs with short duration of
disease or before puberty. Screening individuals with type 1 DM should begin with puberty and after 5 years
disease duration. There are three methods for assessing microalbuminuria: (a) measurement of the urine
albumin-to-creatinine ratio in a random spot collection (preferably the first morning void); (b) 24-hour timed
collection; and (c) timed (e.g., 4- or 10-hour overnight) collection. Microalbuminuria on a spot urine specimen is
defined as an albumin-to-creatinine ratio of 30 to 300 mg/g (3.4 to 34 mg/mmol creatinine). On timed
collections, microalbuminuria is defined as 30 to 300 mg/24 hours or an albumin excretion rate of 20 to 200
mcg/min. Because of day-to-day variability, microalbuminuria should be confirmed on at least two of three
samples over 3 to 6 months unless unequivocal. Additionally, when assessing urine protein or albumin,
conditions that may cause transient elevations in urinary albumin excretion should be excluded. These
conditions include intense exercise, recent urinary tract infections, hypertension, short-term hyperglycemia,
heart failure, and acute febrile illness.5
In type 2 DM, the presence of microalbuminuria is a strong risk factor for macrovascular disease and is
frequently present at the time of diagnosis. Microalbuminuria is a weaker predictor for future end-stage kidney
disease in type 2 versus type 1 DM. Glucose and blood pressure control are most important for the prevention
of nephropathy, and blood pressure control is the most important for retarding the progression of established
nephropathy. ACE inhibitors and ARBs, considered first-line recommended treatment modalities, have shown
efficacy in preventing the clinical progression of renal disease in patients with diabetes. Combined renin
angiotensinaldosterone system blockage (with ACE inhibitors, ARBs, aldosterone receptor blockers, and/or
direct renin inhibitors) cannot currently be recommended for routine practice in nephropathy. Diuretics
frequently are necessary due to the volume-expanded state of the patient and are recommended second-line
therapy. The ADA and the National Kidney Foundation blood pressure goal of <130/80 mm Hg can be difficult
to achieve. Three or more antihypertensives are often needed to treat to goal blood pressures (see also Chap.
29).
Peripheral Vascular Disease and Foot Ulcers
Claudication and nonhealing foot ulcers are common in type 2 DM patients.86 Smoking cessation, correction of
lipid abnormalities, and antiplatelet therapy are important strategies in treating claudicants. Cilostazol may be
useful for reducing intermittent claudication symptoms in select patients. Revascularization is successful in
selected patients, although small vessel disease that cannot be bypassed is common in diabetes. Local
dbridement and appropriate footwear and foot care are vitally important in the early treatment of foot lesions.
In more advanced lesions multiple treatments including grafts, topical wound healing, and even hyperbaric
treatments may be necessary. Diabetic foot care is an excellent example of the adage, an ounce of prevention
is worth a pound of cure. Thus, a foot examination at each visit is recommended. A yearly Semmes-Weinstein
5.07/10-g force monofilament test for sensation can be used to identify high-risk patients who need further
podiatric evaluation.
Coronary Heart Disease
The risk for coronary heart disease (CHD) is two to four times greater in diabetic patients than in
nondiabetic individuals. CHD is the major source of mortality in patients with DM. Multiple risk factor intervention
(lipids, hypertension, smoking cessation, and antiplatelet therapy)5 will reduce the burden of excess
76/88
7/1/2014
macrovascular events. The ADA recommends aspirin therapy in all secondary prevention situations, and if
allergic to aspirin, consider clopidogrel. Recent evidence in primary prevention studies of antiplatelet therapy in
type 2 DM has not shown benefit. The ADA currently recommends that if the 10-year risk of CVD is at least
10%, or the patient is at your judgment high risk, or in women at least 60 years old or men at least 50 years
old, primary prevention antiplatelet therapy can be considered. Epidemiologic data suggest that CHD
prevention guidelines for type 2 DM apply equally to patients with type 1 DM.5 -Blocker therapy supplies an
even greater protection from recurrent CHD events in diabetic patients than in nondiabetic subjects. Masking of
hypoglycemic symptoms is a greater problem in type 1 DM patients than in patients with type 2 DM, although
this risk can be adequately managed with proper glycemic control interventions (see also Chap. 6).
Lipids
The Collaborative Atorvastatin Diabetes Study (CARDS) randomized diabetes subjects with no documented
CVD to atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410). The trial was stopped 2 years early (mean
duration of follow-up was 3.9 years) after meeting the primary efficacy end point of major cardiovascular
events, which were reduced by 37% (P = 0.001). All-cause death was reduced 27% (P = 0.059), and potentially
could have had its significance influenced by the early stoppage of the trial.87 The Heart Protection Study
randomized 5,963 patients aged >40 years with diabetes and total cholesterol >135 mg/dL (>3.49 mmol/L). A
significant 22% reduction (95% CI, 13 to 30) in the event rate for major cardiovascular events was seen with
simvastatin 40 mg/day. This was evident even at lower LDL levels (<116 mg/dL [<3 mmol/L]), and suggests that
30% to 40% reduction in LDL levels regardless of starting LDL levels may be appropriate.88 The ADA
recommends statin therapy, regardless of baseline lipid or LDL-C levels in patients with overt CVD or without
documented CVD who are over the age of 40 and have CVD risk factors besides diabetes.5
The proper use of fibrates in diabetes continues to be controversial. The Fenofibrate Intervention and Event
Lowering in Diabetes (FIELD) was conducted in 9,795 subjects (22% with previously documented CVD) with
type 2 DM given fenofibrate 200 mg daily or placebo. A relative reduction of 11% (P = 0.16) was seen in any
coronary event in conjunction with a slight increase in the risk of all-cause mortality (0.7%; P = 0.18). Reasons
for this have been speculated on, including the increased use of statins in the placebo group, but continue to
be controversial.89 On subset analysis, only subjects without CVD had a significant reduction in CVD events.
The lipid arm of the ACCORD90 reported on 5,518 subjects randomized to fenofibrate or placebo given with
low-dose simvastatin (20 mg/day). Fenofibrate addition did not significantly lower cardiovascular events (0.92;
95% CI, 0.79 to 1.08). Niacin in combination with a statin recently failed to improved CVD outcomes as well.
The NCEP-ATP III15 guidelines classify the presence of DM as a CHD risk equivalent, and therefore recommend
that LDL-C be lowered to <100 mg/dL (<2.59 mmol/L). An optional LDL goal in high-risk DM patients, such as
those who already have CHD, has been updated to <70 mg/dL (<1.81 mmol/L)91 (Table 57-12). The primary
goal of treatment is to obtain the LDL-C goal. After the LDL-C goal is reached (usually with a statin), via NCEPATP, triglycerides are possibly considered for pharmacologic management, assuming unresponsiveness to
glycemic control efforts, weight management, and exercise. In such situations, a nonHDL-C goal is established
(a surrogate for all apolipoprotein Bcontaining particles). The nonHDL-C goal for patients with DM is <130
mg/dL (<3.36 mmol/L). Niacin or a fibrate can be added to reach that goal if triglycerides are 201 to 499 mg/dL
(2.27 to 5.64 mmol/L), although there is little evidence this will lower CVD. Patients with marked
hypertriglyceridemia (500 mg/dL [5.65 mmol/L]) are at risk for pancreatitis. Efforts to reduce triglycerides with
glycemic control, elimination of other secondary causes (including medications), and drug therapy (fibrates,
statins, and potentially niacin) are effective treatment strategies. Readers are also referred to the Chapters 3
and 11 for further information.
Table 57-12 Classification of Lipid and Lipoprotein Levels in Adults
77/88
7/1/2014
Param eter Goal
Treatm ent (In Order of Preference)
LDL
cholesterol
<100 mg/dL (<2.59 mmol/L) <70 mg/dL (<1.81

mmol/L)a
Lifestyle; HMG-CoA reductase inhibitors; cholesterol absorption inhibitor; niacin

or fenofibrate
HDL
cholesterol
Men: >40 mg/dL (>1.03 mmol/L)
Lifestyle; nicotinic acid; fibric acid derivatives
Women: >50 mg/dL (>1.29 mmol/L)

Triglycerides <150 mg/dL (<1.70 mmol/L)
Lifestyle; glycemic control; fibric acid derivatives; high-dose statins (in those
w ith high LDL)
HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low -density lipoprotein.
aMay be optimal goal in patients w ith preexisting cardiovascular disease.
See references 5, 91, and 92.
Hypertension
The role of hypertension in increasing microvascular and macrovascular risk in patients with DM has been
confirmed in the UKPDS.44 The ADA has loosened its goals for blood pressure (<140/80 mm Hg) in patients
with DM.5 The ACCORD blood pressure arm studied type 2 DM patients, with a goal of achieving a systolic
blood pressure of either <120 mm Hg (achieved 119 mm Hg) or <140 mm Hg (133 mm Hg achieved).92 The
lower pressure group did not have lower CVD or renal outcomes, but did have a lower risk of stroke. A goal of
<130 mm Hg can still be considered in patients at high risk of a stroke or if renal disease is present. ACE
inhibitors and ARBs are generally recommended for initial therapy, as they have shown to be cardioprotective,
and likely have special renal protection. Many patients require multiple agents, on average three agents, to
obtain goals, so diuretics, calcium channel blockers, and -blockers frequently are useful as second and third
agents. African Americans need special consideration. They receive renoprotection from ACE inhibitors or
ARBs, but as a population may lower blood pressure slightly less with these agents. It is recommended that
combination therapy with a diuretic or calcium channel blocker be considered as first-line therapy. After initial
therapy, which agent to add next is still controversial. Blood pressure goals are generally more difficult to
achieve than glycemic goals or lipid goals in most diabetic patients. Readers are referred to Chapter 3 for more
information.
Transplantation
Whole pancreas and islet cell transplantation are options in patients with type 1 DM; those with end-stage renal
disease also receive kidney transplantation. Lifelong immunosuppression is required.
Personalized Pharmacotherapy
Individualization of therapy in DM is based on several factors. There is no optimal regimen in diabetes, and it is
mostly based on reaching glycemic goals. In type 1 DM, as insulin must be used, it is to tailor the insulin
regimen to the lifestyle of the patient. This almost always involves basalbolus therapy, individualized based on
SMBG readings. In addition, if the patient does not mind being attached to a pump, therapy can be further
tailored to the patient. It may in unusual circumstances involve simplification of the regimen to premix insulins,
as basalbolus therapy may not fit into their lifestyle. Elevated glucagon levels in some patients, as the
hormone amylin is low or absent, may require glucagon suppression therapy. FDA-approved therapy includes
addition of pramlintide, but there is evidence for use of nonapproved medications such as GLP-1 receptor
antagonists to act as an alternative to pramlintide, which requires many extra injections per day. In addition,
metformin has been used in some type 1 DM patients who are adherent (and thus at low risk of DKA) but have
suboptimal control of their FPG readings. Metformin use should not be routine, but in examples such as
adolescents who miss injections after frank discussions with patients and parents.
No one regimen in type 2 DM is considered to be optimal for all patients. Common individualization points
78/88
7/1/2014
include mechanism of action, contraindications, side effects, and potential adverse events including
hypoglycemia, efficacy (including fasting vs. postprandial control), long-term safety, ease of use, and cost. In
addition, nonglycemic effects such as weight changes, lipid effects, cardiovascular outcomes, and even
perceived -cell preservation/effects may influence final choices.
Evaluation of Therapeutic Outcomes

A comprehensive pharmaceutical care plan for the patient with DM will integrate considerations of goals to
optimize BG control and protocols to screen for, prevent, or manage microvascular and macrovascular
complications. In terms of standards of care for persons with DM, one can review the document published by
the ADA that outlines initial and ongoing assessments for patients with DM.5 The major performance measure
by the National Committee for Quality Assurance (NCQA), such as Health Plan Employer Data and Information
Set (HEDIS), should assess the ability to meet current standards of care and recognize the minimal treatment
goals for glycemia, lipids, and hypertension, and provide targets for monitoring and adjusting pharmacotherapy
as discussed in various sections above. Publicly reported quality measures continue to move closer to current
guidelines, but lack the ability to differentiate reasons why a patient is not controlled. Glycemic control (tested
minimally yearly; HbA1c <8% [<0.08; <64 mmol/mol Hb] is good control and HbA1c >9% [>0.09; >75 mmol/mol
Hb] is poor control), lipid (percentage of patients with LDL <100 mg/dL [<2.59 mmol/L]), and hypertension
(percentage of patients with blood pressure <130/80 mm Hg, but also with blood pressure <140/90 mm Hg) are
NCQA-based measures. Glycemic control is paramount in managing type 1 or type 2 DM, but as readily
identified from the above discussion, it requires frequent assessment and adjustment in diet, exercise, and
pharmacologic therapies. The ADA also has clinical practice recommendations that are widely cited and
followed.5 Minimally, HbA1c should be measured twice a year in patients meeting treatment goals on a stable
therapeutic regimen. Quarterly assessments are recommended for those whose therapy has changed or who
are not meeting glycemic goals. Fasting lipid profiles should be obtained as part of an initial assessment and
thereafter at each follow-up visit if not at goal, annually if stable and at goal, or every 2 years if the lipid profile
suggests low risk. Documenting regular frequency of foot examinations (each visit), urine albumin assessment
(annually), dilated ophthalmologic examinations (yearly or more frequently with identified abnormalities), and
office visits for follow-up are also important. Assessment for pneumococcal vaccine administration (and onetime revaccination recommended in individuals at least 65 years old), annual administration of influenza
vaccine, new recommendations that all people with diabetes receive the hepatitis B vaccine series, and routine
assessment for and management of other cardiovascular risks (e.g., smoking and antiplatelet therapy) are
components of preventive medicine strategies. The multiplicity of assessments for each patient visit is likely to
be better facilitated utilizing an integrative computer program and electronic medical record, standardized
progress note forms, or flow sheets, which assist the clinician in identifying whether the patient has met
standards of care in the frequency of monitoring and achievement of defined targets of therapy. Adherence
continues to be of issue, as with many chronic diseases, and use of frequent education and potential
simplification of regimens, if possible through combination medications, may be warranted (Table 57-13). In
addition, many patients do not take medications because of tolerance, side effects, and perceived risk versus
benefit from their clinician or from family, friends, or the Internet (Table 57-14).
Table 57-13 Combination Products Available in Type 2 Diabetes Mellitusa
Medication
Metformin and/or metformin extended release
Com bined With
Trade Nam e
Pioglitazone
Actosplus Met
Rosiglitazone
Avandamet
Sitagliptin
Janumet
79/88
7/1/2014
Glimepiride
Pioglitazone
Saxagliptin
Kombiglyze
Linagliptin
Jentadueto
Alogliptin
Kazano
Glyburide
Glucovance
Glipizide
Metaglip
Repaglinide
Prandimet
Pioglitazone
Duetact
Rosiglitazone
Avandaryl
Alogliptin
Oseni
aAt time chapter w ritten.
Table 57-14 Drug Monitoring for Diabetes Mellitus Medications

Medication
Class
Adverse Drug Reaction
Monitoring Param eters
Com m ents
-Glucosidase
inhibitors
GI upset
Gas, bloating, loose stools
Titrate, take in less carbohydrate
Bile acid
sequestrants
Constipation
Bow el movement frequency
Do not use if history of bow el obstruction
Raises triglycerides
Triglycerides
Not recommended TG>500 mg/dL (>5.65 mmol/L)
GI upset
Reflux, nausea, vomiting, stomach

upset, loose stools
Take w ith food and titrate dose; split doses;

consider extended release
Lactic acidosis
Hypoxic states, renal function
Lactate levels usually not measured, but can if

suspected toxicity
Biguanides
DPP-4 inhibitors
Hypersensitivity/angioedema
Skin rash, signs/symptoms of
and exfoliating dermatologic skin angioedema
reactions
Risk factors, such as history of angioedema,

possibly ACE inhibitor use, and past history of
severe dermal drug reactions, should be explored
Pancreatitis
Amylase, lipase, abdominal pain

w ith nausea/vomiting
Discontinue; look for underlying causes
Hypotension
Syncopal symptoms
Stop antihypertensives
Worsening psychiatric issues
Signs/symptoms of underlying
mental illness
Avoid use w ith antipsychotics
CNS effects
Mental
Titrate slow ly
alertness/asthenia/fatigue/headache
Gastrointestinal side effects
Nausea
Titrate slow ly
Signs/symptoms of heart failure,

BNP, w eight
Discontinue
Peripheral edema
Peripheral edema measures
Limit dose, consider diuretic (see text), or

discontinue
Weight gain
Weight
Consider if w eight is fluid or likely caloric intake
Peripheral fractures
None except fracture
Avoid use in osteoporosis and osteopenia
Sulfonylureas
Hypoglycemia
Self-monitored blood glucose
Meglitinides
Hypoglycemia
GLP-1 receptor
agonists
GI
Nausea/vomiting
Titrate slow ly; avoid in gastroparesis
Pancreatitis
Amylase, lipase, abdominal pain

w ith nausea/vomiting
Discontinue; look for underlying causes
C-cell tumors of thyroid
None recommended, calcitonin
Calcitonin could be measured if suspected, has not

occurred in humans to date
GI upset
Nausea/vomiting
Titrate slow ly; avoid in gastroparesis
Dopamine
agonists
Thiazolidinediones Heart failure/pulmonary edema
Amylinomimetic
80/88
7/1/2014
Insulin
Hypoglycemia
Abbreviations
AADE
American Association of Diabetes Educators
ACCORD
Action to Control Cardiovascular Risk in Diabetes
ACE
angiotensin-converting enzyme
ADA
American Diabetes Association
ADVANCE
Action in Diabetes and Vascular Disease
AHA
American Heart Association
ALT
alanine aminotransferase
ARB
angiotensin receptor blocker
BG
blood glucose
BMI
body mass index
CARDS
Collaborative Atorvastatin Diabetes Study
CDE
certified diabetes educator
CGM
continuous glucose monitoring
CHD
coronary heart disease
CI
confidence interval
CLcr
creatinine clearance
CSII
continuous subcutaneous insulin infusion
CVD
cardiovascular disease
CYP450
cytochrome P450
DCCT
Diabetes Control and Complications Trial
DKA
diabetic ketoacidosis
DM
diabetes mellitus
DPP-4
dipeptidyl peptidase-4
eAG
estimated average glucose
EDIC
Epidemiology of Diabetes Interventions and Complications
FFA
free fatty acid
FIELD
Fenofibrate Intervention and Event Low ering in Diabetes
FPG
fasting plasma glucose
GDM
gestational diabetes mellitus
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
HbA 1c
hemoglobin A 1c
HDL
high-density lipoprotein
HDL-C
high-density lipoprotein cholesterol
HEDIS
Health Plan Employer Data and Information Set
HHS
hyperosmolar hyperglycemic state
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HR
hazard ratio
ICA
islet cell antibody
IDF
International Diabetes Federation
IFG
impaired fasting glucose
IGT
impaired glucose tolerance
LADA
latent autoimmune diabetes in adults
LDL-C
low -density lipoprotein cholesterol
Look AHEAD
Look Action for Health in Diabetes
MI
myocardial infarction
MODY
maturity onset diabetes of youth
NCEP-ATP
National Cholesterol Education Program Adult Treatment Panel
NCQA
National Committee for Quality Assurance
NGSP
National Glycohemoglobin Standardization Program
NHLBI
National Heart, Lung, and Blood Institute

81/88
7/1/2014
NPH
neutral protamine Hagedorn
OGTT
oral glucose tolerance test
PAI-1
plasminogen activator inhibitor-1
PPAR-
peroxisome proliferatoractivated receptor
RECORD
Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes
SGLT-2
sodium-dependent glucose cotransporter-2
SMBG
self-monitoring of blood glucose
SUR
sulfonylurea receptor
TZD
thiazolidinedione
UKPDS
United Kingdom Prospective Diabetes Study
VADT
Veterans Affairs Diabetes Trial
VAT
visceral adipose tissue
ZnT8
zinc transporter 8
References
1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General
Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health
and Human Services, Centers for Disease Control and Prevention, 2011.
2. American Diabetes Association. Clinical practice recommendations. Diagnosis and classification of diabetes
mellitus. Diabetes Care 2013;36(Suppl 1): S67S74.
3. Naik R, Lernmark A, Palmer J. Pathophysiology and genetics of type 1 (insulin-dependent) diabetes. In:
Porte D Jr, Sherwin RS, Baron A, Ellenberg M, Rifkin H, eds. Ellenberg & Rifkins Diabetes Mellitus, 6th ed. New
York, NY: McGraw-Hill, 2003:301330.
4. Bennett P, Rewers M, Knowler W. Epidemiology of diabetes mellitus. In: Porte D Jr, Sherwin RS, Baron A,
Ellenberg M, Rifkin H, eds. Ellenberg & Rifkins Diabetes Mellitus, 6th ed. New York, NY: McGraw-Hill,
2003:277300.
5. American Diabetes Association. Standards for medical care in diabetes2013. Diabetes Care
2013;36(Suppl 1):S11S66.
6. American Diabetes Association. Standards of care. Children and adolescents in: Clinical practice
recommendations. Diabetes Care 2013;36(Suppl 1):S40S43.
7. DeFronzo RA. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2
diabetes mellitus. Diabetes 2009;58:773795. [PubMed: 19336687]
8. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe
SG, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the
diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33: 676682.
9. Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: A
systematic review and meta-analysis. Arch Dis Child 2008;93: 512517. [PubMed: 18339654]
10. Winter W, Harris N, Schatz M. Immunological markers in the diagnosis and prediction of autoimmune type
1a diabetes. Clin Diabetes 2002;20:183191.
11. Cherrington AD. Banting Lecture 1997: Control of glucose uptake and release by the liver in vivo. Diabetes
1999;48:11981214. [PubMed: 10331429]
12. McGarry JD. Banting Lecture 2001: Dysregulation of fatty acid metabolism in the etiology of type 2
diabetes. Diabetes 2002;51:718. [PubMed: 11756317]
82/88
7/1/2014
13. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus: Metabolic and molecular implications for identifying
diabetes genes. Diabetes 1997;5:117269.
14. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004;88:787835. [PubMed:
15308380]
15. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive
summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA
2001;285(19):24862497.
16. Alberti KGMM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome. A joint interim statement
of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung,
and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society;
and International Association for the Study of Obesity. Circulation 2009;120:16401645. [PubMed: 19805654]
17. Ervin RB. Prevalence of Metabolic Syndrome among Adults 20 Years of Age and Over, by Sex, Age, Race
and Ethnicity, and Body Mass Index: United States, 20032006. National Health Statistics Reports, No. 13.
Hyattsville, MD: National Center for Health Statistics, 2009.
18. Alexander CM, Landsman PB, Teutsch SM, et al. NCEP-defined metabolic syndrome, diabetes, and
prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes
2003;52(5):12101214. [PubMed: 12716754]
19. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: Findings from the
third National Health and Nutrition Examination Survey. JAMA 2002;287(3):356359. [PubMed: 11790215]
20. Kahn R, Buse J, Ferrannini E, Stern M, American Diabetes Association, European Association for the Study
of Diabetes. The metabolic syndrome: Time for a critical appraisal: Joint statement from the American Diabetes
Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28(9):22892304.
[PubMed: 16123508]
21. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An
American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation
2005;112(17): 27352752. [PubMed: 16157765]
22. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with
type 2 diabetes. N Engl J Med 2003;348:383393. [PubMed: 12556541]
23. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on
the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J
Med 1993; 329:977986.
24. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet 1998; 352:837853.
25. Nathan DM, Kuenen J, Borg R, et al. Translating the A1C assay into estimated average glucose values.
Diabetes Care 2008;31:14731478. [PubMed: 18540046]
26. Malanda UL, Welschen LMC, Riphagen II, et al. Self-monitoring of blood glucose in patients with type 2
diabetes mellitus who are not using insulin. Cochrane Database Syst Rev 2012;(1):CD005060.
27. American Diabetes Association. Nutrition recommendations and interventions for diabetes. Diabetes Care
2008; 31(Suppl 1):S61S78.
83/88
7/1/2014
28. American Diabetes Association. Diabetes mellitus and exercise. Diabetes Care 2010;33(Suppl 1):S26S27.
29. Malmberg K, for the DIGAMI Study Group. Prospective randomised study of intensive insulin treatment on
long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997;314:1512
1515. [PubMed: 9169397]
30. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in
older Americans. N Engl J Med 2011;365:20022012. [PubMed: 22111719]
31. The ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N
Engl J Med 2012;367:319328.
32. Blevins T, Pullman J, Malloy J, et al. DURATION-5. Exenatide once weekly resulted in greater improvements
in glycemic control compared to exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab
2011;96:13011310. [PubMed: 21307137]
33. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2
diabetes: A randomised, open-label, non-inferiority study. Lancet 2008;372:12401250. [PubMed: 18782641]
34. Schor S. The University Group Diabetes Program. A statistician looks at the mortality results. JAMA 1971;
217:16731675.
35. Triplitt C. Drug interactions of medications commonly used in diabetes. Diabetes Spectrum 2006;19:202
211.
36. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854865.
37. Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of vascular events in patients with
type 2 diabetes in the PROactive study prospective pioglitazone clinical trial in macrovascular events: A
randomized controlled trial. Lancet 2005;366:12791289. [PubMed: 16214598]
38. Nissen SE, Wolski K. The effect of rosiglitazone on the risk of myocardial infarction and death from
cardiovascular causes. N Engl J Med 2007;356:115.
39. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral
agent combination therapy for type 2 diabetes (RECORD): A multicentre, randomised, open-label trial. Lancet
2009; 373:21252135. [PubMed: 19501900]
40. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: The STOPNIDDM randomized trial. Lancet 2002;359:20722077. [PubMed: 12086760]
41. Chiasson JL, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and
hypertension in patients with impaired glucose tolerance: The STOP-NIDDM trial. JAMA 2003;290:486494.
[PubMed: 12876091]
42. Stratton IM, Adler AI, Neil HA. Association of glycaemia with macrovascular and microvascular complications
of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ 2000;321:405412. [PubMed:
10938048]
43. Adler AI, Stratton IM, Neil HA. Association of systolic blood pressure with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 36): Prospective observational study. BMJ 2000;321:412419.
[PubMed: 10938049]
44. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular
84/88
7/1/2014
and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998;317:713720.

45. Writing Team for the Diabetes Control and Complications/Epidemiology of Diabetes Interventions and
Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on
development and progression of diabetic nephropathy: The Epidemiology of Diabetes Interventions and
Complications (EDIC) study. JAMA 2003;290:21592167.
46. DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients
with type 1 diabetes. N Engl J Med 2005;353:26432653.
47. Holman RR, Paul SK, Bethel MA, Mathews DR, Neil HAW. 10-Year follow-up of intensive glucose control in
type 2 diabetes. N Engl J Med 2008;359:15771589. [PubMed: 18784090]
48. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in
type 2 diabetes. N Engl J Med 2008;358:25452559.
49. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with
type 2 diabetes. N Engl J Med 2008;358:25602572.
50. Duckworth W, Abraira C, Mortiz T, et al. Glucose control and vascular complications in veterans with type 2
diabetes. N Engl J Med 2009;360:111.
51. Strowig S, Raskin P. Intensive management of insulin-dependent diabetes mellitus. In: Porte D Jr, Sherwin
RS, eds. Ellenberg & Rifkins Diabetes Mellitus, 5th ed. Stamford, CT: Appleton & Lange, 1997:709733.
52. Schade DS, Valentine V. To pump or not to pump. Diabetes Care 2002;25:21002102. [PubMed:
12401763]
53. Kort H, Koning EJ, Rabelink TJ, et al. Islet transplantation in type 1 diabetes. BMJ 2011;342:d247.
54. Inzucchi SE, Bergenstal RM, Buse JB. Management of hyperglycemia in type 2 diabetes: A patient-centered
approach: Position statement of the American Diabetes Association (ADA) and the European Association for
the Study of Diabetes (EASD). Diabetes Care 2012;35: 13641379. [PubMed: 22517736]
55. Holman RR, Farmer AJ, Davies MJ, et al. Three-year efficacy of complex insulin regimens in type 2
diabetes. N Engl J Med 2009;361:17361747. [PubMed: 19850703]
56. Triplitt CL. How to initiate, titrate, and intensify insulin treatment in type 2 diabetes. US Pharm 2007;32:10
16.
57. Araki A, Iimuro S, Sakurai T, et al. Japanese Elderly Diabetes Intervention Trial Study Group. Long-term
multiple risk factor interventions in Japanese elderly diabetic patients: The Japanese Elderly Diabetes
Intervention Trial: Study design, baseline characteristics and effects of intervention. Geriatr Gerontol Int
2012;12(Suppl 1):717.
58. Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care 2012;35:26502664.
[PubMed: 23100048]
59. Sinclair AJ, Paolisso G, Castro M, et al., European Diabetes Working Party for Older People. European
Diabetes Working Party for Older People 2011 clinical guidelines for type 2 diabetes mellitus. Executive
summary. Diabetes Metab 2011; 37(Suppl 3):S27S38.
60. Langer O, Conway DL, Berkus MD, Xenakis EM. A comparison of glyburide and insulin in women with
gestational diabetes mellitus. N Engl J Med 2000;343: 11341138. [PubMed: 11036118]
61. Cheng YW, Chung JH, Block-Kurbisch I, Inturrisi M, Caughey AB. Treatment of gestational diabetes
85/88
7/1/2014
mellitus: Glyburide compared to subcutaneous insulin therapy and associated perinatal outcomes. J Mater
Fetal Neonatal Med 2012;25(4):379384. [PubMed: 21631239]
62. Coetzee EJ, Jackson WP. Pregnancy in established non-insulin-dependent diabetics. A five-and-a-half year
study at Groote Schuur Hospital. S Afr Med J 1980;58: 795802. [PubMed: 6777880]
63. Coetzee EJ, Jackson WP. Oral hypoglycaemics in the first trimester and fetal outcome. S Afr Med J
1984;65: 635637. [PubMed: 6369573]
64. Hellmuth E, Damm P, Mlsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet
Med 2000;17:507511. [PubMed: 10972579]
65. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for
the treatment of gestational diabetes. N Engl J Med 2008;358:20032015. [PubMed: 18463376]
66. Nicholson W, Bolen S, Witkop CT, et al. Benefits and risks of oral diabetes agents compared with insulin in
women with gestational diabetes: A systematic review. Obstet Gynecol 2009;113:193. [PubMed: 19104375]
67. Dhulkotia JS, Ola B, Fraser R, Farrell T. Oral hypoglycemic agents vs insulin in management of gestational
diabetes: A systematic review and metaanalysis. Am J Obstet Gynecol 2010;203:457. [PubMed: 20739011]
68. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2004;27(1):s88s90.
69. Laffel L. Sick-day management in type 1 diabetes. Endocrinol Metab Clin North Am 2000;29:707723.
[PubMed: 11149158]
70. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. A
consensus statement from the American Diabetes Association. Diabetes Care 2009;32:13351343. [PubMed:
19564476]
71. Hirsch IB. Sliding scale insulinTime to stop sliding. JAMA 2009;301:213214. [PubMed: 19141770]
72. Malmberg K, Norhammar A, Wedel H, Rydn L. Glycometabolic state at admission: Important risk marker of
mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: Long-term
results from the Diabetes and InsulinGlucose Infusion in Acute Myocardial Infarction (DIGAMI) study.
Circulation 1999;99:26262632. [PubMed: 10338454]
73. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl
J Med 2001;345:13591367.
74. Moghissi ES, Korykowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and
American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care
2009;32:11191131. [PubMed: 19429873]
75. The NICE-SUGAR Study Investigators. Intensive versus conventional glycemic control in critically ill patients.
N Engl J Med 2009;360:12831297.
76. American Diabetes Association. Preconception care of women with diabetes. Diabetes Care 2004;27(Suppl
1): S76S78.
77. Mahmud M, Mazza D. Preconception care of women with diabetes: A review of current guideline
recommendations. BMC Womens Health 2010;10:5. [PubMed: 20113524]
78. Spollett G. Hyperglycemia in HIV/AIDS. Diabetes Spectrum 2006;19:163166.
79. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle
intervention or metformin. N Engl J Med 2002;346:393403.
86/88
7/1/2014
80. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic -cell function and prevention of type
2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes
2002;51:27962803. [PubMed: 12196473]
81. The Dream Trial Investigators. The effect of ramipril on the incidence of diabetes. N Engl J Med 2006;355:
15511562.
82. The DREAM Trial Investigators. The effect of rosiglitazone on the frequency of diabetes in patients with
impaired glucose tolerance or impaired fasting glucose. A randomised controlled trial. Lancet 2006;368:1096
1105.
83. DeFronzo R, Tripathy D, Schwenke D, et al. Pioglitazone for diabetes prevention in impaired glucose
tolerance. N Engl J Med 2011;364:11041115. [PubMed: 21428766]
84. Haas L, Maryniuk M, Beck J, et al. National standards diabetes self-management education. Diabetes Care
2013;36(Suppl 1):S100S108.
85. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care
2004;27:14581486. [PubMed: 15161806]
86. Boulton AJM, Armstrong DG, Albert SF, et al. Comprehensive foot exam and risk assessment. Diabetes
Care 2008;31:16791685. [PubMed: 18663232]
87. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with
atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): A multicentre,
randomised placebo controlled trial. Lancet 2004;364:685696. [PubMed: 15325833]
88. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with
simvastatin in 5963 people with diabetes: A randomised placebo-controlled trial. Lancet 2003;361:20052016.
89. The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795
people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet 2005;366: 1849
1861.
90. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes. N Engl J Med 2010;362:
15631574 [erratum 362:1748].
91. Grundy SM, Cleeman JI, Merz CN. Implications of recent clinical trials for the National Cholesterol Education
Program Adult Treatment Panel III guidelines. Circulation 2004;110:227239. [PubMed: 15249516]
92. The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J
Med 2010;362:16281630.
Copyright McGraw-Hill Global Education Holdings, LLC.

All rights reserved.
Your IP address is 1.2.217.87
87/88
7/1/2014
National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes by age among adults 20
years of age: United States, 20052008. (Centers for Disease Control and Prevention, 2011 National Diabetes
Fact Sheet athttp://www.cdc.gov/diabetes/pubs/factsheet11.htm.)
Rate of new cases of type 1 and type 2 diabetes among youth aged <20 years, by race/ethnicity, 20022005.
(NHW, non-Hispanic whites; NHB, non-Hispanic blacks; H, Hispanics; API, Asians/Pacific Islanders; AI, American
Indians.) (Centers for Disease Control and Prevention, 2011 National Diabetes Fact Sheet at
http://www.cdc.gov/diabetes/pubs/factsheet11.htm.)
Scheme of the natural history of the -cell defect in type 1 diabetes mellitus. (Copyright 2008 American
Diabetes Association. From Medical Management of Type 1 Diabetes, 5th ed.Reprinted with permission from
the American Diabetes Association.)
The relationship between fasting plasma insulin and fasting plasma glucose in 177 normal-weight individuals.
Plasma insulin and glucose increase together up to a fasting glucose of 140 mg/dL (7.8 mmol/L). When the
fasting glucose exceeds 140 mg/dL (7.8 mmol/L), the cell makes progressively less insulin, which leads to an
overproduction of glucose by the liver and results in a progressive increase in fasting glucose. (Reprinted from
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin N Am 2004;88:787835, Copyright 2004,
with permission from Elsevier.)
Whole-body glucose disposal, a measure of insulin resistance, is reduced 40% to 50% in obese nondiabetic
and lean type 2 diabetic individuals. Obese diabetic individuals are slightly more resistant than lean diabetic
patients. (From DeFronzo RA. Diabetes Reviews 1977;5:177269.)
Relationship between insulin and glucose over the course of a day and how various insulin and amylinomimetic
regimens could be given. (A, aspart; CSII, continuous subcutaneous insulin infusion; D, detemir; G, glargine;
GLU, glulisine; L, lispro; P, pramlintide; N, NPH; R, regular.)
Position Statement on the Treatment of Type 2 Diabetes Mellitus: American Diabetes Association and
European Association for the Study of Diabetes. (Adapted from reference 54.)
A1C goals. See www.texasdiabetescouncil.org for current algorithms. (Reprinted with permission from the
Texas Diabetes Council.)
Insulin algorithm for type 2 DM in children and adults. See www.texasdiabetescouncil.org for current algorithms.
(Reprinted with permission from the Texas Diabetes Council.)
88/88

Diabetes Mellitus

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Diabetes Mellitus

Uploaded by

Copyright:

Available Formats

7/1/2014

Pharmacotherapy: A Pathophysiologic Approach, 9e >

Chapter 57. Diabetes Mellitus

Diabetes Mellitus: Introduction

Pathogenesis, Diagnosis, and Classification

Other genetic syndromes sometimes associated w ith diabetes

aOther rare forms may exist for all categorizations.

Gestational Diabetes Mellitus

92 mg/dL (5.1 mmol/L)

180 mg/dL (10 mmol/L)

153 mg/dL (8.5 mmol/L)

HbA 1c 6.5% (0.065; 48 mmol/mol Hb)

aDiagnosis to be confirmed if not unequivocal hyperglycemia (see Table 57-3).

>102 cm (>40 in)

150 mg/dL (1.70 mmol/L)

<40 mg/dL (<1.03 mmol/L)

<50 mg/dL (<1.29 mmol/L)

110 mg/dL (6.1 mmol/L)

Categorical Cut Points

Elevated w aist circumferencea

Population- and country-specific definitions

Elevated triglycerides (drug treatment for elevated

150 mg/dL (1.7 mmol/L)

Reduced HDL-C (drug treatment for reduced HDL-C is an

40 mg/dL (1.03 mmol/L) in males 50 mg/dL

hypertension is an alternate indicator)

100 mg/dL (2.59 mmol/L)

glucose is an alternate indicator)

AHA/NHLBI (ATP III)

Asia (including Japanese)

Japanese Obesity Society

Cooperative Task Force

Metabolic Syndrome: Fact or Fiction?

Obese or history of obesity

Need for insulin therapy

Years after diagnosis

Hyperosmolar hyperglycemic state

Microvascular complications at diagnosis

Macrovascular complications at or before diagnosis

aClinical presentation can vary w idely.

Treatment: Diabetes Mellitus

To screen for diabetes a FPG, 2-hour 75-g OGTT, or HbA 1c is appropriate

In adults, measure fasting lipid profile at least annually

severe hypoglycemia, limited life expectancy, advanced microvascular/macrovascular complications or

Saturated fat should be <7% of total calories

Monitoring carbohydrate intake by carbohydrate counting, exchanges, or experienced estimation is

Systolic blood pressure should be treated to <140 mm Hg

Diastolic blood pressure should be treated to <80 mm Hg

Initial drug therapy should be w ith an ACE inhibitor or ARB

Use aspirin (75162 mg daily) for secondary cardioprotection

General Approach to Treatment

Glycemic Goal Setting and Hemoglobin A1c

<7% (<0.07; <53 mmol/mol/Hb)a 6.5% (0.065; 48 mmol/mol Hb)

ACE and AACE

Preprandial plasma glucose

70130 mg/dL (3.97.2 mmol/L) <110 mg/dL (<6.1 mmol/L)

Postprandial plasma glucose

<180 mg/dLb (<10 mmol/L)

<140 mg/dL (<7.8 mmol/L)

Plasma glucose goal

Before meals bedtime/overnight

100180 (5.610 mmol/L) 110200 (6.111.1 mmol/L)

7.5% to 8.5% (<0.085; <69 mmol/mol Hb)

School age (612)