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Pharmacotherapy: A Pathophysiologic Approach, 9e >

Chapter 57. Diabetes MellitusCurtis 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 ininsulin 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, sedentarylifestyle, 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 ininsulin secretion). They differ in clinical presentation, onset, etiology, and progression of disease. Both are associated withmicrovascular and macrovascular disease complications.

Diagnosis of diabetes is made by four criteria: fasting plasma glucose ≥126 mg/dL (≥7 mmol/L), a 2-hour value from a 75-g oralglucose tolerance test ≥200 mg/dL (≥11.1 mmol/L), a casual plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L) with symptoms ofdiabetes, or a hemoglobin A1c [HbA1c] ≥6.5% (≥0.065; ≥48 mmol/mol Hb). The diagnosis should be confirmed by repeat testing ifobvious hyperglycemia is not present.

Goals of therapy in DM are directed toward attaining normoglycemia (or appropriate glycemic control based on the patient’scomorbidities), reducing the onset and progression of retinopathy, nephropathy, and neuropathy complications, intensive therapy forassociated 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 oralantihyperglycemic medication proven to reduce the risk of total mortality, according to the United Kingdom Prospective DiabetesStudy (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 alsoreported that control of hypertension in patients with diabetes will not only reduce the risk of retinopathy and nephropathy but alsoreduce cardiovascular risk.

Short-term (3 to 5 years), intensive glycemic control does not lower the risk of macrovascular events as reported by the Action inDiabetes 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, asevidenced by the UKPDS and DCCT follow-up studies. Significant reductions in macrovascular risk may take 15 to 20 years. Thissustained reduction in microvascular risk and new reduction in macrovascular risk has been coined metabolic memory.

Knowledge of the patient’s quantitative and qualitative meal patterns, activity levels, pharmacokinetics of insulin preparations, andpharmacology of oral and injected antihyperglycemic agents is essential to individualize the treatment plan and optimize bloodglucose control while minimizing risks for hypoglycemia and other adverse effects of pharmacologic therapies.

Type 1 DM treatment necessitates insulin therapy. Currently, the basal–bolus insulin therapy or pump therapy in motivatedindividuals often leads to successful glycemic outcomes. Basal–bolus therapy includes a basal insulin for fasting and postabsorptivecontrol, and rapid-acting bolus insulin for mealtime coverage. Addition of mealtime pramlintide in patients with uncontrolled or erraticpostprandial glycemia may be warranted.

Type 2 DM treatment often necessitates use of multiple therapeutic agents (combination therapy), including oral and/or injectedantihyperglycemics and insulin, to obtain glycemic goals due to the persistent reduction in β-cell function over time. Slowing, but notarresting, β-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 adversecardiovascular events or death. Smoking cessation, use of antiplatelet therapy as a secondary prevention strategy and in selectprimary prevention situations, aggressive management of dyslipidemia—primary 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)—andtreatment 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. Lifestylechanges, dietary restriction of fat, aerobic exercise for 30 minutes five times a week, and weight loss form the backbone of successfulprevention. 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 arecrucial to successful outcomes. Multidisciplinary teams of healthcare professionals including physicians (primary care,

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endocrinologists, ophthalmologists, and vascular surgeons), podiatrists, dietitians, nurses, pharmacists, social workers, behavioralhealth specialists, and 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 diabetesmellitus.

6. Understand common laboratory, procedures, and physical examination components that should be performed on initial evaluation ofa 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 medicationsfor diabetes mellitus.

9. Learn about the implications of key clinical trials in the management of glucose, hypertension, and dyslipidemia for the treatment ofdiabetes mellitus.

10. Construct and individualize rationale therapeutic regimens, and follow-up of these regimens, for treatment of type 1 and type 2diabetes 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, andmonitoring parameters for each.

13. Develop treatment regimens (nonpharmacologic and pharmacologic) for common concomitant conditions and complicationsassociated 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.

Diabetes Mellitus: Introduction

Diabetes mellitus (DM) is a heterogeneous group of metabolic disorders characterized by hyperglycemia. It is associated withabnormalities 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 onefourth of these patients being undiagnosed, and an additional 79 million at high risk for the development of diabetes. The economicburden of DM approximated $218 billion in 2007, for diabetes and prediabetes. This is representative of an annual cost for each citizen ofthe 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 renaldisease in the United States. It also accounts for approximately 65,000 lower extremity amputations annually. Finally, a cardiovascularevent 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 longduration.1

Optimal management of the patient with DM will reduce or prevent complications, decreasing morbidity and mortality while improvingquality of life. Research, clinical trials, and drug development efforts over the past several decades have provided valuable informationthat 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

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Type 1 DM accounts for 5% to 10% of all cases of DM and is most often due to autoimmune destruction of the pancreatic β cells.2Although 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 developmentof β-cell autoimmunity occurs in less than 10% of the genetically susceptible population and progresses to type 1 DM in less than 1% ofthat population.3 There is a direct relation to the prevalence of β-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 associatedwith 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 increaseis not fully understood.

Markers of β-cell autoimmunity are detected in 14% to 33% of persons with adult-onset diabetes. This type of DM is referred to as latentautoimmune 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 intermittentinsulin 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 Cushing’s syndrome may also cause diabetes. Any disease of the exocrine pancreas suchas cystic fibrosis, pancreatitis, and hereditary hemochromatosis can damage β 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 furtherdiscussion.

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% inpersons aged 20 or older; this prevalence is increasing. It is estimated that for every four persons who are diagnosed with DM, oneperson 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; 39to 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 diabetesmellitus (GDM) (see Classification of Diabetes below) or delivery of a baby weighing >9 lb (>4 kg); history of vascular disease; presence ofacanthosis 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 oftype 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 inadolescent type 2 DM is related to an increase in overweight/obesity and sedentary lifestyle, in addition to genetic predisposition.6 Mostcases of type 2 DM are polygenetic; the underlying pathophysiology remains uncertain7 (Figs. 57-1 and 57-2).

FIGURE 57-1

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National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes by age among adults ≥20 years of age: United States,2005–2008. (Centers for Disease Control and Prevention, 2011 National Diabetes Fact Sheet

athttp://www.cdc.gov/diabetes/pubs/factsheet11.htm.)

FIGURE 57-2

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Rate of new cases of type 1 and type 2 diabetes among youth aged <20 years, by race/ethnicity, 2002–2005. (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 clinicalmanifestation 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 aninadequate compensatory increase in insulin secretion. Women who develop diabetes due to the stress of pregnancy are classified ashaving 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 diabetesb (β-cell destruction, usually leading to absolute insulin deficiency)Immune-mediatedIdiopathic

2. Type 2 diabetesa (may range from predominantly insulin resistance with relative insulin deficiency to apredominantly insulin secretory defect with insulin resistance)


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3. Other specific typesGenetic defects of β-cell function

Chromosome 20q, HNF-4α (MODY 1)Chromosome 7p, glucokinase (MODY 2)Chromosome 12q, HNF-1α (MODY 3)Other rare formsChromosome 13q, insulin promoter factor-1 (MODY 4)Chromosome 17q, HNF-1β (MODY 5)Chromosome 2q, neurogenic differentiation 1/β-cell e-box transactivator 2 (MODY 6)Chromosome 9q, carboxyl ester lipase (MODY 7)Mitochondrial DNA

Genetic defects in insulin actionType A insulin resistanceLeprechaunismRabson-Mendenhall syndromeLipoatrophic diabetes

Diseases of the exocrine pancreasPancreatitisTrauma/pancreatectomyNeoplasiaCystic fibrosisHemochromatosisFibrocalculous pancreatopathy

EndocrinopathiesAcromegaly

Cushing’s syndromeGlucagonomaPheochromocytomaHyperthyroidismSomatostatinomaAldosteronoma

Drug or chemical inducedVacor (Pyriminil)PentamidineNicotinic acidGlucocorticoidsThyroid hormoneDiazoxideβ-Adrenergic agonistsThiazidesPhenytoinγ-InterferonOthers

InfectionsCongenital rubellaCytomegalovirusOthers

Uncommon forms of immune-mediated diabetes“Stiff-man” syndromeAnti-insulin receptor antibodies

Other genetic syndromes sometimes associated with diabetesDown’s syndromeKlinefelter’s syndromeTurner’s syndromeWolfram’s syndromeFriedreich’s ataxiaHuntington’s chorea


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Laurence-Moon-Bieldel syndromeMyotonic dystrophyPorphyriaPrader-Willi syndrome

4. Gestational diabetes mellitus (GDM)

aOther rare forms may exist for all categorizations.

bPatients with 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;20:1183–1197. Reproduced by permission of the

American Diabetes Association.2

Type 1 Diabetes

This form of diabetes results from autoimmune destruction of the β cells of the pancreas. Evidence of β-cell autoimmunity, includingICAs, antibodies to glutamic acid decarboxylase, islet protein tyrosine phosphatase-like molecule IA2, and/or antibodies to insulin, ispresent at the time of diagnosis in 90% of individuals. Type 1 diabetes is often thought to most commonly present in children andadolescents; however, it can occur at any age. Younger individuals typically have a more rapid rate of β-cell destruction and often presentwith ketoacidosis. Adults may maintain sufficient insulin secretion to prevent ketoacidosis for many years; this is referred to as latentautoimmune 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 (beinginsufficient to normalize plasma glucose levels), with progressively lower insulin secretion over time. Most individuals with type 2 diabetesexhibit abdominal obesity, which itself causes insulin resistance. In addition, hypertension, dyslipidemia (high triglyceride levels and lowHDL-C levels), and elevated plasminogen activator inhibitor-1 (PAI-1) levels, which contribute to a hypercoagulable state, are oftenpresent in these individuals. Due in part to these factors, patients with type 2 diabetes are at increased risk of developing macrovascularcomplications in addition to microvascular complications. Type 2 diabetes has a strong genetic predisposition and is more common in allethnic groups other than those of European ancestry.4,5

Gestational Diabetes Mellitus

GDM is defined as glucose intolerance that is first recognized during pregnancy. Hormone changes during pregnancy result in increasedinsulin resistance, and GDM may ensue when the mother cannot adequately compensate with increased insulin secretion to maintainnormoglycemia. In most, glucose intolerance occurs near the beginning of the third trimester, although risk assessment and interventionwhen 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 andmortality.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. Patientstypically exhibit mild hyperglycemia at an early age, but diagnosis may be delayed, depending on the severity of presentation. Thedisease 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 insulinresistance refers to the clinical syndrome of acanthosis nigricans, virilization in women, polycystic ovaries, and hyperinsulinemia. Incontrast, anti-insulin receptor antibodies may block the binding of insulin. This was referred to in the past as type B insulin resistance.

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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 ofdiagnosis, screening for type 1 DM in the asymptomatic general population is not recommended.5 Screening for β-cell autoantibodystatus in high-risk family members may be appropriate; however, such screening is most often recommended in the context of clinicaltrials 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 ≥25kg/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 thefasting plasma glucose (FPG), HbA1c, or 2-hour oral glucose tolerance test (OGTT). Adults without risk factors should be screenedstarting 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 ofsuspicion 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 adolescentsare developing type 2 DM. The ADA, by expert opinion, recommends that overweight (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 type2 diabetes in first- and second-degree relatives; Native Americans, African Americans, Hispanic Americans, and Asians/South PacificIslanders; 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 thechild’s 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 ata 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 isreasonable to screen women with risk factors for the development of diabetes as soon as feasible. If the initial screening is negative, theyshould undergo retesting at 24 to 28 weeks’ gestation. Screening for GDM is done with a standard 75-g OGTT. The diagnosis of GDM isconfirmed when any one plasma glucose value measured at baseline (fasting), 1 hour, or 2 hours meets the diagnostic criteria. Thesecriteria 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

Time Plasma Glucose

Fasting ≥92 mg/dL (5.1 mmol/L)

1 hour ≥180 mg/dL (10 mmol/L)

2 hours ≥153 mg/dL (8.5 mmol/L)

One abnormal value = diagnostic of GDM. Should be performed at 24–28 weeks’ 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.

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Diagnosis of Diabetes

The diagnosis of diabetes requires the identification of a glycemic cut point, which discriminates normals from diabetic patients. Thecut 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. HbA1c ≥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 assaya

2. Fasting plasma glucose ≥126 mg/dL (7 mmol/L). Fasting is defined as no caloric intake for at least 8 hoursa

3. 2-hour plasma glucose ≥200 mg/dL (≥11.1 mmol/L) during an OGTT. The test should be performed as describedby the World Health Organization, using a glucose load containing the equivalent of 75-g anhydrous glucosedissolved in watera

4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucoseconcentration ≥200 mg/dL (≥11.1 mmol/L)

aIn the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat

testing.

The HbA1c was not recommended in the past due to many nonstandardized assays. Most laboratories now use a method that is NationalGlycohemoglobin 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 measuresglycemic exposure over the past 2 to 3 months, in contrast to a single-day, single-point glucose evaluation. In addition, patients do nothave 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-foldincrease in risk of diabetes, yet does not consistently identify patients with IFG or IGT. In addition, there are slight race differences innormal HbA1c levels. One-third fewer individuals with diabetes are identified using the A1C ≥6.5% (≥0.065; ≥48 mmol/mol Hb) versus aFPG ≥126 mg/dL (≥7 mmol/L), yet more providers may be more likely to diagnose diabetes from an A1C than from an obviously elevatedFPG level. The ADA continues to recommend three other glucose criteria for the diagnosis of DM in nonpregnant adults (Table 57-3). Ifthe 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 anincreased risk for diabetes. The HbA1c lower limit of 5.7% (0.057; 39 mmol/mol Hb) was chosen due to its good specificity, although ithas a low sensitivity, to identify patients at increased risk for diabetes. IFG continues to be defined as a plasma glucose of at least 100mg/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 lessthan 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)

100–125 mg/dL (5.6–6.9 mmol/L)Diabetes mellitusa

FPG ≥126 mg/dL (7 mmol/L)2-hour postload plasma glucose (oral glucose tolerance test)Impaired glucose tolerance (IGT)

2-hour postload glucose 140–199 mg/dL (7.8–11 mmol/L)

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Diabetes mellitusa2-hour postload glucose ≥200 mg/dL (≥11.1 mmol/L)

HbA1cIncreased risk of diabetes mellitus

HbA1c 5.7–6.4% (0.057–0.064; 39–46 mmol/mol Hb)

Diabetes mellitusaHbA1c ≥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 measurementcan be affected by anemias and several hemoglobinopathies, which necessitates the use of one of the plasma glucose criterion in theseindividuals.

Pathogenesis


Type 1 DM results from pancreatic β-cell failure with “absolute” deficiency of insulin secretion. Most often this is due to immune-mediateddestruction of pancreatic β cells, but rare unknown or idiopathic processes may also contribute. There often is a long preclinical period ofimmune-mediated β-cell destruction later followed by onset of hyperglycemia when 80% to 90% of the β cells have been destroyed.Occasionally there is a period of transient remission called the “honeymoon” phase, before established disease develops along with therequirement for lifelong insulin therapy and the potential risk of diabetes-related complications (Fig. 57-3).

FIGURE 57-3

Scheme of the natural history of the β-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.)

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 unknownwhether there are one or more inciting factors such as cow’s milk (or lack of breast-feeding), or viral, dietary, or other environmental

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exposures that initiate the autoimmune process.2,3 Vitamin D deficiency has been observed to be more prevalent in patients who developtype 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 β-cell antigens. Themost commonly detected antibody associated with type 1 DM is the ICA. Other autoantibodies include insulin, glutamic aciddecarboxylase 65, and zinc transporter 8 (ZnT8). These antibodies are generally considered markers of disease rather than mediators ofβ-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-degreerelatives. Once insulin autoantibodies are detected, there is an increased risk of development of additional autoantibodies andprogression to diabetes. β-Cell autoimmunity may precede the diagnosis of type 1 DM by up to 9 to 13 years. Autoimmunity may remit insome individuals, or can progress to absolute β-cell failure in others. Other autoimmune disorders frequently associated with type 1 DMinclude Hashimoto’s thyroiditis, Graves’ disease, Addison’s disease, vitiligo, and celiac sprue. The extent of involvement can range fromno 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 withincreased risk (DR3 and DR4) while others are protective (DRB1*04008-DQB1*0302 and DRB1*0411-DQB1*0302) on chromosome 6.10Additional 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 thedisease.

The autoimmune destruction of pancreatic β-cell function results in hyperglycemia due to an absolute deficiency of insulin. Insulin lowersblood glucose (BG) by a variety of mechanisms, including stimulation of tissue glucose uptake, suppression of glucose production by theliver, and suppression of free fatty acid (FFA) release from fat cells.11 The suppression of FFAs plays an important role in glucosehomeostasis. 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 non–insulin-dependent tissues such as the brain, neurons, andothers. Brain glucose uptake occurs at the same rate during fed and fasting periods. The remaining 25% of glucose metabolism takesplace in the liver and muscle, which is dependent on insulin. In the fasting state approximately 85% of glucose production is derived fromthe liver, and the remaining amount is produced by the kidney. Glucagon, produced by pancreatic α cells, is secreted in the fasting stateto oppose the action of insulin and stimulate hepatic glucose production and glycogenolysis. Glucagon and insulin secretion are closelylinked; one increases while the other decreases to keep plasma glucose levels normal. In the fed state, carbohydrate ingestion increasesthe plasma glucose concentration and stimulates insulin release from the pancreatic β cells. The resultant hyperinsulinemia (a)suppresses hepatic glucose production, (b) stimulates glucose uptake by peripheral tissues, and (c) suppresses glucagon release (inconjunction 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 maintenanceof total body glucose homeostasis. Small increments in the plasma insulin concentration exert a potent antilipolytic effect, leading to amarked reduction in the plasma FFA levels. The decline in plasma FFA concentrations results in an increased glucose uptake in muscleand 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, andthe 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 β 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 β-cell dysfunction, first-phase insulin release, seen with an IV bolus ofglucose, is deficient. First-phase insulin is released if there is stored insulin in the β 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 releasedcan no longer normalize plasma glucose, dysglycemia, including prediabetes and diabetes, can ensue. Both β-cell mass and function inthe pancreas are reduced. β-Cell failure is progressive, and starts years prior to the diagnosis of diabetes. People with T2DM lose ˜5% to7% of β-cell function per year of diabetes. The reasons for this loss are likely multifactorial including (a) glucose toxicity; (b) lipotoxicity; (c)

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insulin resistance; (d) age; (e) genetics; and (f) incretin deficiency. Age results in declining β-cell responsiveness and possibly mass. β-Cellfailure predisposition is also present in high-risk ethnicity/races. Glucotoxicity involves glucose levels chronically exceeding 140 mg/dL(7.8 mmol/L). The β cell is unable to maintain elevated rates of insulin secretion, and releases less insulin as glucose levels increase (Fig.57-4).7,13,14

FIGURE 57-4

The relationship between fasting plasma insulin and fasting plasma glucose in 177 normal-weight individuals. Plasma insulin and glucoseincrease 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 βcell makes progressively less insulin, which leads to an overproduction of glucose by the liver and results in a progressive increase infasting glucose. (Reprinted from DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin N Am 2004;88:787–835, Copyright ©

2004, with permission from Elsevier.)

Incretins

In the type 2 diabetic patient, decreased postprandial insulin secretion is due to both impaired pancreatic β-cell function and a reducedstimulus for insulin secretion from gut hormones. The role gut hormones play in insulin secretion is best shown by comparing the insulinresponse to an oral glucose load versus an isoglycemic IV glucose infusion. In nondiabetic control individuals 73% more insulin isreleased in response to an oral glucose load compared with reproducing the oral glucose load’s plasma glucose curve by giving IVglucose. This increased insulin secretion in response to an oral glucose stimulus is referred to as “the incretin effect” and suggests thatgut-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 nowknown that two hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), are responsible for over 90% of the increasedinsulin secretion seen in response to an oral glucose load. Patients with type 2 diabetes remain sensitive to GLP-1 while GIP levels arenormal or elevated in T2DM.7

GLP-1 is secreted from the L cells, with the highest L-cell concentration in the distal intestinal mucosa, in response to mixed meals. SinceGLP-1 levels rise within minutes of food ingestion, neural signals and possibly proximal GI tract receptors stimulate GLP-1 secretion. Theinsulinotropic action of GLP-1 is glucose dependent, and for GLP-1 to enhance insulin secretion, glucose concentrations must be higherthan 90 mg/dL (5 mmol/L). In addition to stimulating insulin secretion, GLP-1 suppresses glucagon secretion, slows gastric emptying, andreduces food intake by increasing satiety. These effects of GLP-1 combine to limit postprandial glucose excursions. GIP is secreted by K

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cells in the intestine and may have a role with insulin secretion during near-normal glucose levels and may act as an insulin sensitizer inadipocytes. However, GIP has no effect on glucagon secretion, gastric motility, or satiety. The half-lives of GLP-1 and GIP are short (<10minutes). Both hormones are rapidly inactivated by removal of two N-terminal amino acids by the enzyme dipeptidyl peptidase-4 (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 thatcauses diabetes in the majority of T2DM. Genetically a minority may have the TCF7L2 gene defect, which is associated with a decreasedresponse 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 glucoseproduction is increased by ˜0.5 mg/kg/min. Consequently, during the overnight sleeping hours the liver of an 80-kg diabetic individual withmodest fasting hyperglycemia adds an additional 35 g of glucose to the systemic circulation. This increase in fasting hepatic glucoseproduction 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. T2DMpatients also fail to suppress glucagon in response to a meal and may even have a paradoxical rise in glucagon levels. Thus, hepaticinsulin resistance and hyperglucagonemia result in continued production of glucose by the liver. Therefore, T2DM patients have twosources of glucose in the postprandial state: one from the diet and one from continued glucose production from the liver. These sourcesof 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 inskeletal muscle. In response to a physiologic increase in plasma insulin concentration, muscle glucose uptake increases linearly, reachinga 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 tostimulate leg glucose uptake is reduced by 50%. Impaired intracellular insulin signaling is a well-established abnormality, with notableimpairments at almost every step of activation due to insulin resistance, lipotoxicity, and glucotoxicity. The compensatoryhyperinsulinemia required to overcome impaired insulin signaling (insulin resistance) can activate an alternative pathway through MAPkinase, 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 riskof dysfunction with high-fat diets (Fig. 57-5).13,14

FIGURE 57-5


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Whole-body glucose disposal, a measure of insulin resistance, is reduced 40% to 50% in obese nondiabetic and lean type 2 diabeticindividuals. Obese diabetic individuals are slightly more resistant than lean diabetic patients. (From DeFronzo RA. Diabetes Reviews

1977;5:177–269.)

Peripheral (Adipocyte)

In obese nondiabetic and T2DM, basal plasma FFA levels are increased and fail to suppress normally after glucose ingestion. FFAs arestored as triglycerides in adipocytes and serve as an important energy source during conditions of fasting. Insulin is a potent inhibitor oflipolysis, and restrains the release of FFAs from the adipocyte by inhibiting the hormone-sensitive lipase enzyme. It is now recognized thatchronically elevated plasma FFA concentrations can lead to insulin resistance in muscle and liver, and impair insulin secretion. In additionto FFAs that circulate in plasma in increased amounts, T2DM patients have increased stores of intracellular fat products in muscle andliver, and the increased fat content correlates closely with the presence of insulin resistance in these tissues. Excess lipolysis from fat canalso 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 insulinresistance as lean T2DM patients. Subsets of obese, but metabolically normal patients (6% to 30%) do exist, as well as nonobese, butmetabolically abnormal patients, so broad categorization of risk for a patient needs to be confirmed by further examination.

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 variationin insulin resistance seen. It represents 20% of fat in men and 6% of fat in women. Central obesity can be easily assessed using waistcircumference, which is a good surrogate marker for VAT. This fat tissue has been shown to have a higher rate of lipolysis thansubcutaneous fat, resulting in an increase in FFA production. These fatty acids are released into the portal circulation and drain into theliver, 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-α, interleukin 6, angiotensinogen, PAI-1, and resistin, which contribute toinsulin resistance, hypertension, and hypercoagulability. These factors drain into the portal circulation and reduce insulin sensitivity inperipheral 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

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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 proinflammatorycondition. Patients with metabolic syndrome do have a higher risk for CVD, and at least a fivefold increase in their risk of type 2 DM, ifthey do not already have type 2 DM. The metabolic syndrome does not identify synergism among identified risk factors, but ratheradditive risk, leading many to question its relevance above adequate risk factor identification and aggressive treatment. It may be usefulto 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 57-5).15,16

Table 57-5 Defining the Metabolic Syndrome

Defining the Metabolic Syndrome NCEP-ATP III: Five Components of the Metabolic Syndrome (IndividualsHaving at Least Three Components Meet the Criteria for Diagnosis)

Risk Factor Defining Level

Abdominal obesity Waist circumference

Men >102 cm (>40 in)

Women >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 ≥110 mg/dL (≥6.1 mmol/L)

2009 Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; NationalHeart, Lung, and Blood Institute; American Heart Association; World Heart Federation; InternationalAtherosclerosis Society; and International Association for the Study of ObesityCriteria for Clinical Diagnosis ofthe Metabolic Syndrome (Individuals having at Least Three Components Meet the Criteria for Diagnosis)

Measure Categorical Cut Points

Elevated waist circumferencea Population- and country-specificdefinitions

Elevated triglycerides (drug treatment forelevated triglycerides is an alternateindicator)b

≥150 mg/dL (≥1.7 mmol/L)

Reduced HDL-C (drug treatment for reducedHDL-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 apatient with a history of hypertension is an alternate indicator)

Elevated fasting glucosec (drug treatment ofelevated glucose is an alternate indicator)

≥100 mg/dL (≥2.59 mmol/L)

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Current Recommended Waist Circumference Thresholds for Abdominal Obesity by Organization

Population Organization (Reference) Men (Allvalues ≥)

Women(All values≥)

Europid IDF 94 cm 80 cm

White WHO94 cm(increasedrisk)

80 cm(increasedrisk)

102 cm(still higherrisk)

88 cm (stillhigher 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.

bThe 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.

cMost patients with type 2 diabetes mellitus will have the metabolic syndrome by the

proposed criteria.

Reproduced from reference 15. Reprinted with permission from reference 16, © 2009

American Heart Association, Inc.

SIDEBAR: CLINICAL CONTROVERSY...

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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 andalso referred to as the “insulin resistance syndrome,” “dysmetabolic syndrome,” and “syndrome X.” In 2001, the National CholesterolEducation Program (NCEP) Adult Treatment Panel (ATP) III formally defined the metabolic syndrome as a clustering of risk factors thatinclude 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 DiabetesFederation (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 developingCVD and DM.18 This epidemic has also been described in children and adolescents19 and is expected to expand as the US obesity ratescontinue to climb.

However, in 2005 the ADA in conjunction with the European Association for the Study of Diabetes released a joint statement critical of theclinical utility of the metabolic syndrome.20 They concluded in their statement that there is no doubt that CVD risk factors cluster incertain individuals, although they assert the definition is imprecise and its use as a CVD marker is questionable. They also state that thereis critical information missing to warrant its designation as a syndrome. A swift rebuttal from the AHA and NHLBI was released weekslater encouraging the continued use of the metabolic syndrome concept.21 In their statement, the authors stressed that the metabolicsyndrome is not considered a singular entity and that it is a syndrome with no single pathogenesis. The authors of the statement alsoargue that the distinction of the metabolic syndrome should allow clinicians to approach patients as a whole with an emphasis onintensive lifestyle management. Those in the diabetes community and who authored the ADA/EASD statement contend that there is noadditional benefit from identifying these clusters of CVD risk factors over measuring and treating them individually. They maintain the lackof predictive capabilities limits the metabolic syndrome’s utility as a CVD marker.

The use of the metabolic syndrome in clinical practice remains a controversy. Clinicians should always take care to individualize therapyfor patients who present with high CVD risk. Patient’s individual goals, values, and resources should be considered when tailoring atreatment 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. Approximately75% will develop the disorder before age 20 years, but the remaining 25% develop the disease as adults. Individuals with type 1 DM areoften thin and are prone to develop diabetic ketoacidosis (DKA) if insulin is withheld, or under conditions of severe stress with an excessof 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 initiallypresent with vague complaints such as weight loss and fatigue. Polyuria, polydipsia, and polyphagia may not be apparent unless acomprehensive 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 1DM patients are diagnosed without multiple symptoms or DKA when they have blood tests drawn for other reasons. This rarepresentation 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 forseveral years.10 Often these patients are diagnosed secondary to unrelated blood testing. Lethargy, polyuria, nocturia, and polydipsiacan be seen at diagnosis in type 2 diabetes, but significant weight loss at diagnosis is less common. More often, patients with type 2 DMare 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 inconjunction with other definitive laboratory data to properly classify patients (see also Classical Clinical Presentation of Diabetes Mellitusbelow).

Clinical Presentation: Diabetes Mellitusa

Characteristic Type 1 DM Type 2 DM

Age <30 yearsb >30 yearsb

Onset Abrupt Gradual

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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 widely.

bAge 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.

cType 1 may present acutely with symptoms of polyuria, nocturia, polydipsia, polyphagia,

and weight loss.

dType 2 children and adolescents are more likely to present with ketones, but after the

acute phase may be treated with 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, toameliorate symptoms, to reduce mortality, and to improve quality of life.5 Early treatment with near-normal glycemia will reduce the riskfor 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 thelikelihood of development of macrovascular disease. Hyperglycemia not only increases the risk for microvascular disease but alsocontributes to poor wound healing, compromises white blood cell function, alters capillary function, and leads to classic symptoms ofDM. DKA and hyperosmolar hyperglycemic state (HHS) are severe manifestations of poor diabetes control, almost always requiringhospitalization. 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 andhypoglycemia, especially severe hypoglycemia, and altering the glycemic goal to match the patient’s morbidities are necessary.Evidence-based guidelines, as published by the ADA, may help in the attainment of these goals (Table 57-6).5

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Table 57-6 Selected American Diabetes Association Evidence-Based Recommendationsa

RecommendationArea Specific Recommendation

EvidenceLevelb

Screening fordiabetes

Screen overweight or obese at any age; screen those without risk factorsbeginning at age 45 years B

To screen for diabetes a FPG, 2-hour 75-g OGTT, or HbA1c is appropriate B

Interval between screenings should be individualized based on risk, or every 3years E

MonitoringHome blood glucose monitoring is recommended for patients on multidose insulinor pump therapy at least prior to meals and snacks, and before events such asdriving

B

Subjects on other therapeutic interventions, including oral agents, may performhome blood glucose monitoring, but ongoing instruction to patient on how toadjust therapy based on monitoring must be in place

E

Quarterly HbA1c in individuals not meeting glycemic goals, twice yearly inindividuals meeting glycemic goals should be performed E

In adults, measure fasting lipid profile at least annually B

Perform an annual urine albumin excretion in type 1 diabetes with duration ≥5years. Type 2 DM from diagnosis B

Perform a screen for distal symmetrical polyneuropathy at diagnosis in type 2 DMand after 5 years’ duration in type 1 DM; screen at least annually thereafter B

A dilated eye examination should be performed within 5 years of diagnosis in type1 DM, and shortly after diagnosis in type 2 DM, with follow-up every year, or every2–3 years as recommended by an eye specialist

B

Glycemic goals HbA1c goal for patients in general is <7% (<0.07; <53 mmol/mol Hb) B

HbA1c goal should be individualized, with <6.5% (<0.065; <48 mmol/mol Hb) ifachieved without significant hypoglycemia or adverse effects in younger, long lifeexpectancy, and no CVD patient

B

Less stringent HbA1c goal (<8% [<0.08; <64 mmol/mol Hb]) may be appropriate inpatients with a history of severe hypoglycemia, limited life expectancy, advancedmicrovascular/macrovascular complications or comorbidities, or in difficult toreach goal patients despite adequate therapy

C

Hospital: Critically ill: 140–180 mg/dL (7.8–10 mmol/L) (A), or more stringentguidelines down to 110–140 mg/dL (6.1–7.8 mmol/L) if without hypoglycemia(C)Non–critically 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)

See text

Treatment

Prevention of type2 diabetes

Patients with IGT (A), IFG (E), or an A1C of 5.7–6.4% (0.057–0.064; 39–46mmol/mol Hb) (E) should attempt weight loss (5–10%), increasing physical activity See text

Metformin may be considered in obese, <60-year-old patients, and women with


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prior GDM with IGT (A), IFG (E), or an A1C 5.7–6.4% (0.057–0.064; 39–46mmol/mol Hb) (E)

See text

Medical nutritiontherapy

Weight loss is recommended for all insulin-resistant/overweight or obeseindividuals. Either low-carbohydrate, low-fat calorie-restricted diets, orMediterranean diets may work

A

In patients with known CVD consider ACE inhibitor therapy (C), as well as aspirinand statin therapy (A) See text

Saturated fat should be <7% of total calories B

Monitoring carbohydrate intake by carbohydrate counting, exchanges, orexperienced estimation is recommended to achieve glycemic goals B

Routine supplementation with antioxidants, such as vitamins E and C, is notadvised due to lack of efficacy A

Physical activity 150 min/wk of moderate-intensity exercise spread over at least 3 days and with nomore than 2 days without exercise A

Resistance training of large muscle groups should be ≥2 times per week A

Blood pressure Systolic blood pressure should be treated to <140 mm Hg B

Diastolic blood pressure should be treated to <80 mm Hg B

Initial drug therapy should be with an ACE inhibitor or ARB C

NephropathyIn treatment of nonpregnant patients with modest (30–299 mg/day) (C) or higherlevels (≥300 mg/day) (A) of urinary albumin excretion, either ACE inhibitors orARBs are recommended

See text

Dyslipidemia The primary goal is an LDL <100 mg/dL (<2.59 mmol/L) if without overt CVD B

Statin therapy should be added to lifestyle, regardless of baseline lipid levels ifpatient has CVD, or is >40 years of age and has one other CVD risk factor A

In patients with overt CVD, using a statin to achieve a LDL <70 mg/dL (<1.81mmol/L) is an option B

Triglycerides lowered to <150 mg/dL (<1.70 mmol/L) and raising HDL to >40mg/dL (>1.03 mmol/L) in men and >50 mg/dL (1.29 mmol/L) in women is desirable C

Antiplatelet Use aspirin (75–162 mg daily) for secondary cardioprotection A

Use aspirin (75–162 mg) for primary prevention in type 1 or 2 DM if the 10-year riskof CVD is >10%, the patient is >50 (men) or >60 (women) with at least oneadditional risk factor present

C

Hospital Critically ill: By IV insulin protocol (E); non–critically ill: scheduled subcutaneousinsulin with basal, nutritional, and correction coverage (C) See text

aBased on American Diabetes Association practice recommendations. Other evidence-

based recommendations available.8

bEvidence levels: A, clear evidence from well-conducted, generalizable, randomized


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controlled trials that are adequately powered; B, supportive evidence from well-conducted

cohort studies or well-conducted case–control study; C, supportive evidence from poorly

controlled or uncontrolled studies or conflicting evidence with weight of evidence

supporting intervention; 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 and11), 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 ofmacrovascular 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 complications in both type1 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 celllife span in a patient can affect HbA1c measurements. Identification of potential problems and then ensuring the test is performed in alaboratory using a method that is NGSP certified and standardized to the DCCT assay (see www.ngsp.org) will minimize issues. Otherstrategies such as measurement of fructosamine, which measures glycated plasma proteins or glycated albumin, may be necessary toassess diabetes control in patients with altered red blood cell life span, although they are less standardized, and not correlated to risk ofcomplications.

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. Forexample, 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 youngerchildren. 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 agegroups of type 1 DM patients are based on the risk of hypoglycemia, the relatively low risk of complications prior to puberty, andpsychological and/or developmental issues (Table 57-7).

Table 57-7 Glycemic Goals of Therapy by Organization

Biochemical Index ADA ACE and AACE

Hemoglobin A1c<7% (<0.07; <53mmol/mol/Hb)a

≤6.5% (≤0.065; ≤48 mmol/molHb)

Preprandial plasma glucose 70–130 mg/dL (3.9–7.2mmol/L) <110 mg/dL (<6.1 mmol/L)

Postprandial plasma glucose <180 mg/dLb (<10mmol/L)

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

ADA plasma glucose and HbA1c goals for type 1 DM by age groupc

Values by age (years) Plasma glucose goal A1C

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Before meals bedtime/overnight

Toddlers and preschoolers(0–6)

100–180 (5.6–10mmol/L)

110–200 (6.1–11.1mmol/L)

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

School age (6–12) 90–180 (5–10mmol/L) 100–180 (5.6–10 mmol/L) <8% (<0.080; <64 mmol/mol Hb)

Adolescents and youngadults (13–19)

90–130 (5–7.2mmol/L) 90–150 (5–8.3 mmol/L) <7.5% (<0.075; <58 mmol/mol

Hb)

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 without significant

hypoglycemia or adverse effects. Less stringent HbA1c goals 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.

bPostprandial glucose measurements should be made 1–2 hours after the beginning of the

meal, generally the time of peak levels in patients with diabetes.

cVulnerability to hypoglycemia and relatively low risk of complication prior to puberty

considered. Adolescents and young adults may have adult goals if without developmental

and psychological issues, and if without excessive hypoglycemia.

See reference 8.

Initial Evaluation of Diabetes Mellitus

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 currentand 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. Laboratoryevaluation should include at a minimum an A1C, lipid profile, liver function tests, thyroid-stimulating hormone level, serum creatinine andelectrolytes, and a urine analysis for microalbuminuria. In type 1 DM, consider screening for celiac disease by measuring tissuetransglutaminase or antiendomysial antibodies. The physical examination and pertinent data should include all vital signs, weight and/orBMI, blood pressure assessment, thyroid palpation, cardiovascular and carotid auscultation, skin integrity, assessment for acanthosisnigricans, and a foot examination, including screening for impaired sensation detection with a 10-g force monofilament.5

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Monitoring for Complications

The ADA recommends initiation of complications monitoring at the time of diagnosis of DM.8 Current recommendations continue toadvocate 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, andthen yearly thereafter. Less frequent testing (every 2 to 3 years) can be implemented on the advice of an eye care specialist. The bloodpressure should be assessed at each visit. The feet should be examined at each visit for distal pulses, skin integrity, calluses, anddeformities, and yearly screening should be done for loss of protective sensation with a distal polyneuropathy tool, such as the 10-g forceSemmes-Weinstein monofilament. A urine test for microalbumin to screen for nephropathy once yearly from diagnosis is appropriate intype 2 DM, and initiated 5 years after diagnosis if the patient has type 1 DM. Yearly testing for lipid abnormalities, and more frequently ifneeded to achieve lipid goals, is recommended. It is generally accepted that a yearly thyroid-stimulating hormone level may beappropriate 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 anymoment easily and relatively inexpensively. At its core, SMBG is a tool to provide structure for a change and/or safety: change, in that thepatient has an opportunity to intervene when a SMBG value is obtained, and safety, as hypoglycemia and hyperglycemia need to beavoided and/or identified and treated. In general, SMBG frequency should match how complicated the regimen is for glycemic controland minimally allow testing to avoid hypoglycemia.

Frequent SMBG is necessary to achieve near-normal BG concentrations if hypoglycemic agents are used. Assessment for hypoglycemiaand hyperglycemia, adjustment of prandial doses of insulin, administration of corrective doses of insulin, change in diet and exercise, andchecking accuracy of continuous glucose monitors are but a few of the reasons a patient may need SMBG at a given time. This isparticularly true in patients with type 1 DM, as most will be intensively managed with insulin. The more intense the pharmacologic regimenis, the more intense the SMBG needs to be (before meals, at bedtime, occasionally after meals, and middle of sleep cycle in patients onmultiple insulin injections or pump therapy whether type 1 or type 2 DM). The optimal frequency of SMBG for patients with type 2 DM onoral agents is unresolved.26 Frequency of monitoring in type 2 DM should be sufficient to facilitate reaching glucose goals and to test forhypoglycemia. The role of SMBG in improving glycemic control in type 2 DM patients is controversial, but has shown to reduce theHbA1c ˜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

Alternate site testing may improve adherence to SMBG recommendations, but only SMBG meters that can “sip” blood onto the strip willaccommodate such testing. Alternate site glucose testing is performed on the palm, forearm, or the thigh. These areas tend to have lessnerve endings and may be more comfortable for a patient, but several cautions must be observed. Interstitial glucose readings identifiedwith alternative site testing will lag behind fingertip capillary blood, as the capillary flow/density is often less in the alternate testing siteswhen compared with that in the fingertip. Alternate site testing is discouraged in any situation where immediate action will be neededbased on the glucose reading, such as testing for hypoglycemia or in patients with hypoglycemia unawareness, wide fluctuations inSMBG, 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 beimportant to him or her. Demonstrate to and then have the patient confirm the monitoring technique to minimize problems. Each meterhas 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 capillarySMBG, and the same cautions as alternate site testing should be followed. CGM can be useful in patients with frequent hypoglycemia orhypoglycemic unawareness, nocturnal hypoglycemia, and for identification of fluctuating glucose patterns and/or previously unknownproblems in patients with higher or lower than expected HbA1c results. CGM still needs to be calibrated after insertion of a new sensorand 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, ifadherent 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 forall medical nutrition therapy is the attainment of optimal metabolic outcomes and the prevention and treatment of complications. It is

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imperative that patients understand the connection between carbohydrate intake, medications, and glucose control. For individuals withtype 1 DM, the focus is on physiologically regulating insulin administration with a balanced diet to achieve and maintain a healthy bodyweight. A healthy meal plan that is moderate in carbohydrates and low in saturated fat (<7% of total calories), with a focus on balancedmeals 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 foodscan 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 goalscan be maintained, there is no reason to deny food choices. Overweight/obese patients with type 2 DM often require caloric restriction topromote weight loss, and portion size and frequency are often issues. The specific diet appears to be less important than if the patientwill adhere to the diet, although low-fat diet for CVD or avoiding a high-protein diet in nephropathy may be appropriate. Rather than a setdiabetic diet, advocate a diet using foods that are within the financial reach and cultural milieu of the patient. Discourage bedtime andbetween-meal snacks, set realistic goals for changes based on what the patient can/will change, and follow up to see how and if thosechanges occurred.27

Activity

In general, most patients with DM can benefit from increased activity.28 Aerobic exercise improves insulin sensitivity and modestlyimproves glycemic control in the majority of individuals, and reduces cardiovascular risk factors, contributes to weight loss ormaintenance, and improves well-being. The patient should choose an activity that he or she is likely to continue. Start exercise slowly inpreviously sedentary patients. It remains unclear which asymptomatic patients should be screened for CVD prior to the beginning of anexercise regimen. Patients with long-standing disease (age >35 years, or >25 years old with DM ≥10 years), patients with multiplecardiovascular risk factors, presence of microvascular disease (especially renal disease), and patients with previous evidence ofatherosclerotic disease should have a cardiovascular evaluation, probably including an electrocardiogram, with further workup related toCVD risk. In addition, several complications (uncontrolled hypertension, autonomic neuropathy, insensate feet, and retinopathy) mayrequire restrictions on the activities recommended. Physical activity goals include at least 150 min/wk of moderate (50% to 70% maximalheart 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 leasttwo 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 (fortype 2 DM only) and insulin (for type 1 or 2). Since 1995, a number of new oral agents, injectables, and insulins have been introduced inthe United States.

The Look Action for Health in Diabetes (Look AHEAD) trial recently reported that no decrease in cardiovascular outcomes from intensivelifestyle changes in type 2 DM subjects was noted after 10 years of follow-up. In addition, intensive lifestyle was not able to obtainintensive glycemic control in the majority of subjects, reiterating the need for early diabetes medication use in conjunction with diet andexercise interventions.

Currently, nine classes of oral agents are approved for the treatment of type 2 diabetes: α-glucosidase inhibitors, biguanides,meglitinides, peroxisome proliferator–activated receptor γ (PPAR-γ) agonists (which are also commonly identified as thiazolidinediones[TZDs] or glitazones), DPP-4 inhibitors, dopamine agonists, bile acid sequestrants, sodium-glucose cotransporter 2 inhibitors, andsulfonylureas. Oral antidiabetic agents are often grouped according to their glucose-lowering mechanism of action. Biguanides and TZDsare often categorized as insulin sensitizers due to their ability to reduce insulin resistance. Sulfonylureas and meglitinides are oftencategorized 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. Endogenouslyproduced insulin is cleaved from the larger proinsulin peptide in the β cell to the active peptide of insulin and inactive C-peptide. Allcommercially 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


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modified and/or “modifiers” added to impart particular physiochemical and pharmacokinetic advantages. Table 57-8 summarizesavailable insulin preparations.

Table 57-8 Available Injectable and Insulin Preparations

Generic Name Manufacturer Analoga Administration OptionsRoomTemperaturebExpiration

Rapid-acting Insulins

Humalog (insulin lispro) Lilly Yes Insulin pen 3 mL, vial, or 3-mL pencartridge 28 days

NovoLog (insulin aspart) Novo Nordisk Yes Insulin pen 3 mL, vial, or 3-mL pencartridge 28 days

Apidra (insulin glulisine) Sanofi-Aventis Yes Insulin pen 3 mL, vial, or 3-mL pencartridge 28 days

Short-acting Insulins

Humulin R (regular) available inU-100 and U-500 Lilly No U-100, 10-mL vial U-500, 20-mL

vial 28 days

Novolin R (regular) Novo Nordisk No 10-mL vial 30 days

Intermediate-acting Insulins

NPH

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 Vial, 3-mL prefilled pen 42 days

Premixed Insulins

Premixed insulin analogs

Humalog Mix 75/25 (75%neutral protamine lispro, 25%lispro)

Lilly Yes Vial, prefilled pen Vial: 28 days;pen: 10 days

Novolog Mix 70/30 (70% aspartprotamine suspension, 30%aspart)

Novo Nordisk Yes Vial, 3-mL prefilled penVial: 28 days;others: 14days

Humalog Mix 50/50 (50%neutral protamine lispro/50%lispro)

Lilly Yes Vial, 3-mL pen Vial: 28 days;pen: 10 days

NPH–regular Combinations

Vial: 28 days;









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Humulin 70/30 Lilly No Vial, 3-mL prefilled pen pen: 10 days

Novolin 70/30 Novo Nordisk No Vial 30 days

Other Injectables

Glucagon-like peptide-1agonists (GLP-1 agonists)

Byetta (exenatide) Amylin/BMS No 5- and 10-mcg pen, ˜60 injections(doses)/pen

30 days ≤25°C(≤77°F)

Victoza (liraglutide) Novo Nordisk Yes 3-mL pen, delivers 0.6-, 1.2-, or1.8-mg dose 30 days

Bydureon (exenatide) Amylin/BMS No 2-mg vial with separate diluent,single-use system

30 days ≤25°C(≤77°F)

Amylinomimetic

Symlin (pramlintide) Amylin Yes1.5-mL pen: delivers 15-, 30-, 45-,or 60-mcg dose; 2.7-mL pen:delivers 60- or 120-mcg dose

30 days

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.

bRoom temperature defined as 15–30°C (59–86°F). 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, allother insulin preparations are available only in U-100 strength. For some patients with type 1 diabetes who require extremely low doses ofinsulin, dilution of U-100 insulin to obtain accurate insulin doses may be necessary. Diluents, instructions on dilution, and empty bottlescan 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 andpork source insulin preparations as of December 2003, and now exclusively use recombinant DNA technology to manufacture insulin. EliLilly and Sanofi-Aventis currently use a non–disease-producing strain of Escherichia coli for synthesis of insulin, whereas Novo Nordiskuses 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 insulincontained enough impurities (300 to 10,000 ppm) to cause local reactions on injection, as well as systemic adverse effects from antibodyproduction. Modern technology has provided less expensive techniques to purify insulin. As a result, all insulin products contain ≤10 ppmof 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. Beforeabsorption through a blood capillary can occur, the hexamer must dissociate first to dimers, and then to monomers. This principle is thepremise 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 humaninsulin; monomeric) insulin with two amino acids transposed, aspart (B-28 aspartic acid human insulin; monomeric and dimeric) insulinwith replacement of one amino acid, and glulisine (B-3 lysine and B-29 glutamic acid) are rapidly absorbed, peak faster, and have shorterdurations of action when compared with regular insulin. Proteins tend to be insoluble near their isoelectric point, and glargine insulin uses


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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 apH 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, itrapidly 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-29position 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 interstitialalbumin, 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 ofaction 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 consideredin the approval process include local injection reactions, antigenicity, efficacy compared with human insulin, insulin receptor bindingaffinity, and insulin-like growth factor 1–receptor 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 ofinsulin from a subcutaneous depot is dependent on several factors, including source of insulin, concentration of insulin, additives to theinsulin preparations (e.g., zinc, protamine), blood flow to the area (rubbing of injection area, increased skin temperature, and exercise inmuscles near the injection site may enhance absorption), and injection site. Regular or neutral protamine Hagedorn (NPH) insulin iscommonly injected in (from most rapid to slowest absorption): abdominal fat, posterior upper arms, lateral thigh area, and superiorbuttocks area. Insulin analogs, unlike regular or NPH insulin, appear to retain their kinetic profile at all sites of injection. U-500 regularinsulin has a delayed onset and peak, and a longer duration of action when compared with U-100 regular insulin; the pharmacokineticprofile 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)

Maximum Duration(Hours) Appearance

Rapid Acting

Aspart 15–30minutes 1–2 3–5 5–6 Clear

Lispro 15–30minutes 1–2 3–4 4–6 Clear

Glulisine 15–30minutes 1–2 3–4 5–6 Clear

Short Acting

Regular 0.5–1 hours 2–3 4–6 6–8 Clear

IntermediateActing

NPH 2–4 hours 4–8 8–12 14–18 Cloudy

Long Acting

Detemir 2 hours —a 14–24 24 Clear

Glargine 4–5 hours —a 22–24 24 Clear

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







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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 insulin’s effect. Variability in absorption, inconsistent suspension of the insulin by the patient or healthcareprovider when drawing up a dose, and inherent insulin action based on the pharmacokinetics of the products may all contribute to a labileglucose response. NPH insulin and all suspension-based insulin preparations should be inverted or rolled gently at least 10 times to fullysuspend 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 beadvantageous when variability in the insulin level may make a large difference in glycemic excursions, as in type 1 DM. It should be notedthat 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 24hours. 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 thisis 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 databetween glargine insulin and detemir insulin are difficult to interpret, as detemir insulin was allowed to be dosed twice daily. Equivalentglycemic 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 insulinpreparations (lispro, aspart, glulisine, and even glargine) is similar to IV regular insulin, but they have no advantages over IV regular insulinand 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% ofinsulin metabolism occurs in the kidney. This may partially explain the lower insulin dosage requirements in patients with end-stage renaldisease.

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 subsequentreports of lung cancer. Technosphere inhaled insulin (Afrezza) was rejected by the FDA due to concerns regarding the redesign of theirdelivery device. Additional trials are underway to assess the safety of the redesigned delivery device in patients with type 1 and type 2DM. 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 reducing microvascular complications.23

Macrovascular Complications

The connection between high insulin levels (hyperinsulinemia), insulin resistance, and cardiovascular events incorrectly leads someclinicians to believe that insulin therapy may cause macrovascular complications. Endogenous hyperinsulinemia in the setting of insulinresistance has been linked to increased cardiovascular events; however, this is not the case with hyperinsulinemia due to exogenousinjectable 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 withinsulin therapy. This group assessed the effect of an insulin–glucose infusion in type 2 DM patients who had experienced an acutemyocardial infarction (MI). Those randomized to insulin infusion followed by intensive insulin therapy lowered their absolute mortality riskby 11% over a mean follow-up period of approximately 3 years. This was most evident in subjects who were insulin-naïve or had a lowcardiovascular 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 onintensive insulin therapy regimens versus those on less-intensive regimens. Also, patients with type 1 DM tend to have morehypoglycemic events compared with type 2 DM patients. In the UKPDS study, performed over 10 years, the percentage of diabeticpatients who needed assistance (third-party or hospitalization) due to a hypoglycemic reaction was 2.3%. The UKPDS reported a rate of36.5% for risk of any hypoglycemic event, including mild, self-treated events. In the DCCT, tighter control produced a risk three timeshigher for severe hypoglycemia compared with conventional therapy. Moreover, insulin was associated with 14% of emergency


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hospitalizations in older Americans using nationally representative public health surveillance data.30 Glycemic goals should incorporatehypoglycemic 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 ofhypoglycemia, and BG monitoring. BG monitoring is essential for those on insulin, and is particularly of value in patients withhypoglycemia unawareness. Patients with hypoglycemia unawareness do not experience the normal sympathetic symptoms ofhypoglycemia (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 leasttemporarily raise their glycemic goals (requiring a reduction in insulin dose) and check their BG level prior to any activities that may bedangerous with a low blood sugar (e.g., driving and certain sports, among others). Proper treatment of hypoglycemia dictates ingestion ofcarbohydrates, with glucose being preferred. Unconsciousness is an indication for either IV glucose or glucagon injection, whichincreases glycogenolysis in the liver. Glucagon use would be appropriate in any situation in which the patient does not have or cannothave ready IV access for glucose administration. Education for reconstitution and injection of glucagon is recommended for close friendsand family of a patient who has recurrent neuroglycopenic events. The patient and close contacts should be informed that it can take 10to 15 minutes for the injection to start raising glucose levels, and patients often vomit during this time. Proper positioning to avoidaspiration 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 isundesirable in most type 2 DM patients, but may be seen as beneficial in underweight patients with type 1 DM. Weight gain appears to berelated to intensive insulin therapy, and can 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 manyinjections into the same injection site. Due to insulin’s anabolic actions, a raised fat mass is present at the injection site with resultantvariable insulin absorption. Lipoatrophy, in contrast, is thought to be due to insulin antibodies or allergic-type reactions with destruction offat at the site of injection. In both cases, injection away from the site with more purified insulin is recommended, although reports oflipoatrophy have been reported with most insulin preparations. Anecdotal evidence has shown that specially formulated cromolyn mayhelp to stabilize the allergic type of reaction.

One large study using administrative data found an association between insulin glargine and cancer. However, several other largedatabase studies and meta-analysis have shown no such association. Glargine in vitro has a higher affinity for IGF-1 than regular humaninsulin, which could theoretically explain the increased risk of cancer, yet in vivo the metabolite of glargine is mostly present. Themetabolite 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 wasseen. Recently, the prospective, randomized Outcome Reduction with Initial Glargine Intervention trial reported no difference in cancerrisk or cardiovascular events with low-dose insulin glargine use over approximately 6 years.31 These data are not definitive, butencouraging.

Drug–Drug Interactions

There are no significant drug–drug interactions with injected insulin, although other medications that may affect glucose control can beconsidered. Detemir does not have albumin binding interactions, as it occupies only a small percent of albumin binding sites. Table 57-10lists common medications known to affect BG levels.

Table 57-10 Medications that may Affect Glycemic Controla

Drug Effect onGlucose Mechanism/Comment

Angiotensin-convertingenzyme inhibitors Slight reduction Improves insulin sensitivity

Alcohol Reduction Reduces hepatic glucose production

α-Interferon Increase Decreases insulin sensitivity/induces counterregulatory hormones

Atypical antipsychotics Increase Decrease insulin sensitivity; weight gain


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Calcineurin inhibitors Increase Decrease insulin secretion

Diazoxide Increase Decreases insulin secretion, decreases peripheral glucose use

Diuretics (thiazides) IncreaseMay increase insulin resistance and/or decrease insulin secretion,K+ change may be in part responsible

Glucocorticoids Increase Impairs insulin action

Fluoroquinolones Increase/decrease Unclear, potential drug interaction with sulfonylureas or change ininsulin secretion

Nicotinic acid Increase Impairs insulin action, increases insulin resistance

Oral contraceptives Increase Unclear

Pentamidine Decrease, andthen increase Toxic to β 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 orincrease lipotoxicity. Dependent on PI

β-Blockers May increase Decreases insulin secretion

Ranolazine Decrease Improves oxidative glucose disposal

Salicylates Decrease Inhibition of IκB kinase-β (IKK-β) (only high doses, e.g., 4–6 g/day)

Sympathomimetics Slight increase Increased glycogenolysis and gluconeogenesis

aThis list is not inclusive of all medications reported to cause glucose changes.

Dosing and Administration

The dose of insulin for any person with altered glucose metabolism must be individualized. In type 1 DM, the average daily requirementfor insulin is 0.5 to 0.6 unit/kg, with approximately 50% being delivered as basal insulin, and the remaining 50% dedicated to mealcoverage. 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 insulinresistance, 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 initiateand 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 U-500. In the inpatient setting, the prescription ofU-500 is often written in volume (mL) and administered using a tuberculin syringe. In an individual prescribed 50 units three times a daybefore meals, this prescription would be written as follows: “U-500 regular insulin, inject 50 units (0.1 mL) subcutaneously three timesdaily before meals.” In outpatients, however, it is often easier for patients to use U-100 insulin syringes. One unit of U-500 insulin drawnup using the markings of a U-100 equals 5 units of insulin. The same prescription as described above would be written as follows: “U-500regular insulin: inject 50 units (10 units as measured by the unit markings of a U-100 syringe) subcutaneously three times daily beforemeals.”

Storage

It is recommended that unopened injectable insulin be refrigerated (2°C to 8°C [36°F to 46°F]) prior to use. The manufacturer’s expirationdate printed on the insulin is used for unopened, refrigerated insulin. Once the insulin is in use, the manufacturer-recommendedexpiration dates will vary based on the insulin and delivery device. Table 57-8 outlines manufacturer-recommended expiration dates forroom temperature (15°C to 30°C [59°F to 86°F]) insulin. For financial reasons, patients may attempt to use insulin preparations longer thantheir expiration dates, but careful attention must be paid to monitoring for glycemic control deterioration and signs of insulin decay


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(clumping, precipitates, discoloration, etc.) if this is attempted.

Glucagon-Like Peptide-1 Agonists

Exenatide

Pharmacology

Exendin 4 is a 39–amino acid peptide isolated from the saliva of the Gila monster (Heloderma suspectum) and shares 53% amino acidsequence with human GLP-1. Exenatide is the synthetic version of naturally occurring exendin 4. Exenatide (Byetta, Bydureon) has beenshown to bind to GLP-1 receptors in many parts of the body including the brain and pancreas but is more resistant to DPP-4 degradationthan endogenous GLP-1. Exenatide and GLP-1 have common glucoregulatory actions. The GLP-1 receptor activity of exenatide ispharmacologic, however, and is approximately three to four times more than the normal peak physiologic GLP-1 activity. Exenatideenhances insulin secretion in a glucose-dependent manner, suppressing inappropriately high postprandial glucagon secretion resulting indecreased 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 hasa tmax of ˜2 hours and a plasma half life of ˜3.3 to 4 hours. Plasma concentrations increase in a dose-dependent manner andconcentrations 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 ofmicrospheres and gradually released over time. Following a single dose, exenatide is released from the microspheres over approximately10 weeks. After initiation of once-weekly injections of 2 mg exenatide suspension, there is a gradual increase in plasma exenatideconcentration 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 byglomerular filtration with subsequent proteolytic degradation. When exenatide is administered to subjects with worsening degrees of renalinsufficiency, there is a progressive prolongation of the half-life, and in dialysis patients, plasma clearance of exenatide is markedlyreduced. The incidence of GI side effects appears to be increased in individuals with impaired renal function, possibly due to higherplasma 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, butHbA1c lowering is dependent on baseline values. Some patients will have greater or lesser reduction in HbA1c. Similar HbA1c reductionis seen in patients on oral agents. Once-weekly extended-release exenatide resulted in significantly greater changes from baselinecompared 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 hassignificant elevations in FPG levels, these should be corrected with other agents and then exenatide added later. It is recommended tolower the sulfonylurea dose only if GLP-1 agonists are started with near-normal glucose levels. Sulfonylureas release insulin in a non–glucose-dependent fashion and can cause hypoglycemia.

Exenatide may aid some patients’ efforts to lose weight. The average weight loss in controlled trials of twice-daily exenatide was 1 to 2 kgover 30 weeks, without dietary advice being given to the patients. Long-term, open-label follow-up on 10 mcg twice a day showscontinued 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 doesnot 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

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several cardiovascular risk factors have been reported. In an open-label study of exenatide 10 mcg twice a day, triglycerides (−37 ± 10mg/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-weeklyextended-release exenatide resulted in greater reduction in total cholesterol and LDL cholesterol compared with twice-daily exenatide.33Nonsignificant reductions in systolic and diastolic blood pressure have been observed; a significant reduction was seen in subjects withabove-normal systolic blood pressure. The greatest improvement in cardiovascular risk factors was, in general, seen in subjects who hadthe greatest weight loss.

Adverse Effects

The most common adverse effects associated with exenatide are GI. Nausea is more likely with twice-daily exenatide (>35%) comparedwith once-weekly extended-release exenatide (˜14%). Vomiting or diarrhea occurs in approximately 10% of patients on twice-dailyexenatide. As these adverse effects appear to be dose related, the patient on twice-a-day exenatide should be started on 5 mcg twice aday 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 daydose, 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 ortransition 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 whenfull, 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 notsubstantially increased. However, when combined with a sulfonylurea or insulin, hypoglycemia may occur. Although exenatide reducesglucagon when the glucose is high, there is no suppression of counterregulatory hormones during hypoglycemia. Exenatide antibodiescan occur, but generally decrease over time and usually do not affect glycemic control. In approximately 5% of patients, titers mayincrease 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 asgallstones, 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 acutepancreatitis. In a patient with a history of pancreatitis, the benefits of using exenatide must be weighed against potential risks. If a patientwith abdominal pain, nausea, and/or vomiting presents, it is best to discontinue exenatide temporarily and confirm that the symptoms arenot a sign of a more serious underlying problem. Exenatide given twice daily does not change the risk of thyroid C-cell tumors in rats anddoes not have a black box warning; no increased risk of C-cell tumors has been reported in humans. Extended-release exenatide has ablack box warning in regards to thyroid C-cell tumors due to rat data. The difference appears to be that the extended release continuallystimulates the GLP-1 receptor on the thyroid of rodents, increasing the risk of thyroid C-cell tumors. No tumors have been reported inhumans.

There have been reports of injection site reactions with extended-release once-weekly exenatide. Nodule injection site reactions are notpainful 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 arean 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 theplatform, 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 theabsorption of other medications. Examples of medications that may be effected include oral pain medications and antibiotics dependenton concentration-dependent efficacy. If rapid absorption of the medication is necessary, it is best to take the mediation 1 hour before, orat least 3 hours after, the injections of twice-daily exenatide. There have been postmarketing reports of increased INR in patients onwarfarin on exenatide, sometimes associated with bleeding. It is advised that INR be monitored frequently until stable on initiation ofexenatide.


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 whentolerability allows and if warranted for glycemic control. Twice-daily exenatide should be injected subcutaneously 0 to 60 minutes beforethe 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 peakeffect of twice-daily exenatide is at approximately 2 hours, so anecdotally the patient may get better appetite suppression if injected anhour 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


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or without meals. Extended-release exenatide is injected immediately after the powder is suspended in the diluent. The process ofextended-release once-weekly exenatide injections is more complex than using the twice-daily exenatide pen. Patients must beinstructed 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 injectinginto 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 alterationis an arginine substituted for lysine at position 34. A C-16 fatty acid (palmitic acid) is attached at position 26 (with a glutamic amino acidspacer 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 ofelevated glucose concentrations, resulting in a reduction in hepatic glucose production. Liraglutide reduces food intake, which may resultin 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 hormoneglucagon.

Pharmacokinetics

After injection of liraglutide, there is self-association into a heptameric structure, binding to albumin first in the interstitial space, then inthe blood, and then in the interstitial space around the GLP-1 receptor that prolongs the half-life. In healthy individuals, the half-life is 13hours, making it suitable for daily administration. Injection into the abdomen, upper arm, and thigh gives clinically similarpharmacokinetics. Maximum concentrations are reached approximately 8 to 12 hours after injection, with steady state reached afterapproximately 3 days. Liraglutide is extensively plasma protein bound (mostly to albumin as previously stated) with an elimination half-lifeof 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 of3% 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 thecase 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 hepaticimpairment may actually lower the AUC by approximately 25%, although the clinical 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 inHbA1c is dependent on the baseline values. Liraglutide lowers FPG level by approximately 25 to 40 mg/dL (1.4 to 2.2 mmol/L), andpostprandial plasma glucose levels are reduced similarly. Due to the longer half-life, liraglutide can suppress glucagon overnight, whichimproves the FPG. Similar to exenatide, liraglutide-treated patients may lose weight. The average weight loss in controlled trials was 1 to3 kg over 26 weeks, and weight loss achieved appeared to be sustained through 2 years. Liraglutide, through decreasing appetite andslowing 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 ofcardiovascular 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% to40% of subjects on 1.8 mg daily. Vomiting occurs in approximately 5% of subjects, and diarrhea occurs in approximately 8% to 15% ofpatients placed on liraglutide. GI adverse effects appear to decrease over time, but approximately 5% to 10% of subjects withdrew dueto 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 astolerated. Randomized trials did not allow for individualized titration, and likely had worse tolerability that can be obtained clinically byindividualization of titration.


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Many episodes of nausea would be better characterized as stomach fullness. To minimize GI side effects, patients should be instructedto eat slowly and stop eating when full, or risk nausea/vomiting. Liraglutide provides glucose-dependent insulin secretion, andhypoglycemic rates when combined with metformin ± a TZD are not substantially increased, but when combined with a sulfonylurea orinsulin, significant hypoglycemia may occur. When combined with a sulfonylurea, the rates of hypoglycemia were similar betweenaddition of liraglutide and that of glargine insulin. Liraglutide antibodies can occur (4% to 13%), but the rates are generally low and do notaffect 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 isneeded, but type 2 DM patients have many risk factors for pancreatitis and the common GI side effects of GLP-1 agonists could maskinitial signs of pancreatitis. If a patient with abdominal pain, nausea, and/or vomiting presents, it is best to discontinue liraglutidetemporarily and if symptoms persist, evaluate for other potential causes, including pancreatitis. Clinicians must weigh the benefits ofliraglutide 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. Rodentmodels reported a higher risk of C-cell tumors of the thyroid, including medullary thyroid carcinoma. Rodents may not be the ideal modelto study this effect as they express a high number of GLP-1 receptors on thyroid C-cells, whereas in humans the expression of GLP-1receptors in the thyroid is minimal. Rodents also have a higher baseline prevalence of C-cell tumors compared with humans. In addition,calcitonin, a marker used to screen for C-cell tumors, may increase by a non–clinically significant amount in select patients. No signal forC-cell tumors in humans or nonhuman primates has been noted thus far. As clinical use increases, however, this will continue to beexamined. Currently no specific additional monitoring of patients is recommended. Nonetheless, liraglutide is contraindicated in patientswith 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 effectedinclude oral pain medications and antibiotics dependent on threshold levels for efficacy. If rapid absorption of the medication isnecessary, it is best to take the mediation 1 hour before, or at least 3 hours after, the injection. Liraglutide may worsen gastroparesis andclinically 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 bemaintained 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 atitration dose, and does not reduce the HbA1c substantially in the majority of patients. This titration is recommended to improve GItolerability. Titration should be individualized based on side effects and clinical response. Liraglutide is dosed once daily, and may begiven independent of meals. As with exenatide, a reduction in insulin secretagogues and insulin may be necessary if the patient is nearglycemic 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 ofamylin (amylinomimetic), a neurohormone cosecreted from the β cells with insulin. Amylin is very low or absent in type 1 DM, and lowerthan normal in type 2 DM patients requiring insulin therapy. Pramlintide is provided as a 37–amino acid polypeptide, which differs inamino acid sequence from human amylin by replacement positions 25 (alanine), 28 (serine), and 29 (serine) with proline. Pramlintidesuppresses inappropriately high postprandial glucagon secretion, increases satiety, which may result in weight loss, and slows gastricemptying 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 theCmax 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 thekidneys, and one active metabolite (2-37 pramlintide) has a similar half-life as the parent compound. No accumulation has been seen inrenal insufficiency, but caution is advised. Injection into the arm may increase exposure and variability of absorption, so injection into theabdomen or thigh is recommended. Moderate to severe renal insufficiency does not affect exposure.

Efficacy


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The average HbA1c reduction is approximately 0.6% (0.006; 7 mmol/mol Hb) with pramlintide, although optimization of the insulin andpramlintide 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 in1.5-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, butwith no weight gain, compared with ˜5-kg weight gain with rapid-acting insulin. Pramlintide decreases prandial glucose excursions, buthas little effect on the FPG concentration. When pramlintide is injected before the meal, gastric emptying may delay absorption ofmealtime nutrients, necessitating delay of rapid-acting insulin. This may be overcome by injecting the mealtime insulin at the conclusionof the meal, or whenever the BG starts to rise. The average weight loss in controlled trials was 1 to 2 kg, without dietary advice beinggiven 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, andvomiting 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 isindicated for use in patients on insulin; thus, hypoglycemia can occur. The risk of severe hypoglycemia early in therapy is higher in type 1DM 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 beeffected include oral pain medications and antibiotics dependent on threshold levels for efficacy. If rapid absorption of the medication isnecessary, 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% whenpramlintide is started to minimize severe hypoglycemic reactions or delayed until postprandial glucose levels rise. Basal insulin may needto 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 themaximally recommended 120-mcg dose as tolerated and warranted based on postprandial plasma glucose concentrations. At least oneclinical trial started at the 120-mcg dose without significantly more intolerability. In type 1 DM, dosing starts at 15 mcg prior to meals, andcan 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 notneed to be covered with pramlintide (recommended if ≥250 kcal [≥1,046 kJ] or ≥30 g of carbohydrate is eaten). Storage information canbe found in Table 57-8.

Sulfonylureas

Pharmacology

The primary mechanism of action of sulfonylureas is enhancement of insulin secretion. Sulfonylureas bind to a specific sulfonylureareceptor (SUR) on pancreatic β cells. Binding closes an adenosine triphosphate–dependent K+ channel, leading to decreased potassiumefflux 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 tothe cell surface and resultant exocytosis of the granule of insulin. Elevated secretion of insulin from the pancreas travels via the portal veinand subsequently suppresses hepatic glucose production.

Classification

Sulfonylureas are classified as first-generation and second-generation agents. The classification scheme is largely derived fromdifferences 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 isimportant to recognize that all sulfonylureas are equally effective at lowering BG when administered in equipotent doses.


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Table 57-11 Oral Agents for the Treatment of Type 2 Diabetes Mellitus

RecommendedStarting Dosage

Drug Namea BrandName Dose Nonelderly Elderly Usual/Maximal

Dose Other

Sulfonylureas

Acetohexamide(Y) Dymelor 250, 500 mg 250

mg/day125–250mg/day 1,500 mg/day

Metabolized inliver; metabolitepotency equalto parentcompound;renallyeliminated

Chlorpropamide(Y) Diabinese 100, 250 mg 250

mg/day100mg/day 500 mg/day

Metabolized inliver; alsoexcretedunchangedrenally

Tolazamide (Y) Tolinase 100, 250, 500mg

100–250mg/day

100mg/day 1,000 mg/day

Metabolized inliver; metaboliteless active thanparentcompound;renallyeliminated

Tolbutamide (Y) Orinase 250, 500 mg1,000–2,000mg/day

500–1,000mg/day

3,000 mg/day

Metabolized inliver to inactivemetabolites thatare renallyexcreted

Glipizide (Y) Glucotrol 5, 10 mg 5 mg/day 2.5–5mg/day 40 mg/day

Metabolized inliver to inactivemetabolites

Glipizide (Y) GlucotrolXL

2.5, 5, 10, 20mg 5 mg/day 2.5–5

mg/day 20 mg/daySlow-releaseform; do not cuttablet

Glyburide (Y) DiaBeta,Micronase

1.25, 2.5, 5mg 5 mg/day 1.25–2.5

mg/day 20 mg/day

Metabolized inliver; eliminationone half renal,one half feces.two activemetabolites

Glyburide,micronized (Y) Glynase 1.5, 3, 6 mg 3 mg/day 1.5–3

mg/day 12 mg/dayBetterabsorption frommicronizedpreparation

Glimepiride (Y) Amaryl 1, 2, 4 mg 1–2mg/day

0.5–1mg/day 8 mg/day

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Short-actinginsulinsecretagogues

Nateglinide (Y) Starlix 60, 120 mg120mg/daywith meals

120mg/daywithmeals

120 mg threetimes a day

Metabolized bycytochromeP450 (CYP450)2C9 and 3A4 toweakly activemetabolites;renallyeliminated

Repaglinide (N) Prandin 0.05, 1, 2 mg0.5–1mg/daywith meals

0.5–1mg/daywithmeals

16 mg/day

Caution withgemfibrozil ortrimethoprim—potentialhypoglycemia

Biguanides

Metformin (Y) Glucophage 500, 850,1,000 mg

500 mgtwice a day

Assessrenalfunction

2,550 mg/dayNo metabolism;renally secretedand excreted

Metformin ER (Y) GlucophageXR

500, 750,1,000 mg

500–1,000mg witheveningmeal

Assessrenalfunction

2,550 mg/day

Take full dosewith eveningmeal or maysplit dose; mayconsider trial ifintolerant toimmediaterelease

Metforminsolution Riomet 500 mg/5 mL 500 mg

dailyAssessrenalfunction

2,000 mg/dayMetformin isindicated inchildren ≥10years old

Thiazolidinediones

Pioglitazone (Y) Actos 15, 30, 45 mg 15 mg/day 15mg/day 45 mg/day

Metabolized byCYP2C8 and3A4; two activemetaboliteshave longerhalf-lives thanparentcompound

Rosiglitazone (N) Avandia 2, 4, 8 mg 2–4mg/day 2 mg/day 8 mg/day or 4

mg twice a day

Limitedavailability.Continuation oftherapy orunable to takepioglitazone.Clinician/patientsign that knownrisk of MI

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Acarbose (Y) Precose 25, 50, 100mg

25 mg oneto threetimes a day

25 mgone tothreetimes aday

25–100 mgthree times aday

Eliminated inbile. Slowtitration key fortolerability. Withmeals

Miglitol (N) Glyset 25, 50, 100mg

25 mg oneto threetimes a day

25 mgone tothreetimes aday

25–100 mgthree times aday

Eliminatedrenally

Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)

Sitagliptin (N) Januvia 100, 50, 25mg

100 mgdaily

25–100mg dailybased onrenalfunction

100 mg daily

50 mg daily ifestimatedcreatinineclearance >30to <50 mL/min(>0.50 to <0.83mL/s); 25 mg ifcreatinineclearance <30mL/min (<0.50mL/s)

Saxagliptin (N) Onglyza 2.5, 5 mg 5 mg daily

2.5–5 mgdailybased onrenalfunction

5 mg daily

2.5 mg daily ifcreatinineclearance <50mL/min (<0.83mL/s) or if onstrong inhibitorsof CYP3A4/5

Linagliptin (N) Tradjenta 5 mg 5 mg daily 5 mg daily 5 mg daily

Notsubstantiallyeliminated byrenal, found infeces. Do notuse with stronginducer ofCYP3A4/p-glycoprotein

Alogliptin (N) Nesina 25, 12.5, 6.25mg 25 mg daily 25 mg 25 mg

˜75% eliminatedunchanged inurine. 12.5 mgCrCl <60mL/min (<1mL/s), 6.25 mg<30–15 mL/min(<0.50–0.25mL/s)

Bile acidsequestrants

6tabletsdaily or

6tabletsdailyorthree

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Colesevelam (N) Welchol

625-mgtablet1.875- and3.75-g oralsuspension

threetabletstwice aday1.875 gtwice aday or3.75 gdaily

tabletstwicea day1.875gtwicea dayor3.75 gdaily

3.75 g/day

Drug–drugabsorptioninteractionspresent, mayincreasetriglycerides;contraindicatedif TG >500mg/dL (>5.65mmol/L)

Dopamine agonist

Bromocriptinemesylate (N) Cycloset 0.8-mg tablets 1.6–4.8 mg

daily1.6–4.8mg daily 4.8 mg daily

Take within 2hours of risingwith food.Significantnausea, otherside effects,and drug–drug,drug–diseaseinteractionsmay occur

aGeneric version available? Y, yes; N, no.

Pharmacokinetics

All sulfonylureas are metabolized in the liver, some to active and others to inactive metabolites. Glyburide metabolites are active, whereasglipizide and glimepiride do not have active metabolites. Cytochrome P450 (CYP450) 2C9 is involved with the hepatic metabolism of themajority of sulfonylureas. Agents with active metabolites or parent drug that are renally excreted require dosage adjustment or use withcaution in patients with compromised renal function. The half-life of the sulfonylurea also relates directly to the risk for hypoglycemia. Thehypoglycemic potential is therefore higher with chlorpropamide and glyburide. The long duration of effect of chlorpropamide may beparticularly problematic in elderly individuals, whose renal function declines with age, and therefore it has great potential foraccumulation, resulting in severe and protracted hypoglycemia. Individuals at high risk for hypoglycemia (e.g., elderly individuals andthose with renal insufficiency or advanced liver disease) should be started at a very low dose of a sulfonylurea with a short half-life.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 fall1.5% to 2% (0.015 to 0.020; 17 to 22 mmol/mol Hb) in drug-naïve 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 sulfonylureamonotherapy. 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 ofFPG) and have significant glucose toxicity or LADA. The other group is those with a good initial response (>30 mg/dL [>1.7 mmol/L] dropof FPG), but which is insufficient to reach their glycemic goals. Over 75% of patients fall into the second group. Factors that portend apositive response include newly diagnosed patients with no indicators of type 1 DM, high fasting C-peptide levels, and moderate fastinghyperglycemia (<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 discussionfollows 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







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University Group Diabetes Program study documented higher rates of coronary artery disease in type 2 patients given tolbutamide, whencompared 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 viaK+ channel closure in the heart. Ischemic preconditioning is the premise that prior ischemia in cardiac tissue can provide greatertolerance of subsequent ischemia. Thus, patients with heart disease potentially have one compensatory mechanism to protect the heartfrom 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 inPharmacokinetics below, those who skip meals, exercise vigorously, or lose substantial amounts of weight are also more likely toexperience hypoglycemia.

Hyponatremia (serum sodium <129 mEq/L [129 mmol/L]) is reportedly associated with tolbutamide, but it is most common withchlorpropamide and occurs in as many as 5% of individuals treated. An increase in antidiuretic hormone secretion is the mechanism forhyponatremia. 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 withimprovement 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 andchlorpropamide 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 willacutely increase. First-generation sulfonylureas, which bind to proteins ionically, are more likely to cause drug–drug interactions thansecond-generation sulfonylureas, which bind nonionically. The clinical importance of protein-binding interactions has been questioned, asthe majority of these drug interactions have been found to be truly due to hepatic metabolism. Drugs that are inducers or inhibitors ofCYP450 2C9 should be monitored carefully when used with a sulfonylurea.35 Additionally, other drugs known to alter BG should beconsidered (Table 57-10).


The usual starting dose and maximum dose of sulfonylureas are summarized in Table 57-11. Lower dosages are recommended for mostagents in elderly patients and those with compromised renal or hepatic function. The dosage can be titrated as soon as every 2 weeksbased on FPG values (use a longer interval with chlorpropamide) to achieve glycemic goals. This is possible due to the rapid increase ofinsulin secretion in response to the sulfonylurea. Of note, immediate-release glipizide’s maximal dose is 40 mg/day, but its maximaleffective dose is about 10 to 15 mg/day. The maximal effective dose of sulfonylureas tends to be about 60% to 75% of their statedmaximum 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 βcells of the pancreas, similarly to sulfonylureas. Both repaglinide (a benzoic acid derivative) and nateglinide (a phenylalanine amino acidderivative) require the presence of glucose to stimulate insulin secretion. As glucose levels diminish to normal, stimulated insulin secretiondiminishes.

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 α1-acid glycoprotein. It is predominantly metabolizedby CYP2C9 (70%) and CYP3A4 (30%) to less active metabolites. Glucuronide conjugation then allows rapid renal elimination. No dosageadjustment is needed in moderate to severe renal insufficiency. Repaglinide is highly protein bound, and is mainly metabolized byoxidative 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 doesnot appear to affect repaglinide, but moderate to severe hepatic impairment may prolong exposure.

Efficacy


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In monotherapy, both significantly reduce postprandial glucose excursions and reduce HbA1c levels. Repaglinide, dosed 4 mg threetimes a day, when compared with glyburide in diet-treated, drug-naïve 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 populationreduced HbA1c values by 0.8% (0.008; 9 mmol/mol Hb). The lower efficacy of these agents versus sulfonylureas should be consideredwhen patients are >1% (>0.01; >11 mmol/mol Hb) above their HbA1c goal. These agents can be used to provide increased insulinsecretion during meals, when it is needed, in patients close to glycemic goals. Also, it should be noted that addition of either agent to asulfonylurea 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 isdue 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% and19%, 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. Gemfibrozilmore than doubles the half-life of repaglinide and has resulted in prolonged hypoglycemic reactions. It is a potent glucuronidationinhibitor and CYP2C8 inhibitor. Trimethoprim, a CYP2C8 inhibitor, increased repaglinide levels by 60%. Nateglinide appears to be a weakinhibitor of CYP2C9 based on tolbutamide metabolism. Although no significant drug–drug interactions have been reported, cautionshould 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 repaglinideis 0.5 mg in subjects with HbA1c <8% (<0.08; <64 mmol/mol Hb) or treatment-naïve patients, increased weekly to a total maximum dailydose 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 eachmeal provides approximately 90% of the maximal glucose-lowering effect. Nateglinide should be dosed at 120 mg prior to meals, anddoes 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/molHb]). If a meal is skipped, the medication can be skipped, and meals extremely low in carbohydrate content may not need a dose. Bothagents may be used in patients with renal insufficiency, and may fit into therapy in patients in need of an insulin secretagogue but havinghypoglycemia 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 approvedin the United States since 1995. Metformin enhances insulin sensitivity of mainly hepatic but also peripheral (muscle) tissues. This allowsfor an increased uptake of glucose into these insulin-sensitive tissues. All the mechanisms of how metformin accomplishes glucosereduction are still being investigated, although adenosine 5′-monophosphate–activated protein kinase activity, tyrosine kinase activityenhancement, increased adenosine 5′-monophosphate, and partial inhibition of the mitochondrial respiratory chain are involved.Metformin has no direct effect on the β cells, although insulin levels are reduced, reflecting increases in insulin sensitivity.

Pharmacokinetics

Metformin has approximately 50% to 60% oral bioavailability, low lipid solubility, and a volume of distribution that approximates bodywater. It is not metabolized and does not bind to plasma proteins. Metformin is eliminated by renal tubular secretion and glomerularfiltration. The average plasma half-life of metformin is 6 hours, although pharmacodynamically, metformin’s antihyperglycemic effects lastmore 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-naïve patients, and retains the ability to reduce FPG levels when they are extremely high (>300 mg/dL [>16.7mmol/L]). The sulfonylureas’ ability to stimulate insulin release from β cells at extremely high glucose levels is often impaired, a conceptcommonly 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 lowerthe risk of pancreatic, colon, and breast cancer in type 2 DM patients. Metformin, potentially through multiple mechanisms includingadenosine 5′-monophosphate–activated protein kinase activity, may act as a growth inhibitor in some cancers and help to kill cancer


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“stem cells” which are resistant to chemotherapy, and liver kinase B1, which is an upstream kinase of adenosine 5′-monophosphate–activated 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 differenceswere seen between therapies with regard to reducing microvascular complications, but the power of the study is questionable.36

Image not available. Macrovascular Complications

Metformin reduced macrovascular complications in obese subjects in the UKPDS.36 It significantly reduced all-cause mortality and risk ofstroke versus intensive treatment with sulfonylureas or insulin. Metformin also reduced diabetes-related death and MIs versus theconventional 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 oralantihyperglycemic 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 andcan 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 areencountered. Increases in the dose may be tried again in several weeks. Anecdotally, extended-release metformin (Glucophage XR) maylessen some of the GI side effects. Metallic taste, interference with vitamin B12 absorption, and hypoglycemia during intense exercisehave 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 mitochondrialrespiratory chain. In addition, any disease state that may increase lactic acid production or decrease lactic acid removal may predisposeto lactic acidosis. Tissue hypoperfusion, such as that due to congestive heart failure, severe lung disease, hypoxic states, shock, orsepticemia, via increased production of lactic acid, and severe liver disease or alcohol, via reduced removal of lactic acid in the liver, allincrease the risk of lactic acidosis. The clinical presentation of lactic acidosis is often nonspecific flu-like symptoms; thus, the diagnosis isusually made by laboratory confirmation of high lactic acid levels and acidosis. Metformin use in renal insufficiency, defined as a serumcreatinine of 1.4 mg/dL (124 μmol/L) in women and 1.5 mg/dL (133 μmol/L) in men or greater, is contraindicated, as it is renallyeliminated. Elderly patients, who often have reduced muscle mass, should have their glomerular filtration rate estimated by a 24-hoururine creatinine collection. If the estimated glomerular filtration rate is less than 60 mL/min (1 mL/s), metformin use should be carefullyevaluated. Recent evidence has reported that metformin may be fairly safe in moderate renal insufficiency. Metformin use can bemodified 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 <0.29mL/s/m2); corresponding actions are to monitor renal function every 3 to 6 months, then limit dose to 50% of maximal dose, and thenstop metformin, respectively. Due to the risk of acute renal failure during IV dye procedures, metformin therapy should be withheldstarting 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 serumconcentrations. At least one case report of lactic acidosis with metformin therapy implicates cimetidine. Theoretically other cationic drugsmay 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 beincreased by 500 mg as tolerated until glycemic goals or 2,500 mg/day is achieved (see Table 57-11). Metformin 850 mg may be doseddaily, 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% ofthe 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 singleevening dose of 2,000 mg/day. Extended-release metformin 750-mg tablets may be titrated as tolerated to the maximum dose of 2,250mg/day, although, as stated above, 1,500 mg/day provides the majority of the glycemic-lowering effect. Twice-daily to three-times-a-daydosing of extended-release metformin may help to minimize GI side effects and improve glycemic control, but will not change theglycemic reduction.

Thiazolidinediones


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Pharmacology

TZDs are also referred to as glitazones. Pioglitazone (Actos) and rosiglitazone (Avandia) are the two currently approved TZDs for thetreatment of type 2 DM (see Table 57-11). TZDs work by binding to the PPAR-γ, 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 atmuscle, liver, and fat tissues indirectly. They cause preadipocytes to differentiate into mature fat cells in subcutaneous fat stores. Smallfat 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 intosubcutaneous fat, a less insulin-resistant storage tissue. Muscle intracellular fat products, which contribute to insulin resistance, alsodecline. TZDs also affect adipokines (e.g., angiotensinogen, tissue necrosis factor-α, interleukin 6, PAI-1), which can positively affectinsulin sensitivity, endothelial function, and inflammation. Of particular note, adiponectin is reduced with obesity and/or diabetes, but isincreased with TZD therapy, which improves endothelial function and insulin sensitivity, and has a potent antiinflammatory effect. Lastly,TZDs appear to improve mitochondrial function through a reduction in FFAs. Cyclin-dependent kinase 5 has also recently been purposedas an important activator of PPAR-γ.

Pharmacokinetics

Pioglitazone and rosiglitazone are well absorbed with or without food. Both are highly (>99%) bound to albumin. Pioglitazone is primarilymetabolized by CYP2C8, to a lesser extent by CYP3A4 (17%), and by hydroxylation/oxidation. The majority of pioglitazone is eliminatedin the feces with 15% to 30% appearing in urine as metabolites. Two active metabolites (M-III and M-IV) are present. Rosiglitazone ismetabolized by CYP2C8, and to a lesser extent by CYP2C9, and also by N-demethylation and hydroxylation. Two thirds is found in urineand one third in feces. The half-lives of pioglitazone and rosiglitazone are 3 to 7 and 3 to 4 hours, respectively. The two active metabolitesof pioglitazone, with longer half-lives, deliver the majority of activity at steady state. Pioglitazone requires no dosage adjustment inmoderate 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 antihyperglycemicaction 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 ˜60to 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 beseen 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 minimalglucose lowering is initially encountered. The efficacy of both drugs is dependent on sufficient insulinemia. If there is insufficientendogenous insulin production (β-cell function) or exogenous insulin delivery via injections, neither will lower glucose concentrationsefficiently. Interestingly, patients who are more obese or who gain weight on either medication tend to have a larger reduction in HbA1cvalues. Pioglitazone consistently decreases plasma triglyceride levels by 10% to 20%, whereas rosiglitazone tends to have a neutraleffect. LDL-C concentrations tend to increase with rosiglitazone 5% to 15%, but do not significantly increase with pioglitazone. Bothappear to convert small, dense LDL particles, which have been shown to be highly atherogenic, to large, fluffy LDL particles that are lessdense. 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-1levels are decreased, and many other adipocytokines are affected, endothelial function improves, and blood pressure may decreaseslightly.


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 macrovascularevents, pioglitazone 45 mg was added to standard therapy in patients who had experienced a macrovascular event or had peripheralvascular 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 legrevascularization) was reduced 10% (P = 0.095). The main secondary end point (all-cause mortality, nonfatal MI, or stroke) was reduced16% (P = 0.027). The seemingly dichotomous results relate to the inclusion of leg revascularization as a primary end point, which wereincreased in the pioglitazone group. Reasons for the increase are speculative, but may relate to more testing/inspection due to peripheraledema. 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 reported higher MI rates withrosiglitazone, 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

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A prospective, multicenter, open-label noninferiority trial in 4,447 patients of rosiglitazone added to background metformin or sulfonylureaversus the active comparator metformin + sulfonylurea was recently reported (Rosiglitazone Evaluated for Cardiovascular Outcomes inOral Agent Combination Therapy for Type 2 Diabetes [RECORD]). Rosiglitazone was noninferior to the comparator for all CV outcomesexcept 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 instroke (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 increasesin ischemic events. The FDA has placed rosiglitazone under a strict risk evaluation and mitigation program, limiting access to patients andprescribers 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 fromthe U.S. market. Newer TZDs do not have the same propensity, but have had postmarketing reports of liver injury. Patients with abnormalalanine aminotransferase (ALT) levels should be started with caution, and if the ALT is >3 times the upper limit of normal, especially if thetotal 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 sodiumand water retention. A reduction in plasma hemoglobin (2% to 4%), attributed to a 10% increase in plasma volume, may result in adilutional 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 inpatients with New York Heart Association Class III and IV heart failure, and great caution should be exercised when given to patients withClass I and II heart failure or other underlying cardiac disease, as pulmonary edema and heart failure have been reported. Edema tends tobe 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 havebeen 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 fataccumulation play a part in explaining the weight gain. TZDs, besides stimulating fat cell differentiation, also reduce leptin levels, whichstimulate appetite and food intake. Average weight gain varies, but a 1.5- to 4-kg weight gain is not uncommon. Rarely, a patient will gainlarge amounts of weight in a short period of time, and this may necessitate discontinuation of therapy. Weight gain positively predicts alarger 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 appearto have a higher risk. These fractures are not osteoporitic in the classic sense, and do not occur in common osteoporosis fracture sitessuch as spine or hip. Most occur in wrists, forearms, ankles, or feet. Versus comparative diabetes therapy, TZDs may increase the risk ofa fracture by 25%. The underlying pathophysiology is speculative, but may relate to TZD effects on the pluripotent stem cell and shuntingof new cells to fat instead of osteocytes as well as altering osteoblasts/osteoclasts. It would be prudent to consider a patient’s riskfactors 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 rodentmodels 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) riskof bladder cancer with pioglitazone at 5 years. Excess risk appears to be mostly in men and smokers, and is dose and durationassociated. 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 precautionsshould 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 norrosiglitazone appears to be an inhibitor or inducer of CYP3A4/2C8 or CYP2C8/CYP2C9, respectively, although drugs that are stronginhibitors or inducers of these pathways (e.g., gemfibrozil or rifampin) may increase or decrease levels of active drug significantly. Thepackage 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 effectivedose 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%


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(0.002 to 0.003; 2 to 3 mmol/mol Hb) more versus 8 mg once daily.

Rosiglitazone’s availability is limited for now, and an active risk evaluation and mitigation program has been implemented due to the riskof ischemic events. Patients and prescribers must sign up through the rosiglitazone website in order to receive the medication from acentral mail-order pharmacy, as local pharmacies no longer carry rosiglitazone. Patients and prescribers must agree either that it iscontinuation of therapy and the risks versus benefits are known to both or that it is a new prescription and that the patient has been fullyinformed of the risk, including MI, and of the alternatives available, including pioglitazone. Pioglitazone is not included in this particularrisk evaluation and mitigation program.

α-Glucosidase Inhibitors

Pharmacology

Currently, there are two α-glucosidase inhibitors available in the United States: acarbose (Precose) and miglitol (Glyset). α-Glucosidaseinhibitors competitively inhibit enzymes (maltase, isomaltase, sucrase, and glucoamylase) in the small intestine, delaying the breakdownof sucrose and complex carbohydrates. They do not cause any malabsorption of these nutrients. The net effect from this action is toreduce the postprandial BG rise. GLP-1 may also be increased. Distal intestinal degradation of undigested carbohydrate by the gut floraresults 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 α-glucosidase inhibitors is limited to the luminal side of the intestine. Some metabolites of acarbose aresystemically absorbed and renally excreted, whereas the majority of miglitol is absorbed and renally excreted unchanged.

Efficacy

Postprandial glucose concentrations are reduced (40 to 50 mg/dL [2.2 to 2.8 mmol/L]), while fasting glucose levels are relativelyunchanged (˜10% reduction). Efficacy on glycemic control is modest (average reductions in HbA1c of 0.3% to 1% [0.003 to 0.010; 3 to 11mmol/mol Hb]), affecting primarily postprandial glycemic excursions. Thus, patients near target HbA1c levels with near-normal FPGlevels, but high postprandial levels, may be candidates for therapy.


α-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 totalnumber of events was very small.40,41 No large cardiovascular study confirming these preliminary results has been done in prediabetesor 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 α-glucosidase inhibitors. Mechanistically, these side effects are caused by distal intestinal degradation of undigested carbohydrate by themicroflora, which results in gas (CO2 and methane) production. Microflora convert the carbohydrate to short-chain fatty acids that aremostly absorbed; thus, there is not a large calorie loss. α-Glucosidase inhibitors should be initiated at a low dose and titrated slowly toreduce GI intolerance. Beano, an α-glucosidase enzyme, may help to decrease GI side effects, but may decrease efficacy slightly, and itis better to decrease carbohydrate or the dose of the α-glucosidase inhibitor.

If a patient develops hypoglycemia within several hours of ingesting an α-glucosidase inhibitor, oral glucose is advised because the drugwill inhibit the breakdown of more complex sugar molecules. Milk, with lactose sugar, may be used as an alternative when no glucose isavailable, 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 andweight 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 (overseveral 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 Table57-11). Titration speed should be varied based on GI side effects to the target dose. Both α-glucosidase inhibitors should be taken withthe first bite of the meal so that drug may be present to inhibit enzyme activity. Only patients consuming a diet high in complexcarbohydrates will have significant reductions in glucose levels. α-Glucosidase inhibitors are contraindicated in patients with short-bowelsyndrome or inflammatory bowel disease, and neither should be administered in patients with serum creatinine >2 mg/dL (>177 μmol/L),

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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 theUnited 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 intype 2 DM, and may contribute a minor amount of insulin secretion but have no effect on glucagon. However, levels of GLP-1 aredeficient 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 levelswithout increase in hypoglycemia when used as monotherapy. These drugs do not alter gastric emptying and do not have significantsatiety 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 12hours. Seventy-nine percent of the dose of sitagliptin is excreted unchanged in the urine by active tubular secretion; however, the organicanion transporter 3 or p-glycoprotein transport may be involved as well. Sitagliptin exposure is increased by approximately 2.3-, 3.8-, and4.5-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 oradverse reaction issue; however, reduction of the dose based on renal function is appropriate, as only 100% of the enzyme can beinhibited, and long-term exposure to higher levels in humans has not been extensively studied. Pharmacodynamically, DPP-4 inhibitionappeared to mirror directly the plasma concentration of sitagliptin. Doses of 50 mg produce at least 80% inhibition of DPP-4 enzymeactivity at 12 hours, and those of 100 mg produce 80% inhibition of DPP-4 enzyme activity at 24 hours. Food has no effect on absorptionkinetics 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 approximately67%. Distribution is similar to the body water compartment. There is negligible protein binding, and one active metabolite, 5-hydroxysaxagliptin, is half as potent a DPP-4 inhibitor as the parent compound, and contributes to activity. Metabolism is by the CYP3A4/5system, and strong inhibitors or inducers will have an effect on activity. The half-lives of saxagliptin and its active metabolite are 2.5 and3.1 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. Themajority (75%) of saxagliptin and 5-hydroxy saxagliptin is renally eliminated, and some renal excretion is seen. In moderate (CLcr 30 to 50mL/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 areincreased 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 healthysubjects. The half-life of linagliptin is approximately 12 hours. The absolute bioavailability of linagliptin is approximately 30%. A high-fatmeal reduces Cmax by 15% and increases AUC by 4%. However, this effect is not clinically relevant and linagliptin may be taken with orwithout food. Linagliptin distributes extensively in tissues and at high concentrations. Seventy percent to 80% is bound to plasmaproteins 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 plasmaproteins and approximately 75% of the dose is found unchanged in the urine. Less than 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 inHbA1c at different baseline values is very small. As these drugs are well tolerated, adjustment in the dose due to adverse effects isunlikely. They tend to have a shallow dose–response curve.

Microvascular and Macrovascular Complications


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HbA1c levels are reduced, which has been related to a reduction in microvascular complications, but no outcome data are available todate.


Significant drug–drug interactions with sitagliptin are unlikely. Sitagliptin is metabolized approximately 20% by CYP450 3A4 with someCYP450 2C8 involvement, but is neither an inhibitor nor an inducer of any CYP450 enzyme system. It is a p-glycoprotein substrate, buthad 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, aninducer, can decrease active levels by 50%. However, moderate to strong inhibitors or inducers of CYP3A4/5, such as diltiazem orketoconazole, can increase the AUC of saxagliptin by approximately twofold, with a corresponding decrease in the formation of the activemetabolite 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 whenadministered 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 drug–drug 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 inmonotherapy or in combination with medications that have a low incidence of hypoglycemia, DPP-4 inhibitors do not increase the risk ofhypoglycemia. Headache and nasopharyngitis, potentially related to the drug, may be slightly more common with DPP-4 inhibitors, but nosignificant 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 hormone–releasinghormone, vasoactive intestinal polypeptide, and others), potentially affecting other regulatory systems. DPP-4 (also known as CD26) playsan important role for T-cell activation. Theoretically the inhibition of DPP-4 could be associated with adverse immunologic reactions.Saxagliptin results in a dose-related reduction in absolute lymphocyte count in up to 0.5% to 1.5% of patients. In most, recurrence is notobserved with reexposure. However, it may recur with rechallenge in some patients. The clinical relevance is not known, but if prolongedinfection is encountered, it is logical to measure lymphocyte counts and consider discontinuation.


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 <50mL/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 onedose: 5 mg daily, and does not require dose adjustment in renal insufficiency or related to concomitant drug therapy. Alogliptin, similar tositagliptin, 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 dose–responsecurve, 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 colesevelam’s mechanism of action to lower plasma glucose levels is in the intestinal lumen, a systemic effect due to theintestinal lumen effect or some combination of these two is unknown. Possible mechanisms include effects on the farnesoid X and TGR5receptors within the intestine as well as effects on farnesoid X receptor within the liver. There is evidence that colesevelam may affect thesecretion 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.

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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 3.8g/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 baselineLDL-C concentrations of ˜105 mg/dL (˜2.72 mmol/L). Triglycerides increased when combined with sulfonylureas or insulin, but not withmetformin. Colesevelam is weight neutral. Pediatric patients (10 to 17 years of age) have been studied for cholesterol reduction, but notfor 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 drug–drug interactions with colesevelam. The most important include levothyroxine, glyburide, andoral contraceptives. In addition, phenytoin, warfarin, digoxin, and fat-soluble vitamins have postmarketing reports of altered absorption. Itis 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-solublevitamin supplementation, this may have implications for associated conditions. Other drugs that are very fat-soluble such as cyclosporineA, drugs that may be affected by a change in fat-soluble vitamin status such as warfarin and vitamin K, or conditions that may bepotentially 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 historyof major GI surgery. It also should not be used in patients with significant swallowing or esophageal issues, as it may worsen theunderlying condition or cause obstruction. Colesevelam should be taken with a large amount of water to lower the risk of the aboveissues. 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 baselinetriglyceride levels, and colesevelam is contraindicated in patients with a triglyceride >500 mg/dL (>5.65 mmol/L). Close monitoring isrecommended if the baseline triglycerides >300 mg/dL (3.39 mmol/L). Colesevelam is contraindicated in patients with a history oftriglyceridemia-induced pancreatitis, and prudent clinical judgment should be used in any patient with a history of pancreatitis andelevated 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 packetsmust 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. Alldosage 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. Lowhypothalamic dopamine levels, especially on waking, are augmented, which may decrease sympathetic tone and output. These effectsare 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 plasmaconcentration is about 1 hour if taken without food, but with food it is 90 to 120 minutes. Bromocriptine is highly protein bound, and has avolume 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 isapproximately 6 hours. Plasma exposure is increased in females by approximately 18% to 30%, but no dosage adjustment is currentlyrecommended.


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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 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. Asbromocriptine is highly protein bound, it may increase the unbound fraction of other highly protein-bound drugs. Several drug–drug andpotential drug–disease 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 bromocriptinemay increase migraine and ergot-related nausea and vomiting. There are case reports of hypertension and tachycardia whenadministered with sympathomimetic drugs in postpartum women, and bromocriptine should not be given to this group of potentialpatients. 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 comparatorgroup. Nausea, rhinitis, headache, asthenia, dizziness, constipation, and sinusitis all occurred in over 10% of subjects. Nausea occurredin 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% ofcompletors 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 inpatients with low, normal blood pressure. Somnolence was reported in 4.3% of patients on bromocriptine, compared with 1.3% in theplacebo, 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 werenot 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 dosemay 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 itis unclear if another commercial dose could be made available). The minimal effective dose is 1.6 mg daily. It is recommended to betaken 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 anyagent 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 todate 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, butalso in development is semaglutide.

Selective Sodium-Dependent Glucose Cotransporter-2 Inhibitors (SGLT-2 Inhibitors)

SGLT-2 inhibitors work in the kidney to block the reabsorption of some glucose. Normally, all glucose is reabsorbed back into thesystemic circulation from the kidney at normal glucose levels: about 10% through the SGLT-1 receptor, and 90% through the SGLT-2receptor. Early data have shown approximately 50 to 80 g of glucose per day may be allowed to pass into the urine with SGLT-2inhibition. This lowers systemic glucose and allows weight loss. Glucose levels may be lowered in both type 1 and type 2 DM by thismechanism of action. Safety data have shown a slightly higher rate of genitourinary yeast infections. SGLT-1 is involved with glucoseabsorption in the gut, and inhibition of SGLT-1 has been historically thought to cause GI toxicity, but this is unclear and dual inhibitorsmay be marketed. Canagliflozin (Invokana) is currently the farthest in development, but several are being developed. Dapagliflozin has


















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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 incomplications of DM. Animal studies and some human studies suggested that the worse the glycemia, the greater the risk ofcomplications. But “the glucose hypothesis” was not ultimately accepted as proven until the publication of the DCCT in 1993.23 In thisstudy, 1,441 patients with type 1 DM were divided into two groups: those without complications (726 subjects, primary prevention) andthose with early microvascular complications (715 subjects, secondary prevention). These two groups were then again divided into twogroups: one randomized to receive conventional therapy (one or two shots of insulin daily and infrequent SMBG with no attempt tochange therapy based on home BG readings) and the other to receive intensive therapy (>3 injections of insulin daily or insulin pump, withfrequent SMBG and alteration of insulin therapy based on SMBG results, plus frequent contact with a health professional). After 6.5 years,mean follow-up 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 retinopathyprogression 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 morecommon and weight gain greater with intensive therapy. A nonstatistically significant reduction in coronary events was seen in theintensively treated group as compared with the conventional group. The DCCT revolutionized therapy of DM, demanding that stricterglycemic 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 reducingthe 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 therapyunless the patient was symptomatic or had FPG >270 mg/dL [>15 mmol/L]), versus intensive therapy starting with either sulfonylureas orinsulin, aimed at keeping the FPG <108 mg/dL (6 mmol/L). A subset of obese patients was studied using metformin as the primarytherapeutic 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 medianHbA1c is 7% (0.07; 53 mmol/mol Hb) as compared with 7.9% (0.079; 63 mmol/mol Hb).24

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 conventionalrisk 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 systolicblood pressure above 130 mm Hg for protection against complications. β-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 andmacrovascular 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 ofapproximately 8% (0.08; 64 mmol/mol Hb). Despite similar HbA1c values, continued microvascular and new macrovascular benefit wasseen. Microvascular benefits were maintained for 10 to 15 years, and at 17 years of follow-up, a 57% (P = 0.02) reduction in death, firstoccurrence 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

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majority of the follow-up. After a mean follow-up of 8.5 years, a 24% (P = 0.001) reduction in microvascular complications (during theUKPDS, 25% reduction was reported) and a significant reduction in MI (15%; P = 0.014) and all-cause mortality (13%; P = 0.007) in theintensively treated group versus the conventional group were reported.47 Early glycemic control may have long-standing benefits topatients over several decades, despite later glycemic control deterioration. This concept is being called metabolic memory or the legacyeffect. These studies lay the framework for why early intensive glycemic control is important not only for short-term but also for long-termprevention of complications.

ACCORD, ADVANCE, and VADT

The Action to Control Cardiovascular Risk in Diabetes (ACCORD),48 Action in Diabetes and Vascular Disease (ADVANCE),49 andVeterans 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 (goalHbA1c <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), andthe intensive glycemic group achieved a HbA1c of 6.4% (0.064; 46 mmol/mol Hb), whereas standard glycemic control achieved a HbA1cof 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 aninterim analysis reported an increased rate of mortality in the intensive arm (1.41%/y vs. 1.14%/y; HR, 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 inthe intensive therapy group. In addition, on subset analysis, individuals with a baseline HbA1c <8% (<0.08; <64 mmol/mol Hb) or noprevious CVD had a significant reduction in the primary outcome. Increased mortality, though substantially increased in the intensivegroup, could not be associated with a specific medication, hypoglycemia (higher in intensive group), lipid levels, or weight gain. Thedichotomous results have been hard to explain, although the ACCORD investigators reported that in the intensive group, it was subjectswho could not attain intensive glycemic control goals who were at higher risk, not subjects who did achieve the goal. A 20% higher risk ofdeath 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-drivengoals). Extended-release gliclazide, a sulfonylurea available outside of the United States, was used as first-line therapy in the intensivegroup versus no gliclazide in the standard therapy group, although multiple other agents were needed in both groups. A baseline HbA1cwas 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 newor 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 to1.06) 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 highestof the three trials (9.4% [0.094; 79 mmol/mol Hb]). Multiple medications including insulin were used to achieve glycemic control. Theintensive 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 revascularizationwas 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 affectthe risk of macrovascular risk in type 2 DM. ACCORD reported that a subset of subjects who could not achieve intensive glycemic controlmay be at higher risk of death, but identifying these patients and implementing this recommendation into clinical practice may prove to bechallenging. As previously mentioned in Long-Term Followup of DCCT (EDIC) and UKPDS above, reduction of macrovascular events fromimproved glycemic control may take over a decade to come to fruition.

Therapeutics

Knowledge of the patient’s quantitative and qualitative meal patterns, activity levels, pharmacokinetics of insulin preparations andother injectables, and pharmacology of oral and antidiabetic agents for type 2 DM is essential to individualize the treatment plan anoptimize 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 practicedifference 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

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available) were given. Modifications of insulin led to longer-acting insulin suspensions and the use by many patients of one or twoinjections of longer-acting insulin each day. Because self-monitored BG and HbA1c testing were not available at that time, patients andpractitioners had no idea how well 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 highlyvariable in older patients and patients with renal disease. The advent of SMBG and HbA1c testing in the 1980s revolutionized the care ofdiabetes, enabling patients and practitioners to directly access BG for assessment, and enabling the patient to make instantaneouschanges 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 commonlyinsulin, as well as with exercise. The goal is to allow the patient to live as normal a life as possible. Understanding the principles ofglucose 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 andpostabsorptive period, with prandial spikes of insulin after eating (“bolus”) (Fig. 57-6).51 Insulin sensitivity and insulin secretion are notconstant throughout the day, however, which renders the concept of stable basal insulin requirements to be inaccurate. However, in mostclinical situations, attempting to emulate normal secretion of insulin is a useful paradigm for understanding and applying insulin treatmentfor the management of type 1 DM. The other basic principle to consider is that the timing of insulin onset, peak, and duration of effectmust match meal patterns and exercise schedules to achieve near-normal BG values throughout the day.

FIGURE 57-6

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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 areasonable classification; however, a single injection of any insulin preparation daily will in no way mimic normal physiology, and thereforeis 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 ofan intermediate-acting insulin such as NPH and a “bolus” rapid-acting insulin or regular insulin before breakfast, and again before theevening meal. The presumption is made that the morning intermediate-acting insulin gives basal insulin for the day and covers the middaymeal, the morning bolus insulin covers breakfast, the evening intermediate-acting insulin gives basal insulin for the rest of the day, andthe evening bolus insulin covers the evening meal. If patients are very compulsive about consistency of timing of their injections andmeals and intake of carbohydrate, such a strategy may be acceptable. However, the vast majority of patients are not sufficientlypredictable in their schedule and food intake to allow “tight” glucose control with such an approach.

A modification that can be made to the above regimen is the movement of the evening NPH to bedtime (now three total injections perday) because the fasting glucose in the morning is too high or there is hypoglycemia in the early hours of sleep. This approach improvesglycemic 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 basal–bolus concept attempts to replicate normal insulin physiology with a combination of intermediate- or long-acting insulin toprovide the basal component, and rapid-acting insulin to provide the bolus or premeal component. Various long-acting insulins have beenused to provide the basal insulin component, including once- or twice-daily NPH, detemir, or glargine. Insulin glargine and insulin detemirare 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. Therapid onset of action and short time course of rapid-acting insulin analogs more closely replicate normal physiology than does regularinsulin. The patient varies the amount of before meal rapid-acting insulin injected, depending on the preprandial BG level, the anticipatedactivity (upcoming exercise may reduce insulin requirement), and anticipated carbohydrate intake. Many patients start with a prescribeddose of insulin before meals that they vary by use of an “adjusted scale insulin” or “correction factor” to normalize a high premeal plasmaglucose reading. Patients on more advanced regimens later may adjust the amount of mealtime insulin based on anticipatedcarbohydrate intake.

A “correction factor” can be calculated as a starting point to estimate the approximate plasma glucose–lowering 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 unitswould require multiplying by 0.0555) divided by the total daily insulin dose in number of units that the patient currently uses. For rapid-


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acting insulin analogs, a factor of 1,700 is more often used when calculating the correction factor. For example, if a patient is currentlytaking 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 glucoseapproximately 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 inpeople with type 1 DM. Instead of using a prescribed or preset dose of rapid-acting insulin before meals, patients can self-adjust theirpremeal dose based on the estimated grams of carbohydrates that will be consumed. Although general algorithms for carbohydratecounting give rough guidelines, each patient will have to adjust the preprandial insulin dosage based on his or her own individualresponse 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 dailydose of insulin in number of units. Therefore, using the example above with a total daily insulin dose of 76 units, we would use 500divided by 76, which estimates that 1 unit of rapid-acting insulin will cover approximately 7 g of carbohydrate. Review of follow-up BGdata before and 2 hours after meals will enable more precise determination of an individual’s 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 patient’s ratio is not close to this recommendation, a reassessment of the regimen should beimplemented. Empirically, patients may be begun on ≈0.6 unit/kg/day with basal insulin 50% of total dose and prandial insulin 20% oftotal dose prebreakfast, 15% prelunch, and 15% presupper. Type 1 DM patients generally require between 0.5 and 1 unit/kg/day. Theneed for significantly higher amounts of insulin suggests the presence of insulin resistance or, less often, of insulin antibodies.

Intensive basal–bolus multi-injection insulin therapy is recommended for all adult patients with type 1 DM at the time of diagnosis toreinforce 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 basal–bolus 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 (startingat 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 doseas intermediate-acting insulin) is an option; however, most often this approach will not be allowed as an aggressive glycemic controloption due to increased risk of hypoglycemia.

Insulin pump therapy (continuous subcutaneous insulin infusion [CSII], generally using a rapid-acting analog insulin) is the mostsophisticated form of insulin delivery. In a motivated patient, CSII may be more efficacious in achieving excellent glycemic control thanmultiple-dose insulin injections. Extensive discussion of this mode of therapy is beyond the scope of this text. Nevertheless, the basicprinciples 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 throughoutthe day. In selected patients, this feature allows better glycemic control with CSII. However, insulin pumps require even greater attentionto detail and frequency of SMBG than does a basal–bolus regimen with four injections daily.52 In appropriately selected patients willing topay sufficient attention to detail of SMBG and insulin administration, CSII can be a very effective form of therapy. CSII is only a tool fordiabetes control, however. Thus, if the patient is not well controlled and/or unwilling to actively control the diabetes on injections, it isunlikely that the patient will have superior control on a pump. CSII placement and adjustment should be made by an experiencedclinician, 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 andsymptoms such as polyuria, polydipsia, and weight gain or loss. Finer insulin adjustments are determined on the basis of the results offrequent 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 hypoglycemiaare tempted to overtreat episodes of hypoglycemia resulting in rebound hyperglycemia afterwards. To minimize this, patients are advisedto 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 ofsimple 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 lessthan 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, particularlyhypoglycemia 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 progressionof disease with autonomic neuropathy. The loss of warning signs of hypoglycemia is a relative contraindication to intensive therapy. Morecommonly, type 1 DM patients have loss of warning signs because of a presumed lower set point for release of counterregulatoryhormones as a result of frequent episodes of hypoglycemia (“hypoglycemia begets hypoglycemia”). In such situations, more normal

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hypoglycemia awareness may be restored by reduction or redistribution of the insulin dose to eliminate significant and/or frequenthypoglycemic episodes.

In children and pubescent adolescents, glycemic goals may need to be tempered with the risks of hypoglycemia. Table 57-7 listsglycemic goals for different age groups of type 1 DM patients. Therefore, it is not unreasonable to use less intense management until thepatient 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 therapyhas not totally eliminated insulin allergies. In most patients local reactions will dissipate over time. If mild reactions at the site of injectionoccur, reassess the insulin injected. Many times the patient is injecting cold insulin, which may cause compensatory local vasodilationaround the injection site in response to the injected cold liquid. Anecdotally, a different type or source of insulin could be tried. If theallergic reaction does not improve or is systemic, insulin desensitization can be carried out. Protocols for desensitization are availablefrom 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 patientsgive 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. Becauseinsulin 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 ofinsulin action accordingly.

2. Choice of insulin injection sites: There is variability of insulin absorption from site to site such that random selection of insulininjection sites may cause wide glucose swings. The most consistent absorption of insulin is from the abdominal wall. Patients areencouraged to take all their injections in the abdomen. If the patient is unable or unwilling to follow this advice, then systematic siterotation is the next preferable option. The patient should always give the insulin injection in the same region of the body the sametime of the day each day. For instance, the arms are always used every morning. Needless to say, the patient should not inject in alimb 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 itcould be due to “rebounding” from a previous low glucose and treating it with excessive amounts of carbohydrate. Fastidious BGtesting, particularly during the night (or selected use of CGM), can assist in sorting this out. Many clinicians do not adequatelydifferentiate type 1 DM from type 2 DM when choosing doses of insulin. Patients with type 1 DM are insulin deficient but have normalinsulin sensitivity. Patients with type 2 DM have varying degrees of insulin resistance. Therefore, a small change in the dose of insulinfor a patient with type 1 DM can have a dramatic effect on glucose concentrations, whereas in patients with type 2 DM and insulinresistance a change in dose many times that amount of insulin has little effect on glucose concentrations. Large changes in insulindose in patients with type 1 DM are not usually indicated unless the patient’s BG control is very poor. Widely erratic BGs and/orweight gain may be due to too high a dose of insulin.

4. Injection technique and BG monitoring: When in doubt, always reevaluate the patient’s technique for insulin dosing, insulininjection, and BG testing. Sometimes simple errors result in unpredictable glycemic control.

Type 1 DM patients who continue to have erratic postprandial control despite implementation of the above strategies may be appropriatefor treatment with pramlintide (Symlin). Pramlintide is not recommended to be mixed with insulin; therefore, the patient will need to takean 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 andpostprandial glycemic goals. Injecting pramlintide prior to the meal and the rapid-acting insulin at the time of or after the meal may bettermatch the appearance of the food with the postprandial increase in glucose due to delayed gastric emptying. The patient must becognizant 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 sulfonylureasor 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 andrecommendations to achieve more stringent glycemic control. Symptomatic patients may initially require treatment with insulin orcombination oral therapy to reduce glucose toxicity (which may reduce β-cell insulin secretion and worsen insulin resistance). Patientswith HbA1c ≈7% (≈0.07; ≈53 mmol/mol Hb) or less are usually treated with therapeutic lifestyle measures and an agent that will not cause

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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 oralagents, or combination therapy. Patients with higher initial HbA1c may benefit from initial therapy with two oral agents, or insulin. Thissection addresses management of hyperglycemia; however, this needs to be balanced within a multifactorial risk reduction framework ofblood pressure reduction, dyslipidemia and antiplatelet therapy, and smoking cessation. All therapeutic decisions should consider theneeds 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% (0.09to 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 DMoften 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, obesepatients (>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 theonly oral antihyperglycemic agent to ever report a reduction in total mortality. Despite this, long-term durability of HbA1c reduction, dueto the inability to stop progressive β-cell failure, is suboptimal with metformin, and patients over several years will often need additionaltherapy. An insulin secretagogue, such as a sulfonylurea, is often added second, although it has clearly been shown that sulfonylureas donot produce durable HbA1c reductions in the majority of patients. Better choices to sustain HbA1c reductions would be a TZD or GLP-1agonist, but each has limitations as well. Goal-oriented therapy is what we currently strive for, meaning the intervention should be inrelation 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 oralagent will result in reaching the glycemic goal, and multiple oral agents or insulin therapy may be appropriate. TZDs may be substituted insituations in which a patient is intolerant of, or has a contraindication to, metformin, understanding that TZDs should be used with cautionin heart failure. Figure 57-7 is a consensus algorithm by the ADA and the European Association for the Study of Diabetes.54 No algorithmcan substitute for good clinical judgment, and algorithms for glycemic control start with the premise that the clinician will identifymedication contraindications, adverse reactions, and comorbidities that may be advantageous or harmful if the medication was taken.

FIGURE 57-7


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Position Statement on the Treatment of Type 2 Diabetes Mellitus: American Diabetes Association and European Association for the Studyof 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 guidetherapy: (a) How long has the patient had diabetes? The longer a patient has had diabetes, the more insulinopenic he or she likely is andthe more likely that insulin therapy will be needed. (b) Fasting, postprandial, or both plasma glucose readings poorly controlled? Somedrugs address postprandial glucose excursions better, whereas some address FPG better. (c) How far do we have to go to goal and whatis 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 andadditionally those comorbidities may drive our HbA1c goal. Based on the ADVANCE, ACCORD, and VADT trials, a HbA1c goal may nowbe above 7% (0.07; 53 mmol/mol Hb) if certain comorbidities are present. See Figure 57-8 for HbA1c individualization based oncomorbidities from the Texas Diabetes Council. Drugs such as metformin, TZDs, sulfonylureas, repaglinide, liraglutide, extended-releaseexenatide, intermediate-acting insulins given at bedtime, and basal insulins control FPG more effectively. Exenatide, DPP-4 inhibitors, α-glucosidase inhibitors, nateglinide, and regular and rapid-acting insulin better control postprandial glucose excursions. We can also guidetherapy based on the risk of hypoglycemia. Metformin, TZDs, liraglutide, exenatide, DPP-4 inhibitors, and α-glucosidase inhibitors have alow risk of hypoglycemia. Combining these agents will allow aggressive targeting of near-normal HbA1c levels while minimizinghypoglycemia and weight gain. Combining these agents early in the diagnosis of type 2 DM is logical to potentially realize themicrovascular and macrovascular reduction seen in the long-term follow-up of UKPDS.

FIGURE 57-8

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A1C goals. See www.texasdiabetescouncil.org for current algorithms. (Reprinted with permission from the Texas Diabetes Council.)

Preserving β-cell function, thus arresting the progressive nature of type 2 DM, could be paradigm changing, but to date medications haveonly shown to slow, not arrest, progression. In the UKPDS, insulin, metformin, or sulfonylureas did not halt β-cell failure. TZDs (out to 5years with rosiglitazone) and GLP-1 agonists (open-label exenatide has shown durable HbA1c reduction to 3 years and liraglutide to 2years) may potentially slow β-cell failure. Pathophysiologically treating type 2 DM for potential β-cell preservation is possible, butunproven. It appears unlikely any one drug class will arrest β-cell failure, necessitating combination therapy. TZD and GLP-1 agonistcombination is logical as TZDs reduce apoptosis of β cells and GLP-1 agonists augment pancreatic function through insulin secretion in aglucose-dependent manner and reduction of inappropriate glucagon, but long-term data are lacking. β-Cell function is heavily damagedby the time type 2 DM is diagnosed, and it is possible that β-cell failure is inevitable by type 2 DM diagnosis. HbA1c reduction isdependent on baseline values, with higher reductions seen with higher values, but, again, therapy should be goal oriented. Triple therapyis 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-1agonist, which can lower glucose levels and increase satiety, reducing the weight gain potential of a TZD, and still has a low risk ofhypoglycemia. A DPP-4 inhibitor may be an alternative, although without weight loss potential, if an injectable product is not preferred. Ifthe 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.Sulfonylureas are often stopped when insulin is added and insulin sensitizers continued. This may be beneficial to decreasehypoglycemia, but continuing the sulfonylurea is permissible until multiple daily injections are started, at which time it should definitely bediscontinued. 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 2DM has changed dramatically in the last few years. Specifically, patients are often “transitioned” to insulin by using a bedtime injection ofan intermediate- or long-acting insulin, and using oral agents primarily for control during the day. This strategy leads to lesshyperinsulinemia during the day and is associated with less weight gain and has equal efficacy and a lower risk of hypoglycemia for up to





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3 years when compared with starting prandial insulin or split-mix twice-daily insulin.55 Because most patients are insulin resistant, insulinsensitizers are commonly used with insulin therapy. Patients with type 2 DM are usually well buffered against hypoglycemia. Patientsshould 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 failto achieve glycemic goals, a conventional multiple daily dose insulin regimen while continuing the insulin sensitizers is often tried. Thismay 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 bolusinjection can be given with the second largest meal of the day, for a total of three injections. After this, the standard basal–bolus model isfollowed. 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 longerexplanation), but if inadequate control is seen, a third dose of mix insulin may be given with the third meal of the day. This allows forbetter prandial coverage, but can also increase the risk of hypoglycemia.56 Use of GLP-1 agonists or pramlintide for prandial coveragecan be considered. GLP-1 agonists, based on chosen drug, can be dosed weekly, daily, or twice daily, whereas pramlintide can be givenbefore each meal. Concerns and problems with insulin administration as addressed in Type 1 Diabetes Mellitus under Therapeutics abovegenerally relate to the therapy of type 2 DM. However, patients with type 2 DM rarely have hypoglycemia unawareness. Also, thevariability 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 insulintherapy options in type 2 diabetes developed by the Texas Diabetes Council. This algorithm gives most options for insulin therapy, butthe choice of regimen should be individualized based on the discussion with the patient.

FIGURE 57-9

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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 α-glucosidaseinhibitors, 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, postprandialglycemic excursions proportionally contribute more than the FPG to the HbA1c percentage when the HbA1c nears goals, and thus willneed to be targeted for optimal glycemic control in many patients. It remains controversial whether targeting after-meal glucoseexcursions will have more of an effect on complications risk than more conventional strategies.

Special Populations

Children and Adolescents with Type 2 DM


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Type 2 DM is increasing in adolescence.1,6 Obesity and physical inactivity seem to be particular culprits in the pathogenesis of thisdisease. Given the many years that the patient will have to live with diabetes, and recent evidence that the time frame after diagnosis formicrovascular complications may mimic that of older adults, extraordinary efforts should be expended on lifestyle modification measuresin an attempt to normalize glucose levels. Failing that strategy, the only labeled oral agent for use in children (10 to 16 years of age) ismetformin, although sulfonylureas are also commonly used in therapy. TZDs and DPP-4 inhibitors have not been adequately studied inchildren, but studies to ascertain safety and efficacy are currently under way. GLP-1 agonist therapy, as it potentially helps the child tolose weight, is attractive, but the long-term effects of this therapeutic modality are unknown. Insulin therapy continues to be the standardtherapy after metformin and a sulfonylurea. In adolescent females, the possibility of future pregnancy should be considered in theprescription 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 risksof hypoglycemia, the extent of comorbidities including severe microvascular disease, CVD, dexterity, self-care and social situations, fallsrisk, mental status, and the probable life span should help determine glycemic goals. If extensive comorbidities, hypoglycemicunawareness, unstable CVD, dementia, high falls risk, or similar diagnosis is made, the clinician may adjust the glycemic goal. Avoidanceof 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 adrenergicsymptoms due to loss of autonomic nerve function as they age. This may raise the rise of neuroglycopenic symptoms shortly afteridentification of hypoglycemia. If the patient is newly diagnosed and does not have the above problems, a goal HbA1c <7% (<0.07; <53mmol/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 mentalstatus issues. If oral agents will work, DPP-4 inhibitors, shorter-acting insulin secretagogues, low-dose sulfonylureas (preferably not long-acting ones), or α-glucosidase inhibitors may be used. The risk for lactic acidosis, which increases with older age and the age-relateddecline in renal function, makes metformin therapy difficult, but lower doses may be used if not contraindicated. In a patient in whomweight gain or loss may not be unwelcome, TZDs or GLP-1 agonists, respectively, may be considered, but falls risk and fracture risk mustbe considered with TZDs. DPP-4 inhibitors or α-glucosidase inhibitors are oral medications that may be advantageous due to a low risk ofhypoglycemia. Simple insulin regimens such as an injection of basal insulin daily may be appropriate for glycemic control in elderlypatients, 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 VADT50 had older individuals who were in their 60s atenrollment. As stated earlier in the chapter, all improved glycemic control but did not reduce the risk of CVD over 3 to 5 years, althoughmore people died in the ACCORD, resulting in termination of the study. ADVANCE reported improvement in nephropathy outcomes, andthis did not differ by age, but otherwise these neutral studies did not report improved microvascular outcomes. In addition, one Japanesestudy had subjects with a mean age of 72 years, and a 6-year follow-up, but changes in glycemia were minimal, thus showing nobenefit.57 This is unfortunate, as up to one in three people in this age category may have type 2 DM. Diabetes in older adults iscomplicated by clinical and functional heterogeneity. Patients may be relatively healthy, free-living adults all the way to the other end ofthe spectrum with assistive living, multiple comorbidities, and cognitive issues. Based on this, what is the optimal medication therapy forthis group of 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) arereasonable. Yet, in the new ADA guidelines and clinical practice recommendations, a patient-centered approach is stated. It is unlikelythat most patients would choose basal insulin as their initial intervention if asked. Also, the cost for basal insulin is not minimal, and onemust ask if it is truly more cost-effective than many other interventions. Severe hypoglycemia must be avoided in this population, as it hasbeen associated with a higher risk of death for more than 1 year after the incident. Any of the agents can avoid severe hypoglycemia ifused properly, but the risk factors for hypoglycemia are: use of insulin or insulin secretagogues, duration of diabetes, antecedenthypoglycemia, erratic meals, exercise, and renal insufficiency. In addition, self-care, visual acuity, and dexterity issues may be of concernin patients.

Medications that do not cause hypoglycemia may be advantageous. Metformin, if not contraindicated, continues to be an excellent firstchoice. As metformin may be used in Stage III CKD, with a reduced dose, this may be a reasonable choice. Second-choice agents suchas 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

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gastroparesis, or normal-weight to underweight patients. α-Glucosidase inhibitors, if close to goal and constipation is an issue, may behelped 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 isimportant for our society that optimal therapy in older adults be properly addressed, as this population will continue to grow, andcurrently there is no consensus. Several organizations have recommendations in regards to older adults,58,59 but recommendations onoptimal 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 ofmiscarriage, necessity of cesarean section delivery, neonatal hypoglycemia, preeclampsia/eclampsia, preterm delivery, shoulderdystocia/birth injury, and hyperbilirubinemia. Dietary therapy to minimize wide fluctuations in BG is of paramount importance.5,8 Intensiveeducational efforts are usually necessary. Pregnant women without DM maintain plasma glucose concentrations between 50 and 130mg/dL (2.8 and 7.2 mmol/L). Normoglycemia is the goal, and failure to maintain this despite dietary interventions often will necessitatemedication use. Goals during therapy are minimally a preprandial goal of ≤90 mg/dL (≤5 mmol/L), and either 1-hour postprandial plasmaglucose levels ≤120 mg/dL (≤6.7 mmol/L) or 2-hour postprandial plasma glucose levels ≤110 mg/dL (≤6.1 mmol/L), and avoidance ofketones as much as possible. In patients who have preexisting type 1 or type 2 DM and become pregnant, premeal, bedtime, andovernight 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). HbA1cduring pregnancy should be less than 6% (<0.06; <42 mmol/mol Hb), but frequent SMBG is the method of choice for monitoring glycemiccontrol. Titration of insulin and switching to more complicated regimens is guided by SMBG results. Use of basal insulins other than NPHis still debated, but with the ease of use of detemir or glargine insulin, their use in GDM is increasing. In addition, pump therapy for theduration of the pregnancy is often instituted, as it can obtain excellent glycemic control and is quickly adjustable. Both metformin andglyburide 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 GDMshould be evaluated 6 weeks after delivery to ensure that normal glucose tolerance has returned. Because these patients’ lifetime risk forthe development of type 2 DM is >50%, periodic assessment after that is warranted.

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 thosepatients who fail to maintain optimal glycemic control during pregnancy with diet and lifestyle modification, traditionally the next step hasbeen to proceed with insulin therapy. More recently, however, some clinicians have begun using oral agents including sulfonylureasand/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.60The control of BG compared with insulin therapy was similar, with less hypoglycemia in the glyburide group. There was not any evidenceof 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 usingglyburide in the first trimester.

A more recent retrospective cohort study of 10,682 women with GDM who required medical therapy, however, revealed that babies bornto women with GDM who were managed on glyburide were more likely to be macrosomic and to be admitted to the intensive care unitcompared 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 toprevent 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 diabetesfound a significantly higher rate of preeclampsia in women treated with metformin compared with women treated with sulfonylurea orinsulin (32% metformin vs. 7% sulfonylureas vs. 10% insulin). The perinatal mortality was also significantly increased in women treatedwith 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 withmetformin (with supplemental insulin if required) or insulin. This study did not find any increased rate of preeclampsia or other perinatalcomplications compared with insulin.65


















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Subsequently there have also been meta-analyses that also revealed no differences in maternal or neonatal outcomes with the use ofglyburide 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 gestationaldiabetes or type 2 DM in pregnancy who fail to achieve optimal control with diet/lifestyle modification alone.68 Moreover, neithermetformin 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 whoprescribe oral agents to manage their patients with diabetes during pregnancy must consider the potential benefits (avoidance ofinjections, decreased cost, and patient preference) against the potential risk (unknown safety, inconsistent effect on the pregnancyoutcomes, and potential liability due to using non–FDA-approved therapy).

Special Situations

Sick Days

Acute self-limited illness rarely presents a major problem for patients with type 2 DM, but can be a significant challenge for insulinopenictype 1 DM patients.69 While caloric intake generally declines, insulin sensitivity also decreases, meaning that it may take greater amountsof 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 extrainsulin is needed during illness. Plan to maintain a meal plan containing 120 to 150 g of carbohydrates per day. We encourage patients tocontinue their usual insulin regimen and to use supplemental rapid-acting insulin based on SMBG results, with additional insulin given ifketonuria develops. Ketone testing should be in type 1 DM patients prone to ketonuria, if two consecutive plasma glucose readings areabove 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 tomaintain hydration, to provide needed electrolytes if there are significant GI or urinary losses, and to provide sugar to keep the patientfrom developing hypoglycemia because of the extra insulin that is usually needed. If patients with type 1 DM are consistentlyhyperglycemic, we suggest they abstain from sugary drinks and increase intake of sugar-free liquids. In contrast, patients with type 2 DMmay need to switch to sugar-free drinks if BG levels are continually elevated. Most patients can be taught how to sufficiently manage sickdays 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. Inpatients 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 presentwith 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 includehyperglycemia, anion gap acidosis, and large ketonemia or ketonuria. Diagnostic criteria for HHS are similar with the exception ofsignificantly 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 ofseveral liters or sodium and potassium deficits of several hundred milliequivalents. Restoration of intravascular volume acutely withnormal saline, followed by hypotonic saline to replace free water, potassium supplements, and constant infusion of insulin restore thepatient’s metabolic status relatively quickly. A flow sheet is often helpful in tracking the fluid and insulin therapies and laboratoryparameters in these patients. Bicarbonate administration is generally not needed and may be harmful, especially in children. Treatment ofthe inciting medical condition is also vital. Hourly bedside monitoring of glucose and frequent monitoring (every 2 to 4 hours) of potassiumis essential. Metabolic improvement is manifested by an increase in the serum bicarbonate or pH. Serum phosphorus usually starts highand plummets to lower-than-normal levels, although replacing phosphorus, while not unreasonable, is of questionable benefit in mostpatients. Fluid administration alone will reduce the glucose concentration, so a decrement in glucose values does not necessarily meanthat the patient’s metabolic status is improving. Rare patients will require larger amounts of insulin than those usually given (5 to 10units/h). We double the patient’s insulin dose if the serum bicarbonate has not improved after the first 4 hours of insulin therapy. Constantinfusion 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) arepreferable to titration of the insulin infusion based on the glucose level. The latter strategy may delay clearance of the ketosis and prolongtreatment. The insulin infusion should be continued until the urine ketones clear and the anion gap closes. Long-acting insulin should begiven 1 to 3 hours prior to discontinuing the insulin infusion. Intramuscular regular insulin or subcutaneous insulin lispro or aspart givenevery 1 to 2 hours can be utilized rather than an insulin infusion in patients without hypoperfusion. Patients may develop hyperchloremicmetabolic acidosis with treatment if they have been given large volumes of normal saline in the course of their treatment. Such a situationdoes not require any specific treatment.

HHS usually occurs in older patients with type 2 DM, at times undiagnosed, or in younger patients with prolonged hyperglycemia and






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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 hypotonicfluids 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 to5.6 mmol/L/h), is not recommended, as it can result in cerebral edema. This is especially true for children with DKA. Mortality is high withthe 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 isnotorious for not controlling glucose and for sometimes resulting in therapeutic misadventures, with wide amplitudes of glycemicexcursions.71 In-hospital mortality is increased in many hyperglycemic conditions. At least one study documented a reduction in mortalityin type 2 diabetes patients with acute MIs72 who receive constant IV insulin during the acute phase of the event to maintain near-normalglucose concentrations. Similar mortality results have been documented in some intensive care unit settings using IV insulin and tightglucose control.72,73 The ADA and American Association of Clinical Endocrinologists released a joint consensus statement on inpatientglycemic control stating that glucose control measures should be implemented if the BG is ≥180 mg/dL (≥10 mmol/L), and maintainedbetween 140 and 180 mg/dL (7.8 and 10 mmol/L).74 The Normoglycemia in Intensive Care Evaluation—Survival Using Glucose AlgorithmRegulation trial, and several other negative trials, has resulted in this loosening of inpatient glycemic goals. Critically ill patients had higher90-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) (achieved144 mg/dL [8 mmol/L]) was targeted.75 For non–critically ill patients there are no established BG goals. Reasonable BG goals for thesepatients are <140 mg/dL (<7.8 mmol/L) premeal and <180 mg/dL (<10 mmol/L) random.5 Many protocols for IV insulin infusion arecurrently available, and implementation for an inpatient setting should use a well-established protocol. It is prudent to stop metformin inall patients who arrive in acute care settings until full elucidation of the reason for presentation can be ascertained, as contraindications tometformin are prevalent in hospitalized patients. Discharge planning is also important, as approximately one third of patients will havenewly diagnosed diabetes and another one third will likely have prediabetes, as determined by obtaining an HbA1c on admission (best) orprior to discharge.

Perioperative Management

Surgical patients may experience worsening of glycemia for reasons similar to those listed above for intercurrent medical illness. Therapyshould be individualized based on the type of DM, nature of the surgical procedure, previous therapy, and metabolic control prior to theprocedure. Patients on oral agents may need transient therapy with insulin to control BG. In patients requiring insulin, scheduled doses ofinsulin or continuous insulin infusions are preferred. For patients who can eat soon after surgery, the time-honored approach of giving onehalf of the usual morning NPH insulin dose with dextrose 5% in water IV is acceptable, with resumption of scheduled insulin, perhaps atreduced doses, within the first day. Patients receiving basal/bolus insulin therapy can continue receiving their usual dose of long-actinginsulin while holding the premeal bolus doses until the patient can tolerate meals. For patients requiring more prolonged periods withoutoral nutrition and for major surgery, such as coronary artery bypass grafting and major abdominal surgery, constant infusion of IV insulinis preferred. Use of IV insulin infusion has been shown to reduce deep sternal wound infections in patients after coronary artery bypassgrafting, although there is no need to start the infusion during or before the procedure. Metformin should be discontinued temporarilyafter 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, asorganogenesis 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 ofmothers with type 1 or type 2 DM. For women with DM controlled by lifestyle measures alone, conversion to insulin as soon as thepregnancy is confirmed is appropriate. Patients previously treated with insulin may need intensification of their regimen to achievetherapeutic 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, concomitantinfections such as hepatitis C, and concomitant medications often used to treat HIV or comorbidities. Pentamidine, used for P. carinii

pneumonia, is directly β-cell toxic in some patients; hypoglycemia may be followed by hyperglycemia. Megestrol, used as an appetitestimulant, can have glucocorticoid-like effects in some patients. In addition, protease inhibitors, used to manage HIV, have been shown topotentially worsen insulin sensitivity, decrease the ability of the β cell to secrete insulin, and/or worsen lipotoxicity. Long-term stavudine








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may also increase the risk of diabetes. Redistribution of fat from medication or HIV infection, with resultant increases in visceral fat anddecreases in subcutaneous fat, is not uncommon. Metformin continues to be the first-line therapy choice for HIV patients, as weight gaincan 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 inappropriate 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 fatapoptosis, 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, β-cell destruction in type 1 DM. In addition, a 24–amino 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 inassociation with exercise can have a dramatic impact on insulin sensitivity and the conversion from IGT to type 2 diabetes. In this studyapproximately 2,000 individuals with IGT were randomized to lifestyle changes (diet, exercise, and weight loss) versus usual care. Thestudy, which was originally planned to be ongoing for 5 years, was stopped early after 2.8 years. The usual care group developeddiabetes 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 ofdeveloping diabetes.79 Surprisingly, a modest amount of diet and exercise yielded impressive results. The exercise program in thelifestyle group was walking 30 minutes 5 days each week. The mean weight loss over the 2.8-year study period was only 8 lb (3.6 kg). Inthe Diabetes Prevention Program79 discussed above, approximately 1,000 of the study patients were randomized to metformin therapy.Metformin therapy reduced the risk of 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 β-cell function. Thus, patients must continue the medication for continued “prevention,” although the question arises if this is merely earlytreatment. Troglitazone, a TZD removed from the market, was able to prevent the development of diabetes in women with a history ofgestational diabetes. Total preservation of β-cell function was demonstrated over a 5-year period in women who had near-normal β-cellfunction at baseline and who initially responded to the drug.80 The preservation of β-cell function was observed for at least 8 monthsafter the drug had been discontinued. The DREAM trial evaluated rosiglitazone and/or ramipril treatment for the delay or prevention oftype 2 DM in impaired glucose-tolerant subjects.81,82 Rosiglitazone 8 mg daily, over approximately 3 years, reduced the incidence oftype 2 diabetes by 60%. In addition, a 37% nonsignificant increase in cardiovascular events was reported. Ramipril 15 mg daily did notsignificantly prevent the conversion to diabetes. It is possible that longer exposure could have made a difference, but the study wasstopped prematurely. In contrast, valsartan, an angiotensin receptor blocker (ARB), administered for 5 years was recently reported toreduce 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 andfound a 72% reduction in the risk of development of diabetes over 2.4 years.83 It should be noted that no pharmacologic agents arecurrently FDA approved or recommended for prevention of type 2 diabetes, although the ADA recommends metformin in conjunction withlifestyle 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 forthis indication.

Patient Education

It is not satisfactory to give patients with DM brief instructions with a few pamphlets and expect them to manage their diseaseadequately.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, andtaking prescribed medications). The American Association of Diabetes Educators (AADE) has developed the AADE7 self-care behaviors ofhealthy eating, being active, monitoring, taking medication, problem solving, reducing risk, and healthy coping, which is a good startingframework for patient discussions. The patient must be involved in the decision-making process and must learn as much about thedisease and associated complications as possible. Emphasis should be placed on the evidence that indicates that complications can beprevented or minimized with glycemic control and management of risk factors for CVD. Recognition of the need for proper patienteducation to empower them into self-care has generated programs for certification in diabetes education for pharmacists. Certifieddiabetes educators (CDEs) must document their patient education hours and sit for a certification examination that assesses the

















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knowledge, tasks, and skills of an educator in order to become certified. An increasing number of nurses, pharmacists, dietitians, andphysicians are becoming CDEs to document to the public that they meet a minimum standard for diabetes education, and to fulfill qualityinitiatives in meeting guidelines for education recognition. Being a CDE does not guarantee reimbursement of services, and CDEs who arenot dietitians will often need to become part of a recognized program to obtain reimbursement. Currently the AADE and ADA haveaccreditation programs.

Treatment of Concomitant Conditions and Complications

Retinopathy

Patients with established retinopathy should see an ophthalmologist or optometrist trained in diabetic eye disease. A dilated eyeexamination is required to fully evaluate diabetic eye disease. Early background retinopathy may reverse with improved glycemic controland optimized blood pressure control. More advanced retinopathy will not fully regress with improved glycemia, but caution should betaken on the expediency of glycemia lowering, as aggressive reductions in glycemia may acutely worsen retinopathy. Thepathophysiology 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 antibodiesgiven by intravitreal injection. Although approved for macular edema, use may also apply to other neovascular ocular conditions. Aprotein kinase C inhibitor has been studied, but results have been modest. Laser photocoagulation has markedly improved sightpreservation 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 focalneuropathy. Distal symmetrical peripheral neuropathy is the most common complication seen in type 2 DM patients in outpatientclinics.85 Paresthesias, perceived hot or cold, numbness, or pain may be the predominant symptom. The feet are involved far more oftenthan the hands as it affects longer nerves first and progresses proximally. Improved glycemic control is the primary treatment and mayalleviate some of the symptoms. If neuropathy is painful, symptomatic pain treatment is indicated, although it will not change the courseof the neuropathy nor has one medication been shown to be superior to another. Treatment may be with low-dose tricyclicantidepressants, anticonvulsants (gabapentin, pregabalin, rarely carbamazepine), duloxetine, venlafaxine, topical capsaicin, and variouspain medications, including tramadol and nonsteroidal antiinflammatory drugs. Duloxetine and pregabalin have FDA approval for thisindication. The numb variant of peripheral neuropathy is not treated with medication, but may lead to pressure areas on the foot andsubsequent ulcer in a subset of patients. Clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, exerciseintolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction (anhidrosis, heatintolerance, gustatory sweating, and/or dry skin), impaired neurovascular function, and hypoglycemic autonomic failure. Gastroparesiscan 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 pacemakersas therapeutic hardware are rarely used, though available. Cisapride, removed from the market several years ago, is still available forcompassionate use and domperidone, available outside of the United States, may be useful. Orthostatic hypotension, after stoppingantihypertensives and liberalizing dietary sodium intake, may require pharmacologic management with mineralocorticoids or adrenergicagonist 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 diarrheais its nocturnal occurrence. Diabetic diarrhea frequently responds to a 10- to 14-day course of an antibiotic such as doxycycline ormetronidazole. In more unresponsive cases, octreotide may be useful. Erectile dysfunction is common in diabetes, and initial treatmentshould include a trial of one of the phosphodiesterase type 5 inhibitors prior to referral. People with diabetes often require the highestdoses of these medications to have an adequate response. Sudomotor dysfunction, as earlier defined, results in loss of sweating andresultant dry, cracked skin. Use of hydrating creams and ointments is needed. Hypoglycemic unawareness requires the patient to avoidhypoglycemia, as the body will slowly increase the glycemic level at which it will signal the autonomic signals, although damage mayseverely 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 Bell’s palsy, may occur. The presentation can be quite dramatic, but the course isusually self-limited, and partial or full recovery happens in a few weeks to months. Carpal tunnel syndrome, caused by radial nerveentrapment, is also more 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.1,5The ADA recommends a screening urinary analysis for albumin at diagnosis in persons with type 2 DM. Precise onset of type 2 DM canrarely be ascertained, and patients will often present at diagnosis with microvascular complications. In type 1 DM, microalbuminuria rarelyoccurs with short duration of disease or before puberty. Screening individuals with type 1 DM should begin with puberty and after 5














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years’ disease duration. There are three methods for assessing microalbuminuria: (a) measurement of the urine albumin-to-creatinine ratioin 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/mmolcreatinine). On timed collections, microalbuminuria is defined as 30 to 300 mg/24 hours or an albumin excretion rate of 20 to 200mcg/min. Because of day-to-day variability, microalbuminuria should be confirmed on at least two of three samples over 3 to 6 monthsunless unequivocal. Additionally, when assessing urine protein or albumin, conditions that may cause transient elevations in urinaryalbumin excretion should be excluded. These conditions include intense exercise, recent urinary tract infections, hypertension, short-termhyperglycemia, 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 ofdiagnosis. Microalbuminuria is a weaker predictor for future end-stage kidney disease in type 2 versus type 1 DM. Glucose and bloodpressure control are most important for the prevention of nephropathy, and blood pressure control is the most important for retarding theprogression of established nephropathy. ACE inhibitors and ARBs, considered first-line recommended treatment modalities, have shownefficacy in preventing the clinical progression of renal disease in patients with diabetes. Combined renin–angiotensin–aldosterone systemblockage (with ACE inhibitors, ARBs, aldosterone receptor blockers, and/or direct renin inhibitors) cannot currently be recommended forroutine practice in nephropathy. Diuretics frequently are necessary due to the volume-expanded state of the patient and arerecommended second-line therapy. The ADA and the National Kidney Foundation blood pressure goal of <130/80 mm Hg can be difficultto 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, andantiplatelet therapy are important strategies in treating claudicants. Cilostazol may be useful for reducing intermittent claudicationsymptoms in select patients. Revascularization is successful in selected patients, although small vessel disease that cannot be bypassedis common in diabetes. Local débridement and appropriate footwear and foot care are vitally important in the early treatment of footlesions. In more advanced lesions multiple treatments including grafts, topical wound healing, and even hyperbaric treatments may benecessary. Diabetic foot care is an excellent example of the adage, “an ounce of prevention is worth a pound of cure.” Thus, a footexamination at each visit is recommended. A yearly Semmes-Weinstein 5.07/10-g force monofilament test for sensation can be used toidentify 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 themajor source of mortality in patients with DM. Multiple risk factor intervention (lipids, hypertension, smoking cessation, and antiplatelettherapy)5 will reduce the burden of excess macrovascular events. The ADA recommends aspirin therapy in all secondary preventionsituations, and if allergic to aspirin, consider clopidogrel. Recent evidence in primary prevention studies of antiplatelet therapy in type 2DM 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 yourjudgment high risk, or in women at least 60 years old or men at least 50 years old, primary prevention antiplatelet therapy can beconsidered. Epidemiologic data suggest that CHD prevention guidelines for type 2 DM apply equally to patients with type 1 DM.5 β-Blocker therapy supplies an even greater protection from recurrent CHD events in diabetic patients than in nondiabetic subjects. Maskingof hypoglycemic symptoms is a greater problem in type 1 DM patients than in patients with type 2 DM, although this risk can beadequately 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 mgdaily (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 theprimary 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 Studyrandomized 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 lowerLDL levels (<116 mg/dL [<3 mmol/L]), and suggests that ˜30% to 40% reduction in LDL levels regardless of starting LDL levels may beappropriate.88 The ADA recommends statin therapy, regardless of baseline lipid or LDL-C levels in patients with overt CVD or withoutdocumented 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. Arelative 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












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be controversial.89 On subset analysis, only subjects without CVD had a significant reduction in CVD events. The lipid arm of theACCORD90 reported on 5,518 subjects randomized to fenofibrate or placebo given with low-dose simvastatin (˜20 mg/day). Fenofibrateaddition did not significantly lower cardiovascular events (0.92; 95% CI, 0.79 to 1.08). Niacin in combination with a statin recently failed toimproved 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 loweredto <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 updatedto <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 NCEP-ATP, triglycerides are possibly considered for pharmacologic management, assuming unresponsivenessto glycemic control efforts, weight management, and exercise. In such situations, a non–HDL-C goal is established (a surrogate for allapolipoprotein B–containing particles). The non–HDL-C goal for patients with DM is <130 mg/dL (<3.36 mmol/L). Niacin or a fibrate canbe 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 lowerCVD. Patients with marked hypertriglyceridemia (≥500 mg/dL [≥5.65 mmol/L]) are at risk for pancreatitis. Efforts to reduce triglycerideswith glycemic control, elimination of other secondary causes (including medications), and drug therapy (fibrates, statins, and potentiallyniacin) 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

Parameter Goal Treatment (In Order of Preference)

LDLcholesterol

<100 mg/dL (<2.59 mmol/L) <70mg/dL (<1.81 mmol/L)a

Lifestyle; HMG-CoA reductase inhibitors; cholesterolabsorption inhibitor; niacin or fenofibrate

HDLcholesterol 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-dosestatins (in those with high LDL)

HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL,

low-density lipoprotein.

aMay be optimal goal in patients with 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 studiedtype 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 (133mm 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 aregenerally recommended for initial therapy, as they have shown to be cardioprotective, and likely have special renal protection. Manypatients require multiple agents, on average three agents, to obtain goals, so diuretics, calcium channel blockers, and β-blockersfrequently are useful as second and third agents. African Americans need special consideration. They receive renoprotection from ACEinhibitors or ARBs, but as a population may lower blood pressure slightly less with these agents. It is recommended that combinationtherapy with a diuretic or calcium channel blocker be considered as first-line therapy. After initial therapy, which agent to add next is stillcontroversial. 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








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Whole pancreas and islet cell transplantation are options in patients with type 1 DM; those with end-stage renal disease also receivekidney 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 reachingglycemic 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 alwaysinvolves basal–bolus 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, asbasal–bolus therapy may not fit into their lifestyle. Elevated glucagon levels in some patients, as the hormone amylin is low or absent, mayrequire glucagon suppression therapy. FDA-approved therapy includes addition of pramlintide, but there is evidence for use ofnonapproved medications such as GLP-1 receptor antagonists to act as an alternative to pramlintide, which requires many extrainjections per day. In addition, metformin has been used in some type 1 DM patients who are adherent (and thus at low risk of DKA) buthave suboptimal control of their FPG readings. Metformin use should not be routine, but in examples such as adolescents who missinjections 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 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, cardiovascularoutcomes, and even perceived β-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 andprotocols to screen for, prevent, or manage microvascular and macrovascular complications. In terms of standards of care for personswith DM, one can review the document published by the ADA that outlines initial and ongoing assessments for patients with DM.5 Themajor performance measure by the National Committee for Quality Assurance (NCQA), such as Health Plan Employer Data andInformation Set (HEDIS), should assess the ability to meet current standards of care and recognize the minimal treatment goals forglycemia, lipids, and hypertension, and provide targets for monitoring and adjusting pharmacotherapy as discussed in various sectionsabove. Publicly reported quality measures continue to move closer to current guidelines, but lack the ability to differentiate reasons why apatient 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 frequentassessment and adjustment in diet, exercise, and pharmacologic therapies. The ADA also has clinical practice recommendations that arewidely cited and followed.5 Minimally, HbA1c should be measured twice a year in patients meeting treatment goals on a stabletherapeutic regimen. Quarterly assessments are recommended for those whose therapy has changed or who are not meeting glycemicgoals. 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 identifiedabnormalities), and office visits for follow-up are also important. Assessment for pneumococcal vaccine administration (and one-timerevaccination recommended in individuals at least 65 years old), annual administration of influenza vaccine, new recommendations that allpeople 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 eachpatient visit is likely to be better facilitated utilizing an integrative computer program and electronic medical record, standardized progressnote forms, or flow sheets, which assist the clinician in identifying whether the patient has met standards of care in the frequency ofmonitoring and achievement of defined targets of therapy. Adherence continues to be of issue, as with many chronic diseases, and use offrequent 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 theirclinician or from family, friends, or the Internet (Table 57-14).

Table 57-13 Combination Products Available in Type 2 Diabetes Mellitusa

Medication Combined With Trade Name

PioglitazoneRosiglitazoneSitagliptin

Actosplus MetAvandametJanumet








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Metformin and/or metformin extended releaseSaxagliptinLinagliptinAlogliptinGlyburideGlipizideRepaglinide

KombiglyzeJentaduetoKazanoGlucovanceMetaglipPrandimet

Glimepiride Pioglitazone Duetact

Rosiglitazone Avandaryl

Pioglitazone Alogliptin Oseni

aAt time chapter written.

Table 57-14 Drug Monitoring for Diabetes Mellitus Medications

Medication Class Adverse Drug Reaction Monitoring Parameters Comments

α-Glucosidaseinhibitors GI upset Gas, bloating, loose stools Titrate, take in less

carbohydrate

Bile acidsequestrants Constipation Bowel movement frequency Do not use if history of

bowel obstruction

Raises triglycerides TriglyceridesNot recommended TG >500 mg/dL (>5.65mmol/L)

Biguanides GI upset Reflux, nausea, vomiting, stomachupset, loose stools

Take with food andtitrate dose; split doses;consider extendedrelease

Lactic acidosis Hypoxic states, renal functionLactate levels usuallynot measured, but can ifsuspected toxicity

DPP-4 inhibitorsHypersensitivity/angioedemaand exfoliating dermatologicskin reactions

Skin rash, signs/symptoms ofangioedema

Risk factors, such ashistory of angioedema,possibly ACE inhibitoruse, and past history ofsevere dermal drugreactions, should beexplored

Pancreatitis Amylase, lipase, abdominal painwith nausea/vomiting

Discontinue; look forunderlying causes

Dopamineagonists Hypotension Syncopal symptoms Stop antihypertensives

Worsening psychiatricissues

Signs/symptoms of underlyingmental illness

Avoid use withantipsychotics

CNS effects Mentalalertness/asthenia/fatigue/headache Titrate slowly







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Gastrointestinal side effects Nausea Titrate slowly

Thiazolidinediones Heart failure/pulmonaryedema

Signs/symptoms of heart failure,BNP, weight Discontinue

Peripheral edema Peripheral edema measuresLimit dose, considerdiuretic (see text), ordiscontinue

Weight gain WeightConsider if weight isfluid or likely caloricintake

Peripheral fractures None except fractureAvoid use inosteoporosis andosteopenia

Sulfonylureas Hypoglycemia Self-monitored blood glucose

Meglitinides Hypoglycemia Self-monitored blood glucose

GLP-1 receptoragonists GI Nausea/vomiting Titrate slowly; avoid in

gastroparesis

Pancreatitis Amylase, lipase, abdominal painwith nausea/vomiting

Discontinue; look forunderlying causes

C-cell tumors of thyroid None recommended, calcitoninCalcitonin could bemeasured if suspected,has not occurred inhumans to date

Amylinomimetic GI upset Nausea/vomiting Titrate slowly; avoid ingastroparesis

Insulin Hypoglycemia Self-monitored blood glucose

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




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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 Lowering in Diabetes

FPG fasting plasma glucose

GDM gestational diabetes mellitus

GIP glucose-dependent insulinotropic polypeptide

GLP-1 glucagon-like peptide-1

HbA1c hemoglobin A1c

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

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IFG impaired fasting glucose

IGT impaired glucose tolerance

LADA latent autoimmune diabetes in adults

LDL-C low-density lipoprotein cholesterol

LookAHEAD 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

NPH neutral protamine Hagedorn

OGTT oral glucose tolerance test

PAI-1 plasminogen activator inhibitor-1

PPAR-γ peroxisome proliferator–activated receptor γ

RECORD Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2Diabetes

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

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92. The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1628–1630.

Copyright © McGraw-Hill Global Education Holdings, LLC.All rights reserved.

Your IP address is 204.154.87.209

National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes by age among adults ≥20 years of age: United States,2005–2008. (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, 2002–2005. (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 β-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 glucoseincrease 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 βcell makes progressively less insulin, which leads to an overproduction of glucose by the liver and results in a progressive increase infasting glucose. (Reprinted from DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin N Am 2004;88:787–835, 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 diabeticindividuals. Obese diabetic individuals are slightly more resistant than lean diabetic patients. (From DeFronzo RA. Diabetes Reviews

1977;5:177–269.)

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 Studyof 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.)


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