Iabetes Ellitus: Section 7. Endocrinologic Disorders

Section 7.
Endocrinologic Disorders
40 DIABETES MELLITUS
Christopher L. Cook, John T. Johnson, and William E. Wade
LEARNING OBJECTIVES
UPON COMPLETION OF THE CHAPTER, THE READER WILL BE ABLE TO:
1. Discuss the incidence and economic impact of diabetes. 2. List screening and diagnostic criteria for diabetes. 3. Distinguish clinical differences in type 1, type 2, and gestational diabetes mellitus. 4. Discuss therapeutic goals for blood glucose, blood pressure, and lipids for a patient with diabetes. 5. Recommend nonpharmacologic therapies, including meal planning and physical activity, for patients with diabetes. 6. Compare oral agents used in treating diabetes by their mechanisms of action, time of action, side effects, contraindications, and effectiveness. 7. Select appropriate insulin therapy based on onset, peak, and duration of action. 8. Develop a comprehensive therapeutic patient monitoring plan for a patient with diabetes based on patient-specic factors.
KEY CONCEPTS Diabetes mellitus (DM) describes a group of

chronic metabolic disorders that are characterized by hyperglycemia and are associated with long-term microvascular, macrovascular, and neuropathic complications. Glycemic control remains the primary objective in managing diabetes and its complications. Type 2 DM is the most prevalent form of diabetes and accounts for approximately 90% to 95% of all diagnosed cases. Type 2 DM is usually slow and progressive in its development and often is preceded by prediabetes. Rising blood glucose levels result from increasing insulin resistance and impaired insulin secretion leading to a situation of relative insulin deciency. Although type 1 DM may appear at any age, it is encountered most commonly in individuals younger than 30 years of age. Type 1 DM is characterized by an absolute deciency in insulin resulting from pancreatic -cell destruction. Patients and clinicians can evaluate blood glucose control through a combination of self-monitoring of blood glucose data and hemoglobin A1c testing.
Several classes of oral agents are available to treat patients with

type 2 DM who are unable to achieve glycemic control through diet and exercise. Insulin is the essential treatment for patients with type 1 DM and can overcome insulin resistance in patients with type 2 DM.
Diabetes mellitus (DM) describes a group of chronic metabolic disorders characterized by hyperglycemia that may result in long-term microvascular, macrovascular, and neuropathic complications. These complications contribute to diabetes being the leading cause of (1) new cases of blindness among adults, (2) end-stage renal disease, and (3) nontraumatic lower limb amputations. In addition, the increased cardiovascular risk associated with DM contributes to it being the sixth leading cause of death in the United States. The nancial impact of DM in 2002 was approximately $132 billion, or 1 of every 10 dollars spent on health care in the United States. This averages to an annual health care cost of $13,243 for diabetics versus $2560 for nondiabetics.1 While prevention and treatment of DM remain a challenge, several landmark studies have shown that complications associated with DM can be delayed or prevented through proper
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SECTION 7 / ENDOCRINOLOGIC DISORDERS
blood glucose management.2,3 Thus glycemic control remains the primary objective in diabetes management.
Risk factors for type 2 diabetes include

First-degree family history of DM (i.e., parents or siblings) Overweight or obese Habitual physical inactivity Race or ethnicity (Native American, Latino/Hispanic American,
EPIDEMIOLOGY AND ETIOLOGY

DM is characterized by a complete lack of insulin, a relative lack of insulin, or insulin resistance. These defects result in an inability to properly use glucose for energy. DM affects an estimated 20.8 million persons in the United States, or 7% of the population. While an estimated 14.6 million persons have been diagnosed, another 6.2 million people who have DM are unaware they have the disease. Worldwide, the number of people with DM is expected to rise to 35% by the year 2025.1 The increasing prevalence of DM is due in part to three inuences: lifestyle, ethnicity, and age. Sedentary lifestyle coupled with greater consumption of high-fat foods and larger portion sizes has resulted in increasing rates of persons being overweight or obese. Current estimates indicate that 65% of the U.S. population is overweight and 30% is obese. Overweight is dened as body mass index (BMI) of greater than 25 kg/m2, whereas a BMI of greater than 30 kg/m2 constitutes obesity. The Centers for Disease Control and Prevention (CDC) estimates that 25% to 33% of Americans do not engage in an adequate amount of daily activity.4 Compounding this lifestyle trend, certain ethnic groups are at a disproportionately high risk of DM. Individuals of American Indian and Alaskan native, African-American, and Hispanic/Latino-American descent have a 1.7 to 2.2 times greater risk of developing DM compared with non-Hispanic whites.1 In addition, AfricanAmerican and Hispanic/Latino-American populations are growing at a faster rate than the general U.S. population. The third contributing factor is increasing age. The prevalence of DM increases with age from approximately 2% of individuals ages 20 to 39 to 20.9% of individuals older than age 60.1 As the population ages, the incidence of DM is expected to increase.
Asian American, African American, and Pacic Islanders)

Prediabetes (i.e., previously identied with impaired glu-
cose tolerance or impaired fasting glucose)

Hypertension (140/90 mm Hg) High-density lipoprotein (HDL) less than 35 mg/dL (0.91
mmol/L) and/or a triglyceride level greater than 250 mg/dL (2.83 mmol/L) History of gestational diabetes or delivery of a baby weighing greater than 9 pounds (4.09 kg) History of vascular disease History of polycystic ovary disease Other conditions associated with insulin resistance (e.g., acanthosis nigricans)5 Type 1 DM, previously referred to as insulin-dependent or juvenile-onset DM, constitutes 5% to 10% of all diagnosed cases of DM. Type 1 DM usually is diagnosed in children and young adults younger than 30 years of age, although the disease can present at any age. This form of the disease is characterized by an absolute deciency in insulin resulting from pancreatic b-cell destruction. Latent autoimmune diabetes in adults (LADA), slow-onset type 1 or type 1.5 DM, is a form of autoimmune type 1 diabetes that occurs in individuals older that the usual age of onset. Patients often are mistakenly thought to have type 2 diabetes because the person is older and may respond initially to treatment with oral hypoglycemic agents. However, these patients do not have insulin resistance, but antibodies are present in the blood that are known to destroy pancreatic -cells. It has been suggested that the easiest way to differentiate between type 1 and type 2 DM is by measuring C-peptide levels. Type 1 diabetics have C-peptide levels below 1 ng/mL (0.33 nmol/L), whereas those with type 2 disease will have values greater than 1 ng/mL (0.33 nmol/L). Glucose intolerance diagnosed in women during pregnancy is called gestational diabetes mellitus (GDM) and occurs in approximately 7% of all pregnancies. Women who have GDM have a 20% to 50% chance of developing diabetes within 5 to 10 years. Risk factors for GDM include obesity, glycosuria, strong family history of DM, age greater than 35 years, prediabetes detected before pregnancy, previous delivery of babies with birth weights greater than 9 pounds (4.09 kg), and ethnicity (African American, Hispanic/Latino American, or American Indian). Clinical detection of and therapy for GDM are important because blood sugar control produces signicant reductions in perinatal morbidity and mortality. Rare forms of DM have been reported and account for 1% to 5% of all diagnosed cases. Causes of these rare forms of DM
Type 2 DM, previously referred to as adult-onset or noninsulin-dependent DM, is the most prevalent form of the disease and accounts for approximately 90% to 95% of all diagnosed cases.1 Type 2 DM is characterized by a relative insulin deciency and insulin resistance. Type 2 DM is usually slow and progressive in its development and often is preceded by prediabetes. The development of prediabetes places the individual at high risk of eventually developing diabetes. It is currently estimated that 41 million persons in the United States have prediabetes. Prediabetes is dened as having either a fasting and/or a postprandial blood glucose level higher than normal but not high enough to be classied as DM. Because progression from prediabetes to diabetes is not inevitable, interventions during prediabetes are gaining popularity.
CHAPTER 40 / DIABETES MELLITUS
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TABLE 401. Medications That May Affect Glycemic Controla

Drug Angiotensin-converting enzyme inhibitors Alcohol -Interferon Diazoxide Diuretics Glucocorticoids Nicotinic acid Oral contraceptives Pentamidine Phenytoin b-Blockers Salicylates Sympathomimetics Clozapine and olanzapine
a
Effect on Glucose Slight reduction Reduction Increase Increase Increase Increase Increase Increase Decrease, then increase Increase May increase Decrease Slight increase Increase
Mechanism/Comment Improves insulin sensitivity Reduces hepatic glucose production Unclear Decreases insulin secretion, decreases peripheral glucose use May increase insulin resistance Impairs insulin action Impairs insulin action, increases insulin resistance Unclear Toxic to b cells; initial release of stored insulin, then depletion Decreases insulin secretion Decreases insulin secretion Inhibition of I-kappa-B kinase-beta (IKK-beta) (only high doses, e.g., 46 g/day) Increased glycogenolysis and gluconeogenesis Unclear; weight gain
This list is not inclusive of all medications reported to cause glucose changes. Reproduced, with permission, from DiPiro et al, Pharmacotherapy, 6th ed. New York: McGraw-Hill; 2005, Table 7210, p. 1346.
include specic genetic conditions, surgery, drugs, malnutrition, infections, and other illnesses. Table 40-1 contains a list of medications that may affect glycemic control. While the use of these medications is not contraindicated in persons with DM, caution and awareness of the effects on blood glucose should be taken into account when managing patient care.
hormones, such as growth factor, cortisol, and epinephrine, increase blood glucose levels. While blood glucose levels vary, the opposing actions of insulin and glucagon, along with the counterregulatory hormones, maintain these values between 70 and 120 mg/dL (3.89 and 6.66 mmol/L).
Type 1 Diabetes PATHOPHYSIOLOGY Normal Carbohydrate Metabolism

The bodys main energy source is the metabolism of glucose. Cells metabolize glucose completely through glycolysis and the Kreb cycle, producing water and carbon dioxide as waste products. Glucose not immediately needed for energy is stored in the liver and muscles as glycogen. Later, when energy is needed, glycogenolysis converts stored glycogen back to glucose. Excess glucose also can be converted to triglycerides and stored in fat cells. Triglycerides subsequently undergo lipolysis, yielding glycerol and free fatty acids. While usually reserved for other functions, proteins also can be converted to glucose through a process called gluconeogenesis. Normal homeostasis is achieved through a balance of the metabolism of glucose, free fatty acids, and amino acids to maintain a blood glucose level sufcient to provide an uninterrupted supply of glucose to the brain.6 Insulin and glucagon are produced in the pancreas by cells known as islets of Langerhans. -Cells make up 70% to 90% of the islets and produce insulin, whereas -cells produce glucagon. The main function of insulin is to decrease blood glucose levels, whereas glucagon, along with other counterregulatory
The primary defect in type 1 DM is an absolute insulin deciency resulting from pancreatic b-cell destruction. -Cell destruction is most commonly the result of an autoimmune process usually precipitated through genetic susceptibility and/or an environmental trigger. Certain genetic markers can be measured to determine if a person is at risk of diabetes. The presence of human leukocyte antigens (HLAs), especially HLADR, is strongly associated with the development of type 1 diabetes. Over 95% of people with type 1 DM have HLA-DR3 and HLA-DR4 present. In addition, persons with DM often develop islet-cell antibodies, insulin autoantibodies, or glutamic acid decarboxylase autoantibodies. More than 90% of persons with type 1 DM have at least one diabetes-related antibody present. As more cells are destroyed, glucose metabolism becomes compromised owing to reduced insulin release following a glucose load. At the time of diagnosis, most patients have a 90% loss of -cell function. The remaining 10% of -cell function at diagnosis creates a honeymoon period during which blood glucose levels are easier to control and smaller amounts of insulin are required. Once this remaining -cell function is lost, patients become completely insulin-decient and require more exogenous insulin. Figure 401 describes the progression of type 1 DM.
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FIGURE 401 Scheme of the natural history of the -cell defect in type 1 DM. (Used, with permission, from DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiological Approach. 6th ed. New York: McGraw- Hill; 2005, Fig. 724, p. 1339.)
Hyperinsulinemia, or high blood levels of insulin, is an early nding in the development of type 2 DM. More insulin is secreted to maintain normal blood glucose levels until eventually the pancreas can no longer produce sufcient insulin. The resulting hyperglycemia is enhanced by extremely high insulin resistance, pancreatic burnout in which -cells lose functional capacity, or both. Patients with type 2 DM typically have approximately 40% -cell function at diagnosis. Decreasing cell function also results in a reduced ability to produce a rstphase insulin response sufcient to signal the liver to stop producing glucose during the fed state. As DM progresses, large numbers of patients with type 2 disease eventually lose all -cell function and require exogenous insulin to maintain blood glucose control.
Insulin Resistance
Type 2 Diabetes
Type 2 DM is characterized by a slow, gradual onset of hyperglycemia that often is asymptomatic. The underlying metabolic dysfunction contributing to this disease is thought to be a combination of both genetic and environmental factors. Rising blood glucose levels result from increasing insulin resistance and impaired insulin secretion leading to relative insulin deciency. Prior to describing these two insulin defects, it is necessary to understand normal insulin action and its role in glucose control.
Normal Insulin Action
Insulin resistance is the primary factor that differentiates type 2 DM from other forms of diabetes. Insulin resistance may be present up to 10 years prior to the diagnosis of DM and can continue to progress throughout the course of the disease. Resistance to insulin occurs most signicantly in skeletal muscle and the liver. Insulin resistance in the liver poses a double threat because the liver becomes nonresponsive to insulin for glucose uptake, and hepatic production of glucose during the fed state does not cease. Hyperglycemia results because ingested glucose and continued hepatic glucose production combine to raise blood glucose levels.
Metabolic Syndrome
During periods of fasting, most circulating glucose is produced in the liver by glycogenolysis. This endogenous production of glucose serves to ensure the brain a constant glucose supply. Insulin secretion during fasting periods is a low, steady basal rate of 0.5 to 1 units/h.6 On eating, blood glucose levels rise, and the insulin-secretion response occurs in two phases. An initial burst, known as rst-phase insulin response, lasts approximately 10 minutes and serves to suppress hepatic glucose production. This bolus of insulin minimizes hyperglycemia during meals and during the postprandial period. The loss of this rst-phase insulin response is an early event in the progression from glucose intolerance to DM. The second-phase insulin response is characterized by a gradual increase in insulin secretion, which stimulates glucose uptake by peripheral insulin-dependent tissues. Approximately 80% to 85% of glucose metabolism during this time occurs in muscle. The slower release of insulin allows the body to respond to the new glucose entering from digestion while maintaining blood glucose levels. A pancreas with normal -cell function is able to adjust insulin production to maintain normal blood glucose levels.
Impaired Insulin Secretion
Insulin resistance has been associated with a number of other cardiovascular risks, including abdominal obesity, hypertension, dyslipidemia, hypercoagulation, and hyperinsulinemia. The clustering of these risk factors has been termed the metabolic syndrome. It is estimated that 50% of the U.S. population older than age 60 have metabolic syndrome. The most widely used criteria to dene the metabolic syndrome were established by the National Cholesterol Education Program Adult Treatment Panel III Guidelines (summarized in Table 402).
TABLE 402. Five Components of the Metabolic Syndrome

Risk Factor 1. Abdominal obesity Men Women 2. Triglycerides 3. HDL cholesterol Men Women 4. Blood pressure 5. Fasting glucose Dening Level Waist circumference Greater than 102 cm (40 in) Greater than 88 cm (35 in) Greater than 150 mg/dL (1.70 mmol/L) Less than 40 mg/dL (1.03 mmol/L) Less than 50 mg/dL (1.29 mmol/L) Greater than or equal to 130/80 mm Hg Greater than or equal to 110 mg/dL (6.11 mmol/L)
AU: proNote: Individuals having at least three of the ve above meet the diagnostic vide full criteria for metabolic syndrome. citation. From ref. 20.
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Patients having this convergence of factors have been found to be at a much higher cardiovascular risk than would be expected from the individual components of the syndrome. Therefore, it is important to assume a more aggressive treatment plan for each of the individual abnormal components. Since prediabetes and DM are one of the component risk factors in the diagnostic criteria, a patient with prediabetes or DM having the convergence of factors may be treated more aggressively than a patient having prediabetes or DM alone.
Patient Encounter, Part 1

MF is a large-framed 32-year-old Caucasian man who is 5 ft, 10 in (177.8 cm) tall and weighs 295 lb (134.09 kg). He has not been to the doctor in 5 years. He is diagnosed with irritable bowel syndrome today. He visits the local free clinic, and the following is discovered when labs and physical assessment are performed: Fasting glucose: 189 mg/dL (10.49 mmol/L) BUN: 13 mg/dL (4.64 mmol/L) Creatinine: 1.2 mg/dL (106.08 mol/L) AST/SGOT: 26 IU/L (0.43 Kat/L) ALT/SGPT: 26 IU/L (0.43 Kat/L) TSH: 1.264 microunits/mL (1.26 mU/L) Total cholesterol: 277 mg/dL (7.16 mmol/L) LDL: 187 mg/dL (4.84 mmol/L) HDL: 29 mg/dL (0.75 mmol/L) Triglycerides: 305 mg/dL (3.45 mmol/L) Hemoglobin A1c: 11% BP (blood pressure): 167/98 mm Hg What information is suggestive of diabetes? What criteria must be met before a diagnosis of diabetes can be made? What type of diabetes do you think MF has based on his clinical characteristics? What challenges can you identify for optimal clinical outcomes through the initial assessments for MF? What additional information do you need to know before creating a treatment plan for this patient?
AU: I am not familiar with this unit of measure---is it OK? AU: I am not familiar with this unit of measure---is it OK?
CLINICAL PRESENTATION AND DIAGNOSIS Screening

Currently, the American Diabetes Association (ADA) recommends routine screening for type 2 DM every 3 years in all adults starting at age 45. Earlier and more frequent screening should be reserved for patients who are at higher risk. The ADA does not recommend screening for type 1 diabetes owing to the low incidence and acute presentation of symptoms.7 See Table 403 for complete screening guidelines.
Gestational Diabetes
Risk assessment for GDM should be performed early in pregnancy with a random glucose test. If the normal diagnostic threshold for diabetes is exceeded during the rst test and conrmed on a subsequent day, a diagnosis of GDM can be made. Otherwise, all women should be screened with an oral
Typical Clinical Presentation of Diabetes Mellitus

Characteristic Age of onset Speed of onset Family history Body type Metabolic syndrome Autoantibodies Symptoms Type 1 DM Childhood or adolescence Abrupt Negative Thin No Present Polyuria, polydipsia, polyphagia, rapid weight loss Present Diabetic ketoacidosis (DKA) Rare Type 2 DM Greater than 40 years old Gradual Positive Obese or history of obesity Often Rare Asymptomatic
Ketones at diagnosis Acute complications Microvascular complications at diagnosis Macrovascular complications at or before diagnosis
Uncommon Rare Common
Rare
Common
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TABLE 403. American Diabetes Association Screening Recommendations for Diabetes Mellitus
Asymptomatic Type 1 The American Diabetes Association does not recommend screening for type 1 diabetes owing the low incidence in the general population and to the acute presentation of symptoms. Asymptomatic Type 2 1. The American Diabetes Association recommends screening for type 2 diabetes every 3 years in all adults beginning at age 45 years old, particularly in those with a body mass index greater than or equal to 25 kg/m2
2. Testing should be considered for persons younger than 45 years old or more frequently in individuals who are overweight (body mass index greater than or equal to 25 kg/m2) and have additional risk factors:
Habitually inactive First-degree relative with diabetes Member of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, Pacic Islander) Delivered a baby weighing greater than 9 lb (4.09 kg) or previous diagnosis of gestational diabetes mellitus Hypertensive (greater than or equal to 140/90 mm Hg) High density lipoprotein (HDL) cholesterol level less than 35 mg/dL (0.91 mmol/L) and/or a triglyceride level greater than 250 mg/dL (2.83 mmol/L) Polycystic ovary syndrome Previous impaired glucose tolerance or impaired fasting glucose Have other clinical conditions associated with insulin resistance (e.g., acanthosis nigricans) History of vascular disease
Type 2 in Children and Adolescents Criteria: Overweight (body mass index greater than 85th percentile for age and sex, weight for height greater than 85th percentile, or weight greater than 120% of ideal for height) Plus any two of the following risk factors:
Family history of type 2 diabetes in rst- or second-degree relatives Race/ethnicity (Native American, African American, Latino/Hispanic American, Asian American, Pacic Islander) Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary disease) Age of initiation: Age 10 or at onset of puberty, if puberty occurs at a younger age Frequency of testing: Every 2 years Test method: Fasting plasma glucose preferred Clinical judgment should be used to test for diabetes in high-risk patients who do not meet these criteria. Gestational Diabetes 1. Risk assessment performed at rst prenatal visit with random glucose screen. 2. All women should be screened with an oral glucose tolerance test between weeks 24 and 28 of gestation unless they are in the low-risk category.
AU: provide full citation. From ref. 5.
glucose tolerance test (OGTT) between weeks 24 and 28 of gestation unless they are in the low-risk category. The diagnostic criteria for OGTT are listed in Table 404. Women considered low risk include those of normal weight before pregnancy; younger than 25 years of age; without rst-degree relatives with diabetes; non-Hispanic, African-American, or Native American ethnicity; and no prior history of glucose intolerance or poor obstetric outcome.5 Any woman diagnosed with GDM should be retested at 6 weeks postpartum. If the fasting plasma glucose (FPG) level is normal, then reassessment for DM should occur every 3 years. Family planning for subsequent pregnancies should be discussed, and monitoring for the development of symptoms of DM should be undertaken.
TABLE 404. Diagnosis of Gestational Diabetes with a 100- or 75-g Glucose Load
Plasma Glucose Time 100-g Glucose Load Fasting 1 hour 2 hours 3 hours 75-g Glucose Load Fasting 1 hour 2 hours mg/dL 95 180 155 140 95 180 155 mmol/L 5.3 10.0 8.6 7.8 5.3 10.0 8.6
Diagnostic Criteria
Diagnosis of DM includes glycemic outcomes exceeding threshold values with one of three testing options (Table 405).
Note: Two or more venous plasma concentrations must be met or exceeded for a positive diagnosis of diabetes to be made. The test should be done in the morning after an 8- to 14-hour fast and after at least 3 days of unrestricted diet and unlimited physical activity. The patient should remain seated and should not smoke during AU: provide full the test. citation. From ref. 8.
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TABLE 405. Criteria for the Diagnosis of Diabetes Mellitus

1. Symptoms of diabetes plus a casual plasma glucose concentration greater than or equal to 200 mg/dL (11.1 mmol/L). Casual is dened as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. OR 2. Fasting plasma glucose greater than or equal to 126 mg/dL (7.0 mmol/L). Fasting is dened as no caloric intake for at least 8 hours. OR 3. Two-hour postload glucose greater than or equal to 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
Note: In the absence of unequivocal hyperglycemia, these criteria should be conrmed by repeat testing on a different day. The oral glucose tolerance test is not recommended for routine clinical use.
production during the fasting state, whereas postprandial glucose levels in the OGTT may reect glucose uptake in peripheral tissues, insulin sensitivity, or a decreased rst-phase insulin response.
TREATMENT Goals of Therapy

DM treatment goals include reducing long-term microvascular and macrovascular complications, preventing acute complications from high blood glucose levels, minimizing hypoglycemic episodes, and maintaining the patients overall quality of life. To achieve these goals, near-normal blood glucose levels are fundamental. Two landmark trials, the Diabetes Control and Complications Trial2 and the United Kingdom Prospective Diabetes Study,3 showed that lowering blood glucose levels decreased the risk of developing chronic complications. A near-normal blood glucose level can be achieved with appropriate patient education. Proper care of DM requires goal setting and assessment for glycemic control, self-monitoring of blood glucose (SMBG) level, monitoring of blood pressure and lipid levels, regular monitoring for the development of complications, dietary and exercise lifestyle modication, and proper medication use. The complexity of proper DM self-care principles has a dramatic impact on a patients lifestyle and requires a highly disciplined and dedicated person to maintain long-term control.
Setting and Assessing Glycemic Targets
From ref. 8.
Conrmation of abnormal values must be made on a subsequent day for diagnosis unless unequivocal symptoms of hyperglycemia exist, such as polydipsia, polyuria, and polyphagia. The ADA recommends FPG determination as the principal tool for diagnosis of DM in nonpregnant adults owing to ease of use, acceptability to patients, and lower cost.7 While the OGTT is more sensitive and modestly more specic than FPG determination, it is difcult to reproduce the results and rarely performed in practice today. The ADA categorizes patients demonstrating impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) as having prediabetes.8 The categorization thresholds of glucose status for FPG determination and the OGTT are listed in Table 406. These two conditions may coexist or may be identied independently. FPG level represents hepatic glucose
TABLE 406. Categorization of Glucose Status
mg/dL Fasting Plasma Glucose (FPG) Normal Impaired fasting glucose (IFG) Diabetes mellitusa 2-Hour Postload Plasma Glucose (Oral glucose tolerance test) Normal Impaired glucose tolerance (IGT) Diabetes mellitusa
AU: provide full citation.
a
mmol/L
Patients and clinicians can evaluate blood glucose control through the combination of the self-monitoring of blood glucose data and the hemoglobin A1c (A1c) test. Self-monitoring of blood glucose enables patients to obtain their current blood glucose level at any time easily and relatively inexpensively. The hemoglobin A1c test provides a weighted-mean blood glucose level from the previous 3 months.
Self-Monitoring of Blood Glucose
Less than 100 100125 Greater than or equal to 126
Less than 5.6 5.66.9 7.0
Less than 140 140199 Greater than or equal to 200
7.8 7.811.1 11.1
Provisional diagnosis of diabetes (diagnosis must be conrmed; see Table 405).
From ref. 8.
Self-monitoring of blood glucose is the standard method for routinely checking blood glucose levels. Each reading provides a point-in-time evaluation of glucose control that can vary widely depending on numerous factors, including food, exercise, stress, and time of day. By examining multiple individual points of data, patterns of control can be established. Therapy can be evaluated from these patterns, and adjustments can be made to improve overall blood glucose control. The ADA premeal plasma glucose goals are 90 to 130 mg/dL (57.22 mmol/L), and peak postprandial plasma glucose goals are less than 180 mg/dL (9.99 mmol/L).5 The American Association of Clinical Endocrinologists (AACE) supports tighter SMBG controls, with premeal goals of less than 110 mg/dL (6.11 mmol/L) and peak
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postmeal goals of less than 140 mg/dL (7.77 mmol/L).9 For patients with type 1 DM, the ADA recommends that SMBG be performed at least three times daily. The frequency of testing in patients with type 2 DM is still controversial. The ADA recommends testing frequently enough to gain and maintain blood glucose control. While the majority of practitioners recommend SMBG to their patients with type 1 DM, the role of SMBG in improving glucose control in type 2 DM is unproven.10 Typically, in SMBG, a drop of blood is placed on a test strip that is then read by a glucometer. Recent technological advancements have decreased the blood sample size required to as small as 0.6 L, provided the capability of alternate site testing, and provided readings in as few as 5 seconds. Many SMBG devices can download or transfer information to a computer program that can summarize and produce graphs of the data. Identifying patterns in the patients blood glucose data can aid practitioners in modifying treatment for better glucose control. Specic therapy adjustment can be made for patterns found at certain times of the day, on certain days, or with large day-to-day variances. While most testing occurs by lancing the ngertip to produce a blood droplet, alternate-site testing has been approved for testing the palm, arm, leg, and abdomen. Alternate-site testing was developed as a means to decrease the pain encountered with repeated ngersticks by using body locations that have a lower concentration of nerve endings. In choosing a glucose meter for a patient, several additional factors may aid in the best selection for the patient. Larger display areas or units with audible instructions and results may be better suited for older individuals and those with visual impairment. Patients with arthritis or other conditions that decrease dexterity may prefer larger meters with little or no handling of glucose strips. Younger patients or busy professionals, on the other hand, may prefer the smaller meters with features such as faster results, larger memories, reminder alarms, and downloading capabilities that facilitate individuals checking their blood glucose levels.
Hemoglobin A1c
Blood Pressure, Lipids, and Monitoring for Complications
The ADA standards of medical care address many of the common comorbid conditions, as well as complications that result from the progression of DM. Table 407 presents goals for blood pressure measurements, lipids values, and monitoring parameters for complications associated with diabetes.
General Approach to Therapy

Type 1 DM
Treatment of type 1 DM requires providing exogenous insulin to replace the endogenous loss of insulin from the nonfunctional pancreas. Ideal insulin therapy mimics normal insulin physiology. The basal-bolus approach attempts to reproduce basal insulin response through the use of intermediate- or longacting insulin, whereas short- or rapid-acting insulin replicates
Patient Encounter, Part 2, The Followup Visit

MF comes back 1 week later for you to review the laboratory results with him and to determine if medications are necessary. When you check his FBG level today, the result is 210 mg/dL (11.66 mmol/L). A diagnosis of DM is made, but you have no other blood glucose records. The following information is gained from MF during the visit: PMH: Occasional sinus infections over the last several years Reports last eye examination about 6 years ago; believes he could use new glasses No other problems reported FH: Father: 64 years old; history of alcohol abuse, hypertension, and myocardial infarction Mother: 62 years old; history of type 2 DM, hypertension, and obesity Sister: 34 years old; history of hypothyroid and obesity SH: Drinks 3 to 4 times per week and smokes cigarettes 1 to 2 packs per day for 20 years No steady employment Meal history: Usually has a donut and large coffee in the mornings, fast-food value meal for lunch, and a diner meal for supper (meat and two vegetables) Physical activity: No regular physical activity routine but does walk around about 30 minutes a day What are your treatment goals for MF regarding blood glucose, blood pressure, and lipids? What nonpharmacologic and pharmacologic approaches are available for MF? Are there any specialist care providers you would refer MF to?
Hemoglobin A1c is the gold standard for evaluating longterm glycemic control.11 Glucose interacts spontaneously with hemoglobin in red blood cells to form glycosolated derivatives. The most prevalent derivative is hemoglobin A1c. Greater amounts of glycosolation occur when blood glucose levels increase. Because hemoglobin has a life span of approximately 120 days, levels of hemoglobin A1c provide a marker reecting the average glucose levels over this timeframe. The ADA goal for persons with DM is less than 7%, whereas the AACE supports a goal of less than 6.5%. Testing hemoglobin A1c levels should occur at least twice a year for patients who are meeting treatment goals and four times per year for patients not meeting goals or those who have had recent changes in therapy.5
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TABLE 407. American Diabetes Association Recommended Goals of Therapy

Area Glycemia Hemoglobin A1c Preprandial plasma glucose Peak postprandial plasma glucosea Blood Pressure Lipids Low-density lipoprotein (LDL) High-density lipoprotein (HDL) Triglycerides Monitoring for Complications Eyes Feet Urinary microalbumin
a
Goals Less than 7% Every 3 months until in goal; then every 6 months 90130 mg/dL (5.07.2 mmol/L) Less than 180 mg/dL (less than 10.0 mmol/L) Less than 130/80 mm Hg Evaluate at every visit Evaluate at least yearly Less than 100 mg/dL (2.59 mmol/L) or less than 70 mg/dL (1.81 mmol/L) if high risk Greater than 40 mg/dL (1.03 mmol/L) for males; greater than 50 mg/dL (1.29 mmol/L) for females Less than 150 mg/dL (1.70 mmol/L) Dilated eye exam yearly Feet should be examined at every visit Yearly
Peak postprandial glucose measurements should be made 1 to 2 hours after the beginning of the meal.
bolus release of insulin physiologically seen around a meal in nondiabetics. A number of different regimens have been used through the years to more closely follow natural insulin patterns. As a general rule, basal insulin makes up approximately 50% of the total daily dose. The remaining half is provided with bolus doses around three daily meals. Exact doses are individualized to the patient and the amount of food consumed. Type 1 DM patients frequently are started on about 0.6 units/kg per day, and then doses are titrated until glycemic goals are reached. Most type 1 DM patients use between 0.6 and 1 unit/kg per day. The most advanced form of insulin therapy is the insulin pump, also referred to as continuous subcutaneous insulin infusion (CSII). Using the short- or rapid-acting insulins only, these pumps are programmed to provide a slow release of small amounts of insulin as the basal portion of therapy, and then larger bolus doses are injected by the patient to account for the consumption of food.
Type 2 DM
Gestational Diabetes
Treatment of type 2 DM has changed dramatically over the past decade with the addition of a number of new drugs and the ADA recommendations to maintain tighter glycemic control. Figure 402 details the current treatment algorithm for type 2 diabetes. Lifestyle modications, including education, nutrition, and exercise, are paramount to managing the disease successfully. Many patients assume that once pharmacologic therapy is initiated, lifestyle modications are no longer necessary. Practitioners should educate patients regarding this misconception. Without lifestyle changes, DM will continue to progress, rendering glycemic control more challenging.
An individualized meal plan consisting of three meals and three snacks per day is recommended commonly in GDM. Preventing ketosis, promoting adequate growth of the fetus, maintaining satisfactory blood glucose levels, and preventing nausea and other undesired gastrointestinal side effects are desired goals in these patients. Controlling blood sugar levels is important to prevent harm to the baby. An abundance of glucose causes excessive insulin production by the fetus, which, if left uncontrolled, can lead to the development of an abnormally large fetus. Infant hypoglycemia at delivery, hyperbilirubinemia, and complications associated with delivery of a large baby also may occur when blood glucose levels are not controlled adequately. Insulin should be used when blood glucose levels are not maintained adequately at target levels by diet and physical activity. Only human insulin should be used for treating GDM to prevent the transfer of anti-insulin antibodies. Oral glucoselowering agents are not recommended during pregnancy. Additionally, women with prepregnancy hypertension and dyslipidemia should have their medications reevaluated at conception.
Nonpharmacologic Therapy
Diet
Despite the popular notion, there is not a diabetic diet. The recommended diet for patients with diabetes is a meal plan low in fat, high in ber, low to moderate in calories, and achieving a balance of the various components and nutrients needed.12 Medical nutrition therapy (MNT) is considered an
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Targets _6.57.0% (<0.51.0% A1c < above reference range) FPG/SMBG <110130 mg/dL 2-hr PPG/SMBG<140180 mg/dL
Initial intervention24
Education/nutrition/exercise5
Targets met A1c every 36 months
FPG/SMBG/PPG targets not met after 1 month Consider initial monotherapy (or early dual therapy6) Sulfonylurea and/or metformin 1,7 Other initial monotherapy options: Pioglitazone/rosiglitazone Nateglinide Repaglinide Acarbose/miglitol Insulin or insulin analog2
Targets met Continue therapy A1c every 36 months
Targets not met after 3 months Combine sulfonylurea-metformin
Other combination options: Metformin or a sulfonylurea plus pioglitazone/rosiglitazone or acarbose/miglitol Metformin plus Nateglinide or repaglinide; or insulin or insulin analog (as mono-or combination therapy)2
Targets met Continue combination therapy A1c every 36 months
Targets not met after 36 months Add bedtime intermediate-acting insulin or once-daily glargine; before supper intermediate-regular insulin or lispro/ aspart mix; add third oral agent; or switch to split dose insulin or insulin analog therapy2; consider referral to endocrinologist
1. 2. 3. 4. 5. 6. 7.
Metformin is the only FDA-approved oral diabetic agent in children (> _ age 10); other oral agents may be used at the discretion of the clinician See Insulin Algorithm for Type 2 Diabetes Mellitus in Children and Adults If initial presentation with FPG _ >260 mg/dL in a symptomatic patient, consider insulin or insulin analog as initial intervention. If initial FPG _ >210 mg/dL or A1c > _9.0%, consider dual oral agent therapy (metformin-sulfonylurea or other options) at presentation. See Medical Nutrition, Weight Loss, and Exercise Algorithms If initial dual oral therapy is initiated, decide on add-on therapy options within 36 months if glycemic targets are not met. Preferred in overweight/obese or dyslipidemic patients.
FIGURE 402 Glycemic control algorithm for type 2 DM in children abd adults. (Used, with permission, from DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiological Approach. 6th ed. New York: McGraw-Hill; 2005, Fig. 728, p. 1356.)
integral component of diabetes management and diabetes self-management education. People with DM should receive individualized MNT, preferably by a registered dietitian. As part of the diabetes management plan, MNT is not a single visit to a dietitian but rather an ongoing continuing dialog to assist the patient to integrate healthier choices into his or her daily lifestyle decisions. As such, MNT should be customized to take into account cultural, lifestyle, and nancial considerations. MNT plans should integrate a variety of foods that the patient enjoys and allow for exibility to encourage patient empowerment and improve patient adherence. During these MNT educational and planning sessions, patients receive instructions on appropriate food selection, preparation, and proper portion control. The primary focus
of MNT for patients with type 1 DM is matching optimal insulin dosing to carbohydrate consumption. In type 2 DM, the primary focus is calorie reduction to achieve weight loss. The ADA does not recommend low-carbohydrate diets in diabetes management. Although carbohydrates are a primary contributor to postmeal glucose levels, they are also an important source of energy, water-soluble vitamins, minerals, and ber. Thus the ADA recommends that carbohydrate intake consist of 45% to 65% of total calories.
Weight Management
Moderate weight loss has been shown to reduce cardiovascular risk, as well as delay or prevent the onset of DM in those with prediabetes. The recommended primary approach to
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weight loss is therapeutic lifestyle change (TLC), which integrates a 500 to 1000 kcal/d reduction in calorie intake and an increase in physical activity.12 A slow but progressive weight loss of 1 to 2 lb (0.450.91 kg) per week is preferred. While individual target caloric goals should be set, a general rule for weight-loss diets is that they should supply at least 1000 to 1200 kcal/d for women and 1200 to 1600 kcal/d for men.
Physical Activity
Patient Encounter, Part 3, Creating a Care Plan

Create a care plan for MFs DM, including Statement of drug-related needs and/or problems Goals for therapy Detailed plan with nonpharmacologic and pharmacologic therapy Plan to follow up to evaluate whether MFs goals for therapy have been achieved and adverse effects avoided
Physical activity is also an important component of a comprehensive DM management program. Regular physical activity has been shown to improve blood glucose control and reduce cardiovascular risk factors, such as hypertension and elevated serum lipid levels. Physical activity is also a primary factor associated with long-term maintenance of weight loss and overall weight control. Regular physical activity also may prevent the onset of type 2 DM in high-risk persons. Prior to initiating a physical activity program, several considerations should be made. Patients should undergo a detailed physical examination, including screening for microvascular or macrovascular complications that may be worsened by a particular activity. Initiation of physical activities in an individual with a history of a sedentary lifestyle should begin with a modest increase in activity. Walking, swimming, and cycling are examples of low-impact exercises that could be encouraged. At the same time, gardening and usual house-cleaning tasks are good exercises as well. Longterm goals are to perform at least 30 minutes of aerobic activity as many days a week as possible.13
Preventing Diabetes
Immunizations
Inuenza and pneumonia are common preventable infectious diseases that increase mortality and morbidity in persons with chronic diseases including DM.5 Yearly inuenza vaccinations, commonly called u shots, are recommended for patients with DM. Pneumococcal vaccination also is recommended for patients with DM as a one-time vaccination for most patients.
Pharmacologic Therapy
A number of therapeutic advancements and new options for managing patients with DM have become available over the past decade, including a-glucosidase inhibitors, biguanides, nonsulfonylurea secretagogues, and thiazolidinediones.15 In addition, a number of new insulin formulations have been added to our armamentarium, including rapid-acting insulins, combination mixtures, and basal insulins.16 Finally, a number of emerging therapies have been approved recently, including pramlintide, exanatide, and inhaled insulin. The following section describes the current oral agents available to treat type 2 DM. Later in this section, the insulins and other injectible medications for type 1 and type 2 DM will be addressed.17, 18
The Diabetes Prevention Program was a 3-year study that showed that lifestyle modications, including exercise (30 minutes/day, 5 days/week) and moderate (5%10%) weight loss, reduce the probability of developing DM by 58% in patients with prediabetes. Results from this study suggest that diet, exercise, and behavior modication are effective in preventing type 2 DM in high-risk patients.14
Psychological Assessment and Care
Mental health and social state have been shown to have an impact on a patients ability to carry out DM management care tasks. Approximately one in four patients with DM experience episodes of major depression. Therefore, clinicians should incorporate psychological assessment and treatment into routine care. The ADA guidelines recommend psychological screening, which includes determining the patients attitudes regarding DM, expectations of medical management and outcomes, mood and affect, general and diabetesrelated quality of life, and nancial, social, and emotional resources. Patients demonstrating noncompliance, depression, an eating disorder, and/or cognitive functioning that impairs judgment should be referred to a mental health specialist familiar with DM.5
Oral agents currently available are indicated in patients with type 2 DM who are unable to achieve glycemic control through diet and exercise. Oral agents commonly used in the management of type 2 DM typically are classied according to their mechanism of action. Insulin secretagogues include sulfonylureas and nonsulfonylurea secretagogues. These agents stimulate and enhance endogenous insulin release. Insulin sensitizers include the thiazolidinediones that decrease insulin resistance in the periphery. The biguanides decrease hepatic glucose output. Each of these agents may be used as monotherapy (Table 408) or in combination with other medications for synergistic effects.
Sulfonylureas
Sulfonylureas represent the rst class of oral antidiabetes agents approved for use in the United States. These drugs are classied as being either rst- or second-generation agents. Both classes of sulfonylureas are equally effective when given at equipotent doses. Today, the vast majority of patients receiving a sulfonylurea are prescribed a second-generation agent.
TABLE 408. Oral Agents for the Treatment of Type 2 Diabetes Mellitus
Generic Available Doses/Day Effect (h) Comments/Cautions Dosage Strengths (mg) Starting Dosage (mg/d) Titration Intervals Maximum Dose (mg)
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Generic Name
Brand
SulfonylureasFirst Generation Major adverse events: Hypoglycemia, weight gain Acetohexamide Dymelor Y 250, 500 250 250 1 35 days 500 Up to 72 12 57 days 1500 Up to 16 Y 100, 250
Chlorpropamide
Diabinese
Tolazamide Y 250, 500 10002000 23 35 days 3000 Up to 12
Tolinase
100, 250, 500
100250
12
Weekly
1000
Up to 24
Tolbutamide
Orinase
Metabolized in liver, excreted in kidneys Caution in elderly and kidney disease, disulram-like reaction with alcohol Excreted via kidney, less side effects than tolbutamide Excreted via kidney, but can be useful in kidney disease
SulfonylureasSecond Generation Major adverse event: Hypopglycemia Glipizide, slow Glucotrol, Y release Glucotrol XL N 5, 10 2.5, 5, 10, 20 1.25, 2.5, 5 5 12 Weekly 20 5 5 12 1 35 days 35 days 40 20
Up to 20 24 Up to 24
Glyburide, micronized 1.5, 3, 6 1, 2, 4 3 12 12 1 Weekly 35 days 12 8
Glimepiride
Diaeta, Micronase, Glynase Amaryl Y Y N N
Up to 24 24
Take immediate release tablets on an empty stomach; caution in elderly Metabolized in liver and excreted in kidneys and bile, caution in elderly 60% renal and 40% liver elimination, take with rst main meal
Nonsulfonylurea Secretagogues Hypoglycemia and weight gain are at a reduced risk due to short duration of action Nateglinide Starlix N 60, 120 120 3 with meals 3 with meals
Not applicable Weekly
120 per meal Up to 4
Repaglinide
Prandin
0.5, 1, 2
0.51
4 per meal; 16 daily
Up to 4
Frequency of dosing dependent on frequency of meals Frequency of dosing dependent on frequency of meals
Biguanides Major adverse events: GI symptoms, nausea, diarrhea, lactic acidosis Metformin Glucophage Y 500, 850, 1000 500 Extended release Glucophage XR N 500, 750 5001000 2 1
12 weeks Weekly
2550 2000
Up to 24 Up to 24
Renally excreted unmetabolized Discontinue if Serum Creatinine Greater than 1.4 (females) or 1.5 (males)
Thiazolidinediones Major adverse events: Edema, weight gain; discontinue use if alanine aminotranferase (ALT) greater than 3 times normal; monitor liver function tests at baseline and periodically thereafter Pioglitazone Actos N 15, 30, 45 15 1 812 weeks 45 24 Metabolism by cytochrome P-450 2C8 and 3A4 pathways, days for onset of action Rosiglitazone Avandia N 2,4, 8 24 12 812 weeks 8 mg/d or Up to 24 Metabolism by cytochrome 4 mg twice P-450 2C8 and 2C9 pathways, daily days for onset of action -Glucosidase Inhibitors Major adverse events: Gastrointestinal symptoms including atulence, cramps, and abdominal distension Acarbose Precose N 25, 50, 100 25 13 with 48 weeks 100 mg Up to 3 Eliminated in bile, take meals 3 times with rst bite of meal, little daily absorption Miglitol Glyset N 25, 50, 100 25 13 with 48 weeks 100 mg Up to 3 Eliminated through meals 3 times kidney and feces, take with rst daily bite of meal Combination Products a a a Glyburide/ Glucovance N 1.25/250 2.55/500 2 with 2 weeks metformin 2.5/500 meals a 5/500 a a Glipizide/ Metaglip N 2.5/250, 2.55/500 2 with 2 weeks metformin 2.5/500, meals 5/500 a a a a Rosiglitazone/ Avandamet N 1/500, 12/500 2 with metformin 2/500, 4/500, meals 2/1000, 4/1000 a a a a Pioglitazone/ Actosplus N 15/500, 15/500 12 metformin Met 15/850 or 15/850
Refer to information for individual products in the combination.
GI, gastrointestinal; h, hour; N, no; Y, yes
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Sulfonylureas enhance insulin secretion by blocking ATPsensitive potassium channels in the cell membranes of pancreatic cells. This action results in membrane depolarization, allowing an inux of calcium to cause the translocation of secretory granules of insulin to the cell surface, and enhances insulin secretion. The extent of insulin secretion depends on the blood glucose level. More insulin is released in response to higher blood glucose levels, whereas the additional insulin secretion from sulfonylureas is less at near-normal glucose levels. Insulin is then transported through the portal vein to the liver, suppressing hepatic glucose production.6 All sulfonylureas undergo hepatic biotransformation, with most agents being metabolized by the cytochrome P-450 2C9 pathway. First-generation sulfonylureas are more likely to cause drug interactions than second-generation agents. All sulfonylureas except tolbutamide require a dosage adjustment or are not recommended in renal impairment. In elderly patients or those with compromised renal or hepatic function, lower starting dosages are necessary. Monotherapy with sulfonylureas generally produce a 1.5% to 2% decline in hemoglobin A1c concentrations and a 60 to 70 mg/dL (3.333.89 mmol/L) reduction in FBG levels. Secondary failure with these drugs occurs at a rate of 5% to 7% per year as a result of continued pancreatic -cell destruction. One limitation of sulfonylurea therapy is the inability of these products to stimulate insulin release from cells at extremely high glucose levels, a phenomenon called glucose toxicity.
Nonsulfonylurea Secretagogues
While producing the same effect as sulfonylureas, nonsulfonylurea secretagogues, also referred to as meglitinides, have a much shorter onset and duration of action. Nonsulfonylurea secretagogues also produce a pharmacologic effect by interacting with ATP-sensitive potassium channels on the cells; however, this binding is to a receptor adjacent to those to which sulfonylureas bind. The primary benet of nonsulfonylurea secretagogues is in reducing postmeal glucose levels by about 40 mg/dL (2.22 mmol/L). These agents have demonstrated a reduction in hemoglobin A1c levels between 0.6% and 1%. Owing to the rapid onset and short duration of action of these agents, nonsulfonylurea secretagogues are to be taken within 15 minutes of a meal. They also may be used in combination therapy with other drugs to achieve synergistic effects. Combining a nonsulfonylurea secretagogue with a sulfonylurea usually improves glucose control.
Biguanides
The only biguanide approved by the Food and Drug Administration (FDA) and currently available in the United States is metformin. Metformin was approved in the United States in 1995, although it has been used extensively in Canada and Europe since 1959. This agent is thought to lower blood glucose by increasing insulin sensitivity in both hepatic and peripheral muscle tissues; however, the exact mechanism of action
remains unknown. Metformin has been shown to reduce hemoglobin A1c levels by 1.5% to 2% and FPG levels by 60 to 80 mg/dL (3.334.44 mmol/L) when used as monotherapy. The response to metformin can vary according to the starting point of the patient. Larger effects can be seen in patients with a higher initial hemoglobin A1c level (e.g., >10%) than in patients beginning therapy with a relatively lower value (e.g., <8%). It is effective in reducing fasting as well as postmeal blood glucose levels. Metformin does not affect insulin release from cells of the pancreas, so hypoglycemia is not a common side effect. While the onset of action begins within days, the maximum therapeutic effect of this agent may not been observed until after 2 weeks of therapy. Metformin also has been shown to produce benecial effects on serum lipid levels and thus has become a rst-line agent for type 2 DM patients with metabolic syndrome. Triglyceride and low-density lipoprotein (LDL) cholesterol levels often are reduced by 8% to 15%, whereas high-density lipoprotein (HDL) cholesterol improves by approximately 2%. A modest weight loss of 2 to 3 kg (4.46.6 lb) also has been reported with metformin therapy. Metformin often is used in combination with a sulfonylurea or a thiazolidinedione for synergistic effects. Metformin does not undergo signicant protein binding and is eliminated from the body unchanged in the urine. Elderly patients with a calculated creatinine clearance of less than 70 to 80 mL/min should not receive this product. It is contraindicated in patients with a serum creatinine level greater than or equal to 1.4 mg/dL (123.76 mol/L) in women and 1.5 mg/dL (132.6 mol/L) in men. Additionally, therapy with metformin should be withheld in patients undergoing radiographic procedures in which a nephrotoxic dye is used. Therapy should be withheld the day of the procedure, as well as for the following 2 to 3 days. Primary side effects associated with metformin therapy are gastrointestinal in nature, including decreased appetite, nausea, and diarrhea. These side effects can be minimized through slow titration of the dose and often subside within 2 weeks. Discontinuation because of side effects occurs in only 3% to 5% of patients. Biguanides such as metformin are thought to inhibit mitochondrial oxidation of lactic acid, thereby increasing the chance of lactic acidosis occurring. Fortunately, the incidence of lactic acidosis in clinical practice is rare. Patients at greatest risk for developing lactic acidosis include those with liver disease or heavy alcohol use, severe infection, heart failure, and shock. Thus it is common practice to evaluate liver function prior to initiation of metformin.
Thiazolidinediones
Commonly referred to as TZDs or glitazones, thiazolidinediones have established a signicant role in type 2 DM therapy. As monotherapy, both rosiglitazone and pioglitazone reduce FPG levels by 30 to 50 mg/dL (1.672.78 mmol/L), and the
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overall effect on hemoglobin A1c is a 1% to 1.5% reduction. Onset of action for thiazolidinediones is delayed for several weeks and may require up to 12 weeks before maximum effects are observed. Combining a sulfonylurea, nonsulfonylurea secretagogue, metformin, or insulin with a thiazolidinedione can improve hemoglobin A1c reductions to 2% to 2.5%. Additional effects of thiazolidinediones are seen in the lipid prole. Both pioglitazone and rosiglitazone increase HDL cholesterol by 3 to 9 mg/dL (0.080.23 mmol/L). Pioglitazone has been shown to decrease serum triglycerides by 10% to 20%, whereas no substantial effect is observed with rosiglitazone. LDL cholesterol concentrations increase by 5% to 15% with rosiglitazone, whereas no signicant increase has been reported for pioglitazone. Thiazolidinediones are known to increase insulin sensitivity by stimulating peroxisome proliferator-activated receptor gamma (PPAR-). Stimulation of PPAR- results in a number of intracellular and extracellular changes, including an increased number of insulin receptors, increased insulin receptor sensitivity, decreased plasma fatty acid levels, and an increase in a host of intracellular signaling proteins that enhance glucose uptake. Thiazolidinediones may produce uid retention and edema; however, the mechanism by which this occurs is not completely understood. It is known that blood volume increases approximately 10% with these agents, resulting in approximately 6% of patients developing edema. Thus these drugs are contraindicated in situations in which an increased uid volume is detrimental, such as heart failure. Fluid retention appears to be dose-related and increases when combined with insulin therapy. A few cases of hepatotoxicity have been reported with rosiglitazone and pioglitazone, but no serious complications have been reported, and symptoms typically reverse within several weeks of discontinuing therapy. Therefore, periodic liver function tests should performed at baseline and during thiazolidinedione therapy. Patients with a baseline alanine aminotransferase (ALT) level greater than 2.5 times the upper limit of normal should not receive a TZD. If ALT levels rise to greater than 3 times the upper limit of normal in patients receiving a TZD, the medication should be discontinued.
-Glucosidase Inhibitors
Patient Encounter, Part 4, Oral to Insulin Therapy

Several years have past since you have been following MFs therapy. He has lost weight down to 230 lb (104.55 kg), and he tries to maintain his diet and exercise. His recent hemoglobin A1c levels have increased up to 8.4% from 7.2% despite combination therapy with sulfonylureas and metformin. The physician believes that it is time to start insulin therapy for MF and asks you to initiate therapy and follow his regimen. What insulin therapy would you choose for MF? How would you transition MF to insulin?
-Glucosidase is an enzyme along the brush border of intestinal cells that breaks down complex carbohydrates into simple sugars, resulting in absorption. -Glucosidase inhibitors work by delaying the absorption of carbohydrates from the intestinal tract, which reduces the rise in postprandial blood glucose concentrations. Gastrointestinal side effects occur as the result of intestinal bacteria in the distal gut metabolizing undigested carbohydrates and producing carbon dioxide and methane gas. -Glucosidase inhibitors are contraindicated in patients with short-bowel syndrome or inammatory bowel disease. In addition, neither drug in this class is recommended for patients with a creatinine clearance of less than 25 mL/min.
Insulins
Acarbose and miglitol are -glucosidase inhibitors currently approved in the United States. As monotherapy, -glucosidase inhibitors reduce FPG concentrations by between 40 and 50 mg/dL (2.222.78 mmol/L); however, hemoglobin A1c reductions range only from 0.3% to 1%. While these agents have been popular in Europe and other parts of the world, they have failed to gain widespread use in the United States. High incidences of gastrointestinal side effects, including atulence (41.5%), abdominal discomfort (11.7%), and diarrhea (28.7%), have limited their use. Low initial doses followed by gradual titration may minimize gastrointestinal side effects.
Insulin is the one agent that can be used in all forms of DM for blood sugar control. Insulin is the essential treatment for patients with type 1 DM and can overcome insulin resistance in patients with type 2 DM. Insulin is available commercially in various formulations that vary markedly in terms of onset and duration of action and the source from which a product is obtained. Insulins can be divided into four separate classes based on their length of action. Most formulations are available as U-100, indicating a concentration of 100 units/mL. Insulin is typically refrigerated, and most vials are good for 28 days at room temperature. Specic details of insulin products are listed in Table 409. The most common route of administration for insulin is subcutaneous injection using a syringe or pen device. Insulin syringes are distinguished according to the syringe capacity, syringe markings, and needle gauge and length. The most common insulin syringe capacities are 30, 50, and 100 units. The 30- and 50-unit syringes are marked at 1-unit increments, whereas the 100-unit syringe is marked at 2-unit intervals. Syringe needles range from 28 to 31 gauge and 5/16to 1/2-in length. The insulin pens are self-contained systems of insulin delivery. The primary advantage of the pen system is that the patient does not have to draw up the dose from the insulin vial.
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TABLE 409. Insulins Agents for the Treatment of Type 1 and Type 2 Diabetes Mellitus
Brand Humalog Novolog Apidra Aventis U-100 1530 12 34 Novo-Nordisk U-100 1530 13 35 Lilly U-100 1530 0.52.5 34 Manufacturer Strength Onset (minutes) Peak (hours) Duration (hours) Administration Options
Generic Name (Insulin)
Rapid-Acting Insulin Lispro
Aspart
Glulisine
10-mL vial, 3-mL cartridge and disposable pen 10-mL vial, 3-mL cartridge and disposable pen 10-mL vial, 3-mL cartridge and disposable pen
Short-Acting Insulin Regular Humulin R Novolin R Humulin N Novolin N Lantus Levmir Aventis Novo-Nordisk U-100 U-100 45 hours 34 hours Flat Flat Lilly Novo-Nordisk U-100 U-100 24 hours 46 812 Novo-Nordisk Lilly U-100, U-500 U-100 3060 23 36
U-100 10-mL vial; U-500 20-mL vial 10-mL vial, 3-mL cartridge, 3-mL Innolet 10-mL vial, 3-mL cartridge 10-mL vial, 3-mL cartridge, 3-mL InnoLet
Intermediate-Acting Insulin Neutral protamine hagadorn Long-Acting Insulin Glargine Detemir
2224 Up to 24
10-mL vial, 3-mL cartridge for Opticlik 10-mL vial, 3-mL cartridge, 3-mL Innolet, 3-mL disposable FlexPen 1016 10-mL vial, 3-mL disposable pen
Combination Insulin Products Neutral protamine hagedorn and regular Eli Lilly Novo Nordisk Eli Lilly Lilly Novo Nordisk U-100 1530 U-100 U-100 U-100 3060 3060 1530 U-100 3060
1.516 212 25.5 16.5 14
1016 1016 1518 Up to 24
Humulin 70/30 Novolin 70/30 Humulin 50/50 Humalog Mix 75/25 Novolog Mix 70/30 Exubera Pzer 1 mg = ~3 units injectible insulin 1020
10-mL vial, 3-mL cartridge, 3-mL Innolet 10-mL vial 10-mL vial, 3-mL disposable pen 10-mL vial, 3-mL cartridge, 3-mL disposable FlexPen 0.51.5 6 1-mg, 3-mg blister packs
Neutral protamine lispro and lispro Neutral protamine aspart and aspart Oral Inhalation Insulin Recombinant human insulin
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Regular Insulin
Regular insulin is unmodied crystalline insulin commonly referred to as natural insulin. It is a clear solution that has a relatively rapid onset and short duration of action. On subcutaneous injection, regular insulin forms small aggregates called hexamers that undergo conversion to dimers followed by monomers before systemic absorption can occur. Therefore, patients should be counseled to inject regular insulin subcutaneously 30 minutes prior to consuming a meal. Regular insulin is the only insulin that can be administered intravenously.
Rapid-Acting Insulin
Novolog Mix 70/30 contains 70% insulin aspart protamine suspension and 30% insulin aspart. The lispro and aspart insulin protamine suspensions were developed specically for these mixture products and will not be commercially available separately.
Oral Inhalation Insulin
Three rapid-acting insulins have been approved in the United States: lispro, aspart, and glulisine. Substitution of one or two amino acids in regular insulin results in the unique pharmacokinetic properties characteristic of these agents. Onset of action of rapid-acting insulins varies from 15 to 30 minutes, with peak effects occurring 1 to 2 hours following administration.
Intermediate-Duration Insulin
The rst inhaled insulin product was approved in early 2006. Exubera, recombinant human insulin, is an alternative to mealtime injectible insulin. It has an onset of action of between 10 to 20 minutes, which is similar to rapid-acting insulin, and a duration of action of around 6 hours, which is similar to regular insulin. Inhaled insulin will not totally replace injectible insulin because long-acting insulin injections are necessary for basal control. This product is available in 1- and 3-mg blister packs, which are equivalent to about 3 to 8 units of injectible insulin. Some patients may need multiple inhalations to attain their mealtime dose. Exubra is not recommended for patients with chronic lung disease such as asthma or chronic obstructive pulmonary disease or patients who smoke.
Insulin Pump Therapy
Neutral Protamine Hagedorn, better known as NPH insulin, is prepared by a process in which protamine is conjugated with regular insulin, rendering a product with a delayed onset but extended duration of action. With the advent of the long-acting insulins, NPH insulin use has declined owing to an inability to predict accurately when peak effects occur and a duration of action of less than 24 hours. Additionally, protamine is a foreign protein that may increase the possibility of an allergic reaction. NPH insulin can be mixed with regular insulin and used immediately or stored for future use up to 1 month at room temperature or 3 months in refrigeration. NPH insulin can be mixed with either aspart or lispro insulins, but it must be injected immediately after mixing. Whenever mixing insulin products with NPH insulin, the shorter-acting insulin should be drawn into the syringe rst.
Long-Duration Insulin
Two long-duration insulin preparations are approved for use in the United States. Glargine and detemir are designed as once-daily-dosing basal insulins. Insulin glargine differs from regular insulin by three amino acids, resulting in a low solubility at physiologic pH. The clear solution is supplied at a pH of 4, which precipitates on subcutaneous administration. Given this property, glargine cannot be administered intravenously or mixed with other insulin products. Both glargine and detemir do not produce peak serum concentrations and can be administered irrespective of meals or time of day.
Combination Insulin Products
A number of combination insulin products are available commercially. NPH is available in combinations of 70/30 and 50/50 with regular insulin. Two short-acting insulin analog mixtures are also available. Humalog Mix 75/25 contains 75% insulin lispro protamine suspension and 25% insulin lispro.
Insulin pump therapy consists of a programmable infusion device that allows for basal infusion of insulin 24 hours daily, as well as bolus administration following meals. As seen in Fig. 403, an insulin pump consists of a programmable infusion device with an insulin reservoir. This pump is attached to an infusion set with a small needle that is inserted in subcutaneous tissue in the patients abdomen, thigh, or arm. Most patients prefer insertion in abdominal tissue because this site provides optimal insulin absorption. Patients should avoid insertion sites along belt lines or in other areas where clothing may cause undue irritation. Infusion sets should be changed every 2 to 3 days to reduce the possibility of infection. Patients use a carbohydrate-to-insulin ratio to determine how many units of insulin are required. To determine an individuals ratio, the 450 rule is used for patients using regular insulin, whereas the 500 rule is used for lispro or aspart pump users. To calculate the ratio using the 500 rule, the patient would divide 500 by his or her total daily dose of insulin. For example, if a patient were using 25 units of insulin daily, his or her carbohydrate-to-insulin ratio would be 500:25, or 20:1. This ratio theoretically means that 1 unit of lispro or aspart insulin should cover 20 g of carbohydrate. If blood sugar levels are below or above the desired blood glucose target, the amount of insulin can be adjusted. Once this ratio is determined, patients can eat more or fewer carbohydrates at a given meal and adjust the bolus dose accordingly. Insulin pump therapy may be used to lower blood glucose levels in any type of DM; however, patients with type 1 DM are the most likely candidates for this form of treatment. Use of an insulin pump may improve blood glucose control, reduce wide uctuations in blood glucose levels, and allow individuals to have more exibility in timing and content of
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FPO
FIGURE 403 Insulin pump.
meals and exercise schedules. Nonetheless, insulin pump therapy is not for everyone. The complexity associated with its use, cost, increased need for blood glucose monitoring, and psychological factors may prevent individuals from using this technology optimally.
Incretin Mimetics
Incretin mimetics are agents with biologic activities similar to incretin hormones but have longer durations of action. Incretin hormones are substances produced by the gastrointestinal tract in response to food that act to stimulate insulin secretion. Obese, insulin-resistant type 2 diabetics have lower levels of incretin hormones. Exanatide is the rst incretin mimetic approved by the FDA and is indicated as adjunct therapy in type 2 DM in which adequate blood glucose control has not been achieved with sulfonylureas, metformin, or both (Table 4010). Hemoglobin A1c reductions ranging from 0.5% to 1% have been observed with this agent, whereas FPG concentrations decrease by 8 to 10 mg/dL (0.440.56 mmol/L). Postprandial glucose values decline by 60 to 70 mg/dL (3.333.89 mmol/L). Exanatide lowers blood glucose levels by producing glucosedependent insulin secretion; reducing postmeal glucagon secretion, which decreases postmeal glucose output; increasing satiety, which decreases food intake; and regulating gastric emptying, which allows nutrients to be absorbed into the circulation more smoothly. Serum levels peak approximately 2 hours after subcutaneous administration. Exanatide
is eliminated renally and is not recommended in patients with a creatinine clearance of less than 30 mL/min. An increased risk of hypoglycemia occurs when exanatide is used in combination with a sulfonylurea; however, this is not encountered in exanatide monotherapy or in conjunction with metformin and/or thiazolidinedione therapy. Side effects include nausea (44%), vomiting (13%), and diarrhea (13%). No major drug interactions have been found with exanatide. The extent and rate of absorption of orally administered drugs may be affected with concomitant use of exanatide; however, no clinical signicance has been established to date. Exanatide is available in 5- and 10-mcg injectible prelled disposable pens. Initial therapy is 5 mcg twice daily, injected before the two largest meals of the day. Meals should be separated by at least 5 to 6 hours. Doses then are increased after a month to 10 mcg if the patients blood glucose is improving and nausea is limited. Exanatide can be given up to 60 minutes before a meal, but practical use indicates that injection just before a meal may decrease nausea. An average weight loss of 3 to 5 pounds (1.362.27 kg) commonly occurs with the 5-mcg dose, whereas a weight loss of 5 to 10 pounds (2.274.55 kg) is observed with the 10-mcg dose.
Amylin
Pramlintide acetate was approved for use in the United States in March 2005 (see Table 40-10). This agent is a synthetic analog of human amylin, which is a naturally occurring
661
TABLE 4010. Noninsulin Injectible Agents for the Treatment of Diabetes Mellitus
Generic Name (Brand) Pramlintidea (Symlin) Type of Diabetes Mellitus 1 Dosage Strengths (mcg)b,c 15, 30, 45, 60 60, 120 Starting Dosage 15 Titration Interval 37 days Maximum Dose (mcg) 60 Time to Effect (min) 20
Doses/Day 3
Comments/Cautions Take just before major meals; reduce insulin by 50% Maintenance dose 3060 mcg Side effects: Hypoglycemia, nausea, vomiting May delay oral drug absorption Take just before morning and evening meal; prelled disposable pen; may delay absorption of oral drugs; separate doses by 1 hour Side effects: Nausea, vomiting, diarrhea, increased hypoglycemia with sulfonylureas
60
37 days
120
20
Exanatidea (Byetta)
5, 10
1 month
10
1530
Generic not available in United States. Pramlintide supplied as 0.6 mg/mL in 5-mL vials. c Exanatide supplied as 250 mcg/mL, 1.2 mL for the 5-mcg prelled pen and 2.4 mL for the 10-mcg per dose prelled pen.
b
neuroendocrine peptide that is cosecreted by the cells of the pancreas in response to food. Amylin secretion is completely or relatively decient in patients with diabetes. Pramlintide is given by subcutaneous injection before meals to lower postprandial blood glucose elevations. However, unlike insulin, it does not cause weight gain. Use of pramlintide actually results in an average weight loss of 2.2 to 4.4 lb (12 kg). Pramlintide is indicated as combination therapy with insulin in patients with type 1 or 2 DM. It has been shown to decrease hemoglobin A1c by an additional 0.4% to 0.5%. Pramlintide slows gastric emptying without altering absorption of nutrients, suppresses glucagon secretion, and leads to a reduction in food intake by increasing satiety. By slowing gastric emptying, the normal initial postmeal spike in blood glucose is reduced. Hypoglycemia, nausea, and vomiting are the most common side effects encountered with pramlintide therapy, although pramlintide itself does not produce hypoglycemia. To decrease the risk of hypoglycemia, doses of short-acting, rapid-acting, or premixed insulins should be reduced by 50% before pramlintide is initiated. Pramlintide is metabolized primarily by the kidneys, but dosage adjustments in liver or kidney impairment are not required. Pramlintide has the potential to delay the absorption of orally administered medications. When rapid absorption is needed for efcacy of an agent, pramlintide should be administered 2 hours before or 1 hour after this drug. Pramlintide should not be used in patients receiving medications that alter gastrointestinal motility, such as anticholinergic agents, or drugs that slow the absorption of nutrients, such as -glucosidase inhibitors.
Treatment of Concomitant Conditions

Coronary Heart Disease
Nearly two-thirds of patients with DM will die of coronary heart disease. Interventions targeting smoking cessation, glycemic control, blood pressure control, lipid management, antiplatelet therapy, and lifestyle changes, including diet and exercise, can reduce the risk of cardiovascular events. Patients with diabetes should receive at least an aspirin daily unless contraindicated. Refer to appropriate chapters in the text concerning coronary heart disease.
Hyperlipidemia
The National Cholesterol Education Program Adult Treatment Panel III guidelines classify the presence of DM to be of the same risk equivalence as coronary heart disease. The primary target for lipid-lowering treatment of the LDL cholesterol is less than 100 mg/dL (2.59 mmol/L). For patients at high cardiovascular risk, the LDL target is 70 mg/dL (1.81 mmol/L). Treatment with an HMG-CoA reductase inhibitor, commonly called a statin, often is required to achieve these goals. After LDL cholesterol goals are reached, triglyceride and HDL goals also should be achieved. Treatments including niacin or brate therapy may be used to reach these secondary goals. However, caution should be used with statin-brate combination therapy because a higher risk of adverse events has been reported (see Chap. 9).
Hypertension
Uncontrolled blood pressure plays a major role in the development of macrovascular events and nephropathy in patients
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with DM. The ADA recommends that blood pressure goals for patients with DM be less than 130/80 mm Hg. In addition, there are several general principles regarding the treatment of hypertension in diabetes patients. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and calcium channel blockers are recommended as initial therapy because of their benecial effects on renal function. Low-dose thiazide diuretics also can be used as either rst- or second-line therapy. The most common use of thiazide diuretics for patients with DM is in synergistic combination with other agents. -Blockers also can be used as either rstor second-line therapies. While -blockers may mask the symptoms of hypoglycemia, it is generally believed that the benet of -blockers outweighs the low risk of hypoglycemia in the patient with type 2 DM. In order to achieve blood pressure goals, most patients require combination therapy with two or three antihypertensive agents (see Chap. 9).
Diabetic Ketoacidosis
Treatment of Acute Complications

Hypoglycemia
Hypoglycemia, or low blood sugar, can be dened clinically as a blood glucose level of less than 50 mg/dL (2.28 mmol/L). Individuals with DM can experience symptoms of hypoglycemia at varying blood glucose levels. Patients who have regular blood glucose levels as high as 300 to 400 mg/dL (16.6522.2 mmol/L) may experience symptoms of hypoglycemia once blood glucose levels are lowered to the middle to upper 100 mg/dL (5.55 mmol/L) range. Most people whose blood glucose levels are controlled adequately may experience symptoms when levels fall below 70 mg/dL (3.89 mmol/L). Symptoms of hypoglycemia include shakiness, sweating, fatigue, hunger, headaches, and confusion. Common causes of hypoglycemia include delayed or inadequate amounts of food intake, especially carbohydrates, excessive doses of medications (i.e., sulfonylureas and insulin), exercising when insulin doses are reaching peak effect, or inadequately adjusted drug therapy in renally or hepatically impaired patients. Patients experiencing symptoms of hypoglycemia should check their blood glucose level, consume 15 g of carbohydrate, and wait 10 to 15 minutes for symptom resolution. Examples of acceptable treatments may include a small box of raisins, 4 oz (118.28 mL) of orange juice, 8 oz (236.56 mL) of skim milk, or three to six glucose tablets. In patients receiving an -glucosidase inhibitor in combination with a sulfonylurea or insulin, hypoglycemia should be treated with glucose tablets or skim milk owing to the mechanism of action of the -glucosidase inhibitors. If the blood glucose level has dropped below 50 mg/dL (2.78 mmol/L), as much as 30 g of carbohydrate may be necessary to raise blood glucose levels adequately. For patients with hypoglycemia experiencing a loss of consciousness, a glucagon emergency kit should be administered by intramuscular or subcutaneous route, and emergency medical personnel should be contacted. The patient should be rolled onto his or her side to prevent aspiration because the majority of patients receiving the glucagon injection will vomit.
Diabetic ketoacidosis (DKA) is a reversible but potentially lifethreatening medical emergency that results from a relative or absolute deciency in insulin. Without insulin, the body cannot use glucose as an energy source and must obtain energy via lipolysis. This process produces ketones and leads to acidosis. While DKA occurs frequently in young patients with type 1 DM on initial presentation, it can occur in adults as well as with patients who have type 2 DM. Often precipitating factors such as infection or errors in administration of insulin or oral diabetes medications can cause DKA. Signs and symptoms develop rapidly over a few hours and commonly include fruity or acetone breath, nausea, vomiting, dehydration, polydipsia, polyuria, and deep, rapid breathing. Nonspecic symptoms include lethargy, headache, and weakness. Hallmark diagnostic criteria for DKA include hyperglycemia (>250 mg/dL, 13.9 mmol/L), ketosis (anion gap > 10), and acidosis (arterial pH 7.25). Typical uid decit is 6 L or more, with major decits of serum sodium and potassium common. The severity of DKA depends on the magnitude of the decrease in arterial pH, serum bicarbonate levels, and the mental state rather than the magnitude of the hyperglycemia. Treatment goals of DKA consist of reversing the underlying metabolic abnormalities, rehydrating the patient, and normalizing the serum glucose. Fluid replacement with normal saline at 1 L/h is recommended to rehydrate the patient and to ensure that the kidneys are perfused. Potassium and other electrolytes are supplemented as indicated by laboratory assessment. The use of sodium bicarbonate in DKA is controversial and generally is not recommended when the pH is greater than or equal to 7.1. Regular insulin at 0.1 to 0.2 unit/kg per hour by continuous intravenous infusion is the preferred treatment in DKA to regain metabolic control rapidly. Once plasma glucose values drop below 250 mg/dL, the insulin infusion may be decreased, and dextrose 5% to 10% can be added to the intravenous uids. During the recovery period, it is recommended to continue administering insulin and to allow patients to eat as soon as possible. Dietary carbohydrates combined with insulin assist in the clearance of ketones. Resolution of DKA is indicated by a blood glucose level of less than 200 mg/dL, a bicarbonate level of greater than or equal to 10 mEq/L, and a venous pH of greater than 7.3. See Table 4011 for the management of DKA.19
Hyperosmolar Hyperglycemic State
Hyperosmolar hyperglycemic state (HHS) is a life-threatening condition similar to DKA that also arises from inadequate insulin, but HHS occurs primarily in older patients with type 2 DM. DKA and HHS also differ in that HHS lacks the lipolysis, ketonemia, and acidosis associated with DKA. Patients with hyperglycemia and dehydration lasting several days to weeks are at the greatest risk of developing HHS. Illness and infection are common precipitating causes of HHS. Two main diagnostic criteria for HHS are a plasma glucose value of greater than 600 mg/dL (33.3 mmol/L) and a serum osmolality of greater
663
TABLE 4011. Management of Diabetic Ketoacidosis

1. Conrm diagnosis ( plasma glucose, positive serum ketones, metabolic acidosis). 2. Admit to hospital; intensive-care setting may be necessary for frequent monitoring or if pH < 7.00 or unconscious. 3. Assess: Serum electrolytes (K+, Na+, Mg2+, Cl, bicarbonate, phosphate) Acid-base statuspH, HCO3, PCO2, b-hydroxybutyrate Renal function (creatinine, urine output) 4. Replace uids: 23 L of 0.9% saline over rst 13 h (510 mL/kg per hour); subsequently, 0.45% saline at 150300 mL/h; change to 5% glucose and 0.45% saline at 100200 mL/h when plasma glucose reaches 250 mg/dL (14 mmol/L). 5. Administer regular insulin: IV (0.1 units/kg) or IM (0.4 units/kg), then 0.1 units/kg per hour by continuous IV infusion; increase 2- to 10-fold if no response by 24 h. If initial serum potassium is <3.3 mmol/L (3.3 mEq/L), do not administer insulin until the potassium is corrected to >3.3 mmol/L (3.3 meq/L). 6. Assess patient: What precipitated the episode (noncompliance, infection, trauma, infarction, cocaine)? Initiate appropriate work-up for precipitating event (cultures, CXR, ECG). 7. Measure capillary glucose every 12 h; measure electrolytes (especially K+, bicarbonate, phosphate) and anion gap every 4 h for rst 24 h. 8. Monitor blood pressure, pulse, respirations, mental status, and uid intake and output every 14 h. 9. Replace K+: 10 mEq/h when plasma K+ <5.5 mEq/L, ECG normal, urine ow and normal creatinine documented; administer 4080 mEq/h when plasma K+ <3.5 mEq/L or if bicarbonate is given. 10. Continue above until patient is stable, glucose goal is 150250 mg/dL, and acidosis is resolved. Insulin infusion may be decreased to 0.050.1 units/kg per hour. 11. Administer intermediate or long-acting insulin as soon as patient is eating. Allow for overlap in insulin infusion and subcutaneous insulin injection.
Note: CXR, chest x-ray; ECG, electrocardiogram; IM, intramuscularly; IV, intravenous. Source: Adapted from M Sperling, in Therapy for Diabetes Mellitus and Related Disorders, American Diabetes Association, Alexandria, VA, 1998; and AE Kitabchi et al: Diabetes Care 24:131, 2001.
retinopathy often causes no visual disturbances and may remain asymptomatic for years. Proliferative retinopathy occurs when new retinal vessels form as a result of retinal ischemia in a process called neovascularization. Vision loss from proliferative retinopathy may range from mild blurring, to obstruction of vision, to complete blindness. Blurred vision is the presenting symptom for many patients who are diagnosed with diabetes. The ADA recommends that patients with DM receive a dilated eye examination annually by an ophthalmologist or optometrist. Glycemic control is the best prevention for slowing the progression of retinopathy. Early retinopathy may be reversed with improved glucose control.
Neuropathy
Peripheral neuropathy is the most common complication reported in type 2 DM. This complication generally presents as pain, tingling, or numbness in the extremities. The feet are affected more often than the hands and ngers. A number of treatment options have been tried with mixed success. Current options include pregabalin, gabapentin, low-dose tricyclic antidepressants, duloxetine, venlafaxine, topiramate, nonsteroidal anti-inammatory drugs, and topical capsaicin. Autonomic neuropathy is also a common complication as DM progresses. Clinical presentation of autonomic neuropathy may include gastroparesis, resting tachycardia, orthostatic hypotension, impotence, constipation, and hypoglycemic autonomic failure. Therapy for each individual autonomic complication is addressed separately.
Microalbuminuria and Nephropathy
than 320 mOsm/kg. The extreme hyperglycemia and large uid decits resulting from osmotic diuresis are major challenges to overcome with this condition. Similar to DKA, the treatment of HHS consists of aggressive rehydration, correction of electrolyte imbalances, and continuous insulin infusion to normalize serum glucose. However, in patients with HHS, blood glucose levels should be reduced gradually to minimize the risk of cerebral edema.
Treatment of Long-Term Complications

Retinopathy
Diabetic retinopathy occurs when the microvasculature that supplies blood to the retina becomes damaged. This damage permits leakage of blood components through the vessel walls. Diabetic retinopathy is the leading cause of blindness in adults aged 20 to 74 years in the United States. Retinopathy is staged as either nonproliferative or proliferative. Nonproliferative
DM is the leading contributor to end-stage renal disease. Early evidence of nephropathy is the presence of albumin in the urine. Therefore, as the disease progresses, larger amounts of protein spill into the urine. The ADA recommends urine protein tests annually in type 2 DM patients. For children with type 1 DM, annual urine protein testing should begin with the onset of puberty or 5 years after the diagnosis of diabetes. The most common form of screening for protein in the urine is a random spot collection for measurement of the urine albumin:creatinine ratio. The desirable value is less than 30 mcg of albumin per milligram of creatinine. Microalbuminuria is dened as between 30 and 300 mcg of albumin per milligram of creatinine. The presence of microalbuminuria is a strong risk factor for future kidney disease in type 1 DM patients. In type 2 DM patients, microalbuminuria has been found to be a strong risk factor for macrovascular disease. Glycemic control and blood pressure control are primary measures for the prevention of progression of nephropathy. ACE inhibitors and angiotensin II receptor blockers prevent the progression of renal disease in type 2 DM patients. Treatment of advanced nephropathy includes dialysis and kidney transplantation.
Foot Ulcers
Lower extremity amputations are one of the most feared and disabling sequelae of long-term uncontrolled DM. A foot
664
ulcer is an open sore that develops and penetrates to the subcutaneous tissues. Complications of the feet develop primarily as a result of peripheral vascular disease, neuropathies, and foot deformations. Peripheral vascular disease causes ischemia to the lower limbs. This decreased blood ow deprives the tissues of oxygen and nutrients and impairs the ability of the immune system to function adequately. Symptoms of peripheral vascular disease include intermittent claudication, cold feet, pain at rest, and loss of hair on the feet and toes. Smoking cessation is the single most important treatment for peripheral vascular disease. In addition, exercising by walking to the point of pain and then resting and resuming can be a vital therapy to maintain or improve the symptoms of peripheral vascular disease. Pharmacologic intervention with pentoxifylline or cilostazol also may be useful to improve blood ow and reduce the symptoms of peripheral vascular disease. Neuropathies play a large part in the development of foot ulcers. Loss of sensation in the feet allows trauma to go unnoticed. Autonomic neuropathy can cause changes in the blood ow, perspiration, skin hydration, and possibly bone composition of the foot. Motor neuropathy can lead to muscle atrophy, resulting in weakness and changes in the shape of the foot. To prevent foot complications, the ADA recommends daily visual examination of the feet and a foot check performed at every physician visit. Sensory testing with a 10-gauge monolament can detect areas of neuropathy. Treatment consists of glycemic control, preventing infection, dbriding dead tissues, applying dressings, treating edema, and limiting ambulation. Untreated foot problems may develop gangrene, necessitating surgical intervention.
Patient Care and Monitoring

1. Assess the patient for development or progression of DM and DM-related complications. 2. Evaluate SMBG for glycemic control, including FPG and postprandial levels. Are the blood glucose values too high or low? Are there specic times of day or specic days not in control? Is hypoglycemia occurring? 3. Assess the patient for changes in quality-of-life measures, such as physical, psychological, and social functioning and well-being. 4. Perform a thorough medication history of prescription, over-the-counter, and herbal product use. Are there any medication problems, including presence of adverse drug reactions, drug allergies, and drug interactions? Is the patient taking any medications that may affect blood glucose control? 5. Review all available laboratory data (some settings may have only patient-reported values) for attainment of ADA goals (see Table 407). What therapy goals are not being met, and what tests or referrals to other members of the health care team are needed? 6. Recommend appropriate therapy, and develop a plan to assess effectiveness. 7. Stress adherence to prescribed lifestyle and medication regimen. 8. Provide patient education on diabetes, lifestyle modications, appropriate monitoring, and drug therapy: What causes DM complications and how de we prevent them? How lifestyle changes including diet and exercise can affect diabetes. How to perform SMBG and what to do with the results. When to take medications and what to expect. What adverse effects may occur? What warning sign should be reported to their physician?
Special Situations
Hospitalized Care
Aggressive treatment of hyperglycemia in hospitalized patients can prevent unnecessary cost to patients and health care systems. When patients are either physically or emotionally stressed, counterregulatory hormones are released, increasing blood glucose levels. Insulin drip therapy for patients with blood glucose levels greater than 140 mg/dL (7.77 mmol/L) is considered superior to sliding-scale insulin. Sliding-scale insulin therapy typically lags the blood glucose level instead of proactively addressing the increased blood glucose levels. Blood glucose levels can be measured by several methods. Arterial samples are usually 5 mg/dL (0.28 mmol/L) higher than capillary values and 10 mg/dL (0.56 mmol/L) greater than venous values. When preparing an insulin infusion for a patient, several factors must be considered. Insulin will adsorb to glass and plastic, reducing the amount of insulin actually delivered by 20% to 30%. Priming the tubing will decrease variability of insulin infused. Therefore, when patients can be converted safely from infusion to needle and syringe therapy, the total daily dose should be reduced by 20% to 50% of the daily infusion amount.
Sick Days
Patients should monitor their blood glucose levels more closely during sick days because it is common for illness to increase values. Additional insulin coverage may be necessary to prevent DKA. Patients should monitor for the presence of urine ketones by a urine dipstick test that changes color in the presence of ketones. Sugar and electrolyte solutions such as sports drinks may be used by type 1 DM patients to prevent dehydration, electrolyte depletion, and hypoglycemia. However, patients with type 2 DM may require sugar-free products if blood glucose levels are
665
elevated consistently. With proper management, patients can decrease their chance of illness-induced hospitalization.
Outcome Evaluation
The success of therapy for DM is measured by the ability of
the patient to manage his or her disease appropriately between health care provider visits. Appropriate therapy necessitates adequate patient education about the disease, development of a meal plan to which patients can comply, and integration of a regular exercise program. Patient care plans should include a number of daily evaluations to be performed by the patient, such as examination of the feet for any sores, cuts, or abrasions; checking the skin for dryness to prevent cracking and chafng; and monitoring blood glucose values as directed. Weekly appraisals of weight and blood pressure are also advised. Until hemoglobin A1c levels are at goal, quarterly visits with the patients primary health care provider are recommended. Table 407 summarizes the specic ADA goals for therapy. The practitioner should review SMBG data and a current hemoglobin A1c level for progress and address any therapeutic or educational issues. At minimum, yearly laboratory evaluation of serum lipids, urinary microalbumin, and serum creatinine should be performed. If the patient is on a thiazolidinedione, liver function tests should be performed at least once a year.
LADA: LDL: MNT: NPH: OGTT: PPAR-: PPG: SGOT: SGPT: SMBG: TLC: TSH: TZDs:
latent autoimmune diabetes in adults low-density lipoprotein cholesterol medical nutrition therapy neutral protamine Hagedorn oral glucose tolerance test peroxisome proliferator activator receptor gamma postprandial glucose serum glutamic oxolacetic transaminase serum glutamic pyruvic transaminase self-monitoring of blood glucose therapeutic lifestyle change thyroid-stimulating hormone thiazolidinediones
Reference lists and self-assessment questions and answers are available at <insert web address here>.
KEY REFERENCES AND READINGS

American Association of Clinical Endocrinologists. Medical guidelines for the management of diabetes mellitus: The AACE system of intensive diabetes self-management2002 update. Endocr Pract 2002; 8(suppl 1):4082. American Diabetes Association. Diabetes Facts and Figures. Available at: www.diabetes.org/diabetes-statistics.jsp; accessed March 28, 2006. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2006; 29(suppl 1):S4S42. Centers for Disease Control and Prevention. Overweight and Obesity Trends. CDC. Available at: www.cdc.gov/nccdphp/dnpa/obesity/index.htm; accessed March 28, 2006. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: Scientic review. JAMA 2003; 289:22542264. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl J Med 1993; 329:977986. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:24862497. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: Scientic review. JAMA 2002; 287:360372. Triplett CL, Reasner CA, Isley WL. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiological Approach. 6th ed. New York: McGraw-Hill;2005. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837853.
ABBREVIATIONS
A1c: AACE: ACE: ADA: ALT: AST: BMI: BP: BUN: CSII: DKA: DM: FPG: GDM: HDL: HHS: HLA: IFG: IG: hemoglobin A1c American Association of Clinical Endocrinologists angiotensin-converting enzyme inhibitors American Diabetes Association alanine aminotransferase aspartate aminotransferase body mass index blood pressure blood urea nitrogen continuous subcutaneous insulin infusion diabetic ketoacidosis diabetes mellitus fasting plasma glucose gestational diabetes mellitus high-density lipoprotein cholesterol hyperosmolar hyperglycemic state human leukocyte antigen impaired fasting glucose Timpaired glucose tolerance

Iabetes Ellitus: Section 7. Endocrinologic Disorders

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Iabetes Ellitus: Section 7. Endocrinologic Disorders

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Section 7.

KEY CONCEPTS Diabetes mellitus (DM) describes a group of

Several classes of oral agents are available to treat patients with

SECTION 7 / ENDOCRINOLOGIC DISORDERS

Risk factors for type 2 diabetes include

EPIDEMIOLOGY AND ETIOLOGY

Asian American, African American, and Pacic Islanders)

cose tolerance or impaired fasting glucose)

CHAPTER 40 / DIABETES MELLITUS

TABLE 401. Medications That May Affect Glycemic Controla

Type 1 Diabetes PATHOPHYSIOLOGY Normal Carbohydrate Metabolism

SECTION 7 / ENDOCRINOLOGIC DISORDERS

TABLE 402. Five Components of the Metabolic Syndrome

CHAPTER 40 / DIABETES MELLITUS

Patient Encounter, Part 1

CLINICAL PRESENTATION AND DIAGNOSIS Screening

Typical Clinical Presentation of Diabetes Mellitus

Uncommon Rare Common

SECTION 7 / ENDOCRINOLOGIC DISORDERS

CHAPTER 40 / DIABETES MELLITUS

TABLE 405. Criteria for the Diagnosis of Diabetes Mellitus

TREATMENT Goals of Therapy

Less than 100 100125 Greater than or equal to 126

Less than 5.6 5.66.9 7.0

Less than 140 140199 Greater than or equal to 200

7.8 7.811.1 11.1

Provisional diagnosis of diabetes (diagnosis must be conrmed; see Table 405).

SECTION 7 / ENDOCRINOLOGIC DISORDERS

Blood Pressure, Lipids, and Monitoring for Complications

General Approach to Therapy

Patient Encounter, Part 2, The Followup Visit

CHAPTER 40 / DIABETES MELLITUS

TABLE 407. American Diabetes Association Recommended Goals of Therapy

SECTION 7 / ENDOCRINOLOGIC DISORDERS

Targets met A1c every 36 months

Targets met Continue therapy A1c every 36 months

Targets not met after 3 months Combine sulfonylurea-metformin

Targets met Continue combination therapy A1c every 36 months

CHAPTER 40 / DIABETES MELLITUS

Patient Encounter, Part 3, Creating a Care Plan

Tolazamide Y 250, 500 10002000 23 35 days 3000 Up to 12

100, 250, 500

Glyburide, micronized 1.5, 3, 6 1, 2, 4 3 12 12 1 Weekly 35 days 12 8

Diaeta, Micronase, Glynase Amaryl Y Y N N

Not applicable Weekly

120 per meal Up to 4

4 per meal; 16 daily

Refer to information for individual products in the combination.

GI, gastrointestinal; h, hour; N, no; Y, yes

SECTION 7 / ENDOCRINOLOGIC DISORDERS

CHAPTER 40 / DIABETES MELLITUS

Patient Encounter, Part 4, Oral to Insulin Therapy

Generic Name (Insulin)

Rapid-Acting Insulin Lispro

Intermediate-Acting Insulin Neutral protamine hagadorn Long-Acting Insulin Glargine Detemir

1.516 212 25.5 16.5 14

1016 1016 1518 Up to 24

CHAPTER 40 / DIABETES MELLITUS

SECTION 7 / ENDOCRINOLOGIC DISORDERS

FIGURE 403 Insulin pump.

CHAPTER 40 / DIABETES MELLITUS

Treatment of Concomitant Conditions