John T. Johnson, Susan Cornell, 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. Distinguish clinical differences in type 1 (T1DM), type 2 (T2DM), and gestational diabetes.
3. List screening and diagnostic criteria for diabetes.
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 monitoring plan for a patient with diabetes based on patient-specific factors.
KEY CONCEPTS
Diabetes mellitus (DM) describes a group of chronic metabolic disorders that are characterized by hyperglycemia and associated with long-term microvascular, macrovascular, and neuropathic complications.
Type 1 DM (T1DM) is usually diagnosed before the age of 30, but can develop at any age. The autoimmune destruction of the β-cells causes insulin deficiency.
Type 2 DM (T2DM) accounts for approximately 90% to 95% of all diagnosed cases, is progressive in its development, and is often preceded by prediabetes. A combination of insulin deficiency, insulin resistance, and other hormonal irregularities, primarily glucagon, are key problems with T2DM. The majority of people with T2DM are overweight, and an increasing number of cases in children have been observed.
Glycemic control remains the primary objective in managing diabetes and its complications, but hypertension and hyperlipidemia are significant comorbidities.
Patients and clinicians can evaluate control of the patient’s diabetes by monitoring daily blood glucose values, hemoglobin A1c or estimated average blood glucose values, blood pressure, and lipid levels.
Oral and injectable agents are available to treat patients with T2DM who are unable to achieve glycemic control through meal planning and physical activity.
Insulin is the primary treatment to lower blood glucose levels for patients with T1DM and the addition of injected amylin may decrease fluctuations in blood glucose levels.
Uncontrolled blood pressure plays a major role in the development of macrovascular events and nephropathy in patients with DM. The American Diabetes Association recommends that blood pressure goals for patients with DM be less than 130/80 mm Hg.
Peripheral neuropathy is the most common complication reported in T2DM. This complication generally presents as pain, tingling, or numbness in the extremities.
Lower extremity amputations are one of the most feared and disabling sequelae of long-term uncontrolled DM. A foot 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.
INTRODUCTION
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: (a) new cases of blindness among adults, (b) end-stage renal disease, and (c) nontraumatic lower limb amputations. While prevention and treatment of DM remain a challenge, several studies have shown that complications associated with DM such as retinopathy and neuropathy can be delayed or prevented through proper blood glucose management.1,2
The increased cardiovascular risk associated with DM contributes to it being the sixth leading cause of death in the United States. In 2007, diabetes caused approximately 284,000 deaths, accounted for more than 15 million workdays absent and an additional 107 million workdays lost due to unemployment disability. The financial impact of DM in 2007 was approximately $174 billion, or one of every five dollars spent on health care in the United States.3
EPIDEMIOLOGY AND ETIOLOGY
DM is characterized by a complete lack of insulin, a relative lack of insulin, or insulin resistance as well as disorders of other hormones. These defects result in an inability to use glucose for energy. DM affects an estimated 23.6 million persons in the United States, or 7% of the population. While an estimated 17.9 million persons have been diagnosed, another 5.7 million people have DM but are unaware they have the disease. Worldwide, the number of people with DM is expected to rise to 35% by the year 2025.3 The increasing prevalence of DM is due in part to three influences: lifestyle, ethnicity, and age.
Lifestyle
Sedentary lifestyle coupled with greater consumption of high-fat foods and larger portion sizes have resulted in increasing rates of persons being overweight or obese. Current estimates indicate that 65% of the U.S. population is overweight and of those, 30% are obese. Overweight is defined as a 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
Ethnicity
In addition to current lifestyle trends and increased body weight, certain ethnic groups are at a disproportionately high risk for developing DM. Individuals of Native American, Native Alaskan, African American, and Hispanic/Latino American descent have 1.7 to 2.2 times greater risk of developing DM when compared with non-Hispanic whites.3 In addition, African American and Hispanic/Latino American populations are growing at a faster rate than the general U.S. population. This is a contributing factor to the rising U.S. population who has DM.
Age
The third factor contributing to the increased prevalence of diabetes is age. The prevalence of DM increases with age from approximately 2% of individuals 20 to 39 years of age to 20.9% of individuals older than 60 years of age.3As the population ages, the incidence of DM is expected to increase.
Type 1 DM (T1DM) usually is diagnosed before the age of 30, but can develop at any age. The autoimmune destruction of the β-cells causes insulin deficiency. Type 2 DM (T2DM) accounts for approximately 90% to 95% of all diagnosed cases, is progressive in its development, and is often preceded by prediabetes. A combination of insulin deficiency, insulin resistance, and other hormonal irregularities, primarily glucagon, are key problems with T2DM. The majority of people with T2DM are overweight and an increasing number of cases in children have been observed.
T1DM is an autoimmune disease in which insulin-producing β-cells in the pancreas are destroyed, leaving the individual insulin-deficient. This is 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 HLA-DR, is strongly associated with the development of T1DM. Over 95% of people with T1DM have HLA-DR3 and HLA-DR4 present. In addition, these individuals often develop islet cell antibodies, insulin autoantibodies, or glutamic acid decarboxylase autoantibodies. More than 90% of persons with T1DM have at least one diabetes-related antibody present. As more β-cells are destroyed, glucose metabolism becomes compromised due to reduced insulin release following a glucose load. At the time of diagnosis, most patients have a 90% loss of β-cell function. The remaining 10% of β-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 β-cell function is lost, patients become completely insulin-deficient and require more exogenous insulin. Diagnosis of T1DM occurs before the age of 30 in approximately 70% of patients. Approximately one in 400 people under the age of 20 are diagnosed with T1DM.
Latent autoimmune diabetes in adults (LADA), slow-onset type 1 or type 1.5 DM, is a form of autoimmune T1DM that occurs in individuals older (over 30 years of age) than the usual age of T1DM onset. Patients often are mistakenly thought to have T2DM because the person is older and may respond initially to treatment with oral blood glucose lowering agents. These patients do not have insulin resistance, but antibodies are present in the blood that are known to destroy pancreatic β-cells.
Measurement of C-peptide levels, insulin levels, and autoantibodies can be used to distinguish between T1DM and T2DM. It has been suggested that the easiest way to differentiate between T1DM and T2DM is by measuring C-peptide levels.5 People with T1DM have C-peptide levels below 1 ng/mL (0.33 nmol/L), whereas those with T2DM will have values greater than 1 ng/mL (0.33 nmol/L). Although different institutions may have varying reference ranges for C-peptide, according to the literature, the standard “normal” range for C-peptide in patients without diabetes is 0.5 to 2 ng/mL (0.17–0.66 nmol/L).5
Prediabetes is defined as having either a fasting and/or a postprandial blood glucose level higher than normal but not high enough to be classified as DM. A fasting blood glucose level greater than 100 mg/dL, but less than 126 mg/dL, or a postprandial blood glucose level greater than 140 mg/dL, but less than 200 mg/dL indicates prediabetes. It is currently estimated that 57 million persons in the United States have prediabetes. The development of prediabetes places the individual at high risk of eventually developing diabetes. Because progression from prediabetes to diabetes is not predictable, interventions during prediabetes are gaining popularity.
T2DM is usually slow and progressive in its development and is often preceded by prediabetes. Risk factors for T2DM 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, Asian American, African American, and Pacific Islanders)
• Prediabetes (i.e., previously identified with impaired glucose tolerance [IGT] or impaired fasting glucose [IFG])
• Hypertension (greater than or equal to 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 4 kg (9 lb)
• History of vascular disease
• History of polycystic ovary disease
• Other conditions associated with insulin resistance (e.g., acanthosis nigricans)6
Gestational diabetes mellitus (GDM) is defined as glucose intolerance in women during pregnancy. This complication develops in approximately 7% of all pregnancies. Women who have GDM have a 40% to 60% chance of developing T2DM.7 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 4 kg (9 lb), and ethnicity (African American, Hispanic/Latino American, or Native American).7 Clinical detection of and therapy for GDM are important because blood sugar control produces significant 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 conditions include specific genetic conditions, surgery, drugs, malnutrition, infections, and other illnesses. Table 43–1contains 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 these patients.
Table 43–1 Medications That May Affect Glycemic Control
PATHOPHYSIOLOGY
Normal Carbohydrate Metabolism
The body’s main fuel source is glucose. Cells metabolize glucose completely through glycolysis and the Kreb cycle, producing adenosine triphosphate (ATP) as energy. Glucose is stored in the liver and muscles as glycogen. When energy is required, glycogenolysis converts stored glycogen back to glucose. Excess glucose also may 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 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 sufficient to provide an uninterrupted supply of glucose to the brain.
Insulin and glucagon are produced in the pancreas by cells in the islets of Langerhans. β-Cells make up 70% to 90% of the islets and produce insulin and amylin, whereas α-cells produce glucagon. The main function of insulin is to decrease blood glucose levels, whereas glucagon, along with other counterregulatory hormones such as growth factor, cortisol, and epinephrine, increases 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 (3.9–6.7 mmol/L).8–10
Normal Insulin Action
Insulin secretion during fasting periods is a low, steady basal rate of 0.5 to 1 unit/h. After food is consumed, blood glucose levels rise, and the insulin-secretion response occurs in two phases.11 An initial burst, known as first 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 first phase insulin response is an early event in the progression from glucose intolerance to DM. The second phase of 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.12 Slower release of insulin allows the body to respond to the new glucose entering from digestion while maintaining blood glucose levels.
Amylin is a naturally occurring hormone that is cosecreted from β-cells with insulin. People with diabetes have either a relative or complete lack of amylin. Amylin has three major mechanisms of action: suppression of postmeal glucagon secretion, regulation of the rate of gastric emptying from the stomach to the small intestine, and the suppression of appetite.
Impaired Insulin Secretion
A pancreas with normal β-cell function is able to adjust insulin production to maintain normal blood glucose levels. Hyperinsulinemia, or high blood levels of insulin, is an early finding in the development of T2DM. More insulin is secreted to maintain normal blood glucose levels until eventually the pancreas can no longer produce sufficient insulin. The resulting hyperglycemia is enhanced by extremely high insulin resistance, pancreatic burnout in which β-cells lose functional capacity, or both. Patients with T2DM typically have approximately 40% β-cell function at diagnosis. Impaired β-cell function results in a reduced ability to produce a first-phase insulin response sufficient to signal the liver to stop producing glucose after a meal. As DM progresses, large numbers of patients with T2DM eventually lose all β-cell function and require exogenous insulin to maintain blood glucose control.13
Insulin Resistance
Insulin resistance is the primary factor that differentiates T2DM 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 significantly in skeletal muscle and the liver. Insulin resistance in the liver poses a double threat since the liver becomes nonresponsive to insulin for glucose uptake, and hepatic production of glucose after a meal does not cease, which leads to elevated fasting and postmeal blood glucose levels.
Impaired Glucagon Secretion
The release of glucagon is impaired in people with T1DM and T2DM. Glucagon is a counterregulatory hormone released by the α-cells that raises blood glucose levels. The release of insulin and the inhibition of glucagon is glucose-stimulated, meaning that as glucose is consumed, the release of insulin increases and the release of glucagon decreases in people without diabetes.14 Most patients with a 10- to 20-year history of T1DM have lost their ability to release glucagon, which increases their risk for hypoglycemic unawareness. People with T2DM have impaired phase 1 and phase 2 insulin release, and some have impaired glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) release, which further reduces the release of insulin. This leads to the liver producing and releasing glucose even in the postprandial state.15
Metabolic Syndrome
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 metabolic syndrome. It is estimated that 50% of the U.S. population older than 60 years of age have metabolic syndrome. The most widely used criteria to define metabolic syndrome were established by the National Cholesterol Education Program Adult Treatment Panel III Guidelines16 (summarized in Table 43–2). Patients having these additional risk 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. As a result, a patient with prediabetes or DM having a convergence of other risk factors should be treated more aggressively than a patient having prediabetes or DM alone.
Table 43–2 Five Components of Metabolic Syndrome
Incretin Effect
A great deal of research is occurring today to develop compounds that enhance the incretin effect, either by mimicking its action or by enabling incretin hormones to remain physiologically active for longer periods of time.15,17–19As early as the late 1960s, Perley and others observed that insulin’s response to oral glucose exceeded that of IV glucose administration.19 It was concluded that factors in the gut, or incretins, affected the release of insulin after a meal is consumed. When nutrients enter the stomach and intestines, incretin hormones are released which stimulates insulin secretion. This was validated by measuring C-peptide and insulin response to the IV and oral glucose loads. GLP-1 and GIP are the two major incretin hormones, with GLP-1 being studied the most. GLP-1 is secreted by the L cells of the ileum and colon primarily, and GIP is secreted by the K cells.
GLP-1 was identified in the early 1980s. It is a 30/31 amino acid peptide that is a product of the glucagons gene. GLP-1 secretion is caused by endocrine and neural signals started when nutrients enter the GI tract. Within minutes of food ingestion, GLP-1 levels rise rapidly. A glucose-dependent release of insulin occurs and dipeptidyl peptidase-IV (DPP-IV) cleaves GLP-1 rapidly to an inactive metabolite. Much of the research on glucose lowering products involves pro longing the action of GLP-1. Other glucose lowering effects of GLP-1 include suppression of glucagons, slowing gastric emptying, and increasing satiety.15,17-19
CLINICAL PRESENTATION AND DIAGNOSIS
Screening
Currently, the American Diabetes Association (ADA) recommends routine screening for T2DM every 3 years in all adults starting at 45 years of age. Earlier and more frequent screening should be reserved for patients who are at higher risk. The ADA does not recommend screening for T1DM due to the low incidence and acute presentation of symptoms.20 See Table 43–320 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 first test and confirmed on a subsequent day, a diagnosis of GDM can be made. Otherwise, all women should be screened with an oral 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 43–4.21 Women considered low risk include those of normal weight before pregnancy; younger than 25 years of age; without first-degree relatives with diabetes; non-Hispanic, non–African American, or non–Native American ethnicity; and no prior history of glucose intolerance or poor obstetric outcome.7,21
Clinical Presentation and Diagnosis of Diabetes Mellitus
Table 43–3 ADA Screening Recommendations for Diabetes
Asymptomatic type 1
The ADA does not recommend screening for T1DM due to the low incidence in the general population and to the acute presentation of symptoms
Asymptomatic type 2
1. The ADA recommends screening for T2DM every 3 years in all adults beginning at 45 years of age, particularly in those with a BMI greater than or equal to 25 kg/m2
2. Testing should be considered for persons younger than 45 years of age or more frequently in individuals who are overweight (BMI 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, Pacific Islander)
• Delivered a baby weighing greater than 4.1 kg (9 lb) or previous diagnosis of GDM
• 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 IGT or IFG
• Other clinical conditions associated with insulin resistance (e.g., acanthosis nigricans)
• History of vascular disease
Type 2 in children and adolescents
Criteria:
• Overweight (BMI 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 T2DM in first- or second-degree relatives
• Race/ethnicity (Native American, African American, Latino/Hispanic American, Asian American, Pacific 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:
FPG 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 first prenatal visit with random glucose screen
2. All women should be screened with an OGTT between weeks 24 and 28 of gestation unless they are in the low-risk category
ADA, American Diabetes Association; BMI, body mass index; FPG, fasting plasma glucose; GDM, gestational diabetes mellitus; IFG, impaired fasting glucose; IGT, impaired fasting glucose; OGTT, oral glucose tolerance test; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
From Ref. 20.
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.
Diagnostic Criteria
Diagnosis of DM includes glycemic outcomes exceeding threshold values with one of three testing options (Table 43–5).21 Confirmation 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.20 While the OGTT is more sensitive and modestly more specific than FPG determination, it is more costly and difficult to reproduce the results and is rarely performed in practice today.
Table 43–4 Diagnosis of GD With a 100 or 75 g Glucose Load
Table 43–6 Categorization of Glucose Status
The ADA categorizes patients demonstrating IFG or IGT as having prediabetes.21 The categorization thresholds of glucose status for FPG determination and the OGTT are listed in Table 43–6.22 These two conditions may coexist or may be identified independently. FPG level represents hepatic glucose production during the fasting state, whereas postprandial glucose levels in the OGTT may reflect glucose upta ke in periphera l tissues, insu lin sensitivity, or a decreased first-phase insulin response.
Table 43–5 Criteria for the Diagnosis of Diabetes
1. Symptoms of diabetes plus a casual plasma glucose concentration greater than or equal to 200 mg/dL (11.1 mmol/L). Casual is defined 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. FPG greater than or equal to 126 mg/dL (7 mmol/L). Fasting is defined as no caloric intake for at least 8 hours
or
3. 2-hours postload glucose greater than or equal to 200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water
FPG, fasting plasma glucose; OGTT, oral glucose tolerance test.
In the absence of hyperglycemia, these criteria should be confirmed by repeat testing on a different day. The OGTT is not recommended for routine clinical use.
From Ref. 21.
TREATMENT
Goals of Therapy
DM treatment goals include reducing long-term micro-vascular and macrovascular complications, preventing acute complications from high blood glucose levels, minimizing hypoglycemic episodes, and maintaining the patient’s overall quality of life. To achieve these goals, near-normal blood glucose levels are fundamental, thus glycemic control remains the primary objective in diabetes management. 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, lifestyle modification, and medications.
Proper care of DM requires goal setting and assessment for glycemic control, self-monitoring of blood glucose (SMBG), monitoring of blood pressure and lipid levels, regular monitoring for the development of complications, dietary and exercise lifestyle modifications, and proper medication use. The complexity of proper DM self-care principles has a dramatic impact on a patient’s lifestyle and requires a highly disciplined and dedicated person to maintain long-term control.
Setting and Assessing Glycemic Targets
Patients and clinicians can evaluate control of the patient’s diabetes by monitoring daily blood glucose values, hemoglobin A1c (A1c) or estimated average glucose (eAG) values, blood pressure, and lipid levels. SMBG enables patients to obtain their current blood glucose level at any time easily and relatively inexpensively. The A1c test provides a weighted-mean blood glucose level from the previous 3 months.
Self-Monitoring of Blood Glucose
SMBG 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 70 to 130 mg/dL (3.9-7.2 mmol/L), and peak postprandial plasma glucose goals are less than 180 mg/dL (10 mmol/L).7 The American Association of Clinical Endocrinologists (AACE) supports tighter SMBG controls, with premeal goals of less than 110 mg/dL (6.1 mmol/L) and peak postmeal goals of less than 140 mg/dL (7.8 mmol/L).23 For patients with T1DM, the ADA recommends that SMBG be performed at least three times daily. The frequency of testing in patients with T2DM 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 T1DM, the role of SMBG in improving glucose control in T2DM is unproven.24
Typically, in SMBG, a drop of blood is placed on a test strip that is then read by a blood glucose monitor. Recent technological advancements have decreased the blood sample size required to as small as 0.3 microliters, provide the capability of alternate site testing, and deliver 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 patient’s blood glucose data can aid practitioners in modifying treatment for better glucose control. Specific therapy adjustments 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 fingertip 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 fingersticks 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 may prefer smaller meters with features such as faster results, larger memories, reminder alarms, and downloading capabilities. Several continuous glucose sensors are now available that work with or independently of insulin pumps. These monitors provide blood glucose readings, primarily through interstitial fluid (ISF). A small sterile disposable glucose-sensing device called a sensor is inserted into the subcutaneous tissues. This sensor measures the change in glucose in ISF, and sends the information to a monitor which stores the results. The monitor must be calibrated daily by entering several blood glucose readings obtained at different times using a standard blood glucose meter.
Hemoglobin A1c
Glucose interacts spontaneously with hemoglobin in red blood cells to form glycosylated derivatives. The most prevalent derivative is A. Greater amounts of glycosylation occur when blood glucose levels increase. Because hemoglobin has a life span of approximately 120 days, levels of A provide a marker reflecting the average glucose levels over this timeframe.25 The ADA goal for persons with DM is less than 7%, whereas the AACE supports a goal of less than 6.5%. Testing A 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.
Estimated Average Glucose
Recently the ADA and several other organizations have introduced replacing the use of A with eAG. This value more closely correlates with readings that patients obtain from their home glucose monitors. The equation to convert from A1c to eAG is: eAG = 28.7 × A1c – 46.7.26 The goal eAG would be 154 mg/dL (8.55 mmol/L) instead of an A of less than 7%, and an eAG of 240 mg/dL (13.32 mmol/L) would be equivalent to an A of 10%.
Ketone Monitoring
Urine/blood ketone testing is important in people with T1DM, in pregnancy with preexisting diabetes, and in GDM. People with T2DM may have positive ketones and develop diabetic ketoacidosis (DKA) if they are ill.
The presence of ketones may indicate a lack of insulin or ketoacidosis, a condition that requires immediate medical attention. When there is a lack of insulin, peripheral tissues cannot take up and store glucose. This causes the body to think it is starving and excessive lipolysis and ketones, primarily /S-hydroxybutric and acetoacetic acid, are produced as byproducts of free fatty acid metabolism in the liver. Glucose and ketones are osmotically active, and when an excessive amount of ketones are formed, the body gets rid of them through urine leading to dehydration. Patients with T1DM should test for ketones during acute illness or stress or when blood glucose levels are consistently elevated above 300 mg/dL (16.65 mmol/L). This commonly occurs when insulin is omitted. Women with pre-existing diabetes before pregnancy or with GDM should check ketones using their first morning urine sample or when any symptoms of ketoacidosis such as nausea, vomiting, or abdominal pain are present. Positive ketone readings are found in normal individuals during fasting and in up to 30% of first morning urine specimens from pregnant women. Urine ketone tests using nitroprusside containing reagents can give false-positive results in the presence of several medications including captopril. False-negative readings have been reported when test strips have been exposed to air for an extended period of time or when urine specimens have been highly acidic, such as after large intakes of ascorbic acid. Currently, available urine ketone tests are not reliable for diagnosing or monitoring treatment of ketoacidosis. Blood ketone testing methods that quantify β-hydroxybutyric acid, the predominant ketone body, are available and are the preferred way to diagnose and monitor ketoacidosis.
Table 43–7 ADA Recommended Goals of Therapy
Home tests for β-hydroxybutyric acid are available. The specific treatment of DKA may differ at institutions but includes rehydration, correction of electrolyte imbalances, and insulin administration.
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 43–7 presents goals for blood pressure measurements, lipids values, and monitoring parameters for complications associated with diabetes.
General Approach to Therapy
Type 1 Diabetes Mellitus
Treatment of T1DM 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 using intermediate- or long-acting insulin, whereas short- or rapid-acting insulin replicates 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 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. T1DM patients frequently are started on about 0.6 unit/kg/day, and then doses are titrated until glycemic goals are reached. Most people with T1DM use between 0.6 and 1 unit/kg/day.
Currently, the most advanced form of insulin delivery is the insulin pump, also referred to as continuous subcutaneous insulin infusion (CSII). Using rapid-acting insulin only, these pumps are programmed to provide a slow release of small amounts of insulin as the basal portion of therapy, and larger boluses of insulin are injected by the patient to account for the consumption of food. Pramlintide, a synthetic analog of the naturally occurring hormone amylin, is another injectable blood glucose lowering medication that can be used in people with T1DM or in people with T2DM using insulin for treatment. A more in-depth description is listed in the pharmacologic treatment section.
Type 2 Diabetes Mellitus
Treatment of T2DM 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. Figures 43-1 and 43-2summarize updated treatment algorithms for T2DM.27 Algorithms from AACE for T2DM can be found at www.aace.com/pub.28 Lifestyle modifications including education, nutrition, and exercise are paramount to managing the disease successfully. Many patients assume that once pharmacologic therapy is initiated, lifestyle modifications are no longer necessary. Practitioners should educate patients regarding this misconception. Because T2DM generally tends to be a progressive disease, blood glucose levels will eventually increase, making insulin therapy and lifestyle modifications the eventual required therapy in many patients. It may be necessary for patients to inject insulin to lower their blood glucose levels. Figure 43–2 is an illustration of a way to start insulin therapy, while keeping the patient on some oral medications. This is usually done when several oral agents have been used with inadequate glucose lowering results.27
Patient Encounter, Part 1
You have developed a collaborative practice with a group of family practice practitioners and run a small apothecary in the same office as theirs. You have established a patient education and monitoring center in conjunction with a registered dietician, nurse practitioner, and physician’s assistant at the office.
EP is a 58-year-old Caucasian male who is 6 ft, 0 in. (183 cm) tall and weighs 118 kg (260 lb). He comes in today for his annual physical. He has a 10-year history of hypertension and elevated cholesterol. His fasting blood sugar today was 190 mg/dL (10.5 mmol/L). He is asked to have fasting labs done and then return to the office in 3 days for a reevaluation. His fasting blood sugar at the return visit is 165 mg/dL (9.2 mmol/L) and additional information from his return visit and labs are listed below.
Labs:
Fasting glucose: 190 mg/dL (10.5 mmol/L) and 165 mg/dL (9.2 mmol/L); BP: 148/86 mm Hg; BUN: 123 mg/dL (43.9 mmol/L); creatinine: 0.9 mg/dL (80 μmol/L); GFR (Modified Diet in Renal Disease [MDRD]) 90.8; AST/SGOT: 19 IU/L (0.32 μKat/L); ALT/SGPT: 20 IU/L (0.33 μKat/L); TSH: 1.26 microunits/mL (1.26 mU/L); total cholesterol: 202 mg/dL (5.23 mmol/L); LDL: 118 mg/dL (3.05 mmol/L); HDL: 43 mg/dL (1.11 mmol/L); triglycerides: 205 mg/dL (2.32 mmol/L); A1c: 7.9%; body fat: 42.8%; waist circumference: 44 inches (112 cm).
PMH: History of hypertension × 10 years; history of elevated cholesterol × 10 years; occasional cold symptoms over the last several years; reports last eye examination about 20 years ago; believes he could use glasses
FH: Father 84 years of age; history of hypertension, stroke, and myocardial infarction; mother 78 years of age; history of T2DM, hypertension, and obesity; sister 56 years of age; history of gestational diabetes mellitus (GDM), T2DM, and obesity
SH: Drinks six packs of beer on weekends and self-reports that he does not smoke or use tobacco products or illegal substances
Meds: Atenolol 50 mg (takes one tablet daily to lower BP); hydrochlorothiazide 25 mg (takes one tablet daily to lower BP); simvastatin 40 mg (takes one tablet daily to lower cholesterol)
Meal History: Fast food for morning and evening meal that is high in carbohydrate and saturated fat. Jelly donuts and coffee for breakfast and peanut butter and banana sandwiches for lunch on other days. High fat meats, starchy vegetables, rolls and sweet tea for supper most nights
PH: No outside work activity. Dances some on stage when performs.
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 EP has based on his clinical characteristics?
What challenges can you identify for optimal clinical outcomes through the initial assessment of EP?
What additional information do you need to obtain before creating a treatment plan and goals with EP?
Gestational Diabetes
An individualized meal plan consisting of three meals and three snacks per day is commonly recommended in GDM. Preventing ketosis, promoting adequate growth of the fetus, maintaining satisfactory blood glucose levels, and preventing nausea and other undesired GI 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. Even though there have been small studies showing the safety of using glyburide, metformin, and insulin glargine during pregnancy, the use of these agents is not recommended as a general rule. In women who develop GDM and cannot control blood glucose levels with lifestyle modifications, the use of insulin aspart, lispro, or regular insulin have category B safety ratings.
FIGURE 43–1. Initiation and adjustment of insulin regimens. Insulin regimens should be designed taking lifestyle and meal schedule into account. The algorithm can only provide basic guidelines for initiation and adjustment of insulin. aPremixed insulins not recommended during adjustment of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportion of rapid-and intermediate-acting insulins is similar to the fixed proportions available. (A1c, hemoglobin A1c; BG, blood glucose; NPH, neutral protamine Hagedorn.) (From Ref. 27.)
Nonpharmacologic Therapy
Medical Nutrition Therapy
Despite the popular notion, there is not a “diabetic diet,” and the recommended meal plan for patients with diabetes should be low in fat, high in fiber, low to moderate in calories, and achieve a balance of the various components and nutrients needed.27 Medical nutrition therapy (MNT) is considered an 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 should not be a single education session, but rather an ongoing dialog. MNT should be customized to take into account cultural, lifestyle, and financial considerations. MNT plans should integrate a variety of foods that the patient enjoys and allow for flexibility 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 T1DM is matching optimal insulin dosing to carbohydrate consumption. In T2DM, the primary focus is portion control and controlling blood glucose, blood pressure and lipids through individualizing limits of carbohydrates, saturated fats, sodium, and calories.
Carbohydrates are the primary contributor to postmeal glucose levels. There have been recent studies showing the benefit of low carbohydrate meal plans, especially to enhance weight loss. Total daily carbohydrate levels should not be less than 135 g for most patients and should make up approximately 40% of calories. The percentage of fat, protein, and other components of the meal should be individualized based on the specific goals of the patient.
FIGURE 43–2. Algorithm for the metabolic management of T2DM; reinforce lifestyle interventions at every visit and check A1c every 3 months until A1c less than 7% and then at least every 6 months. The interventions should be changed if A1c greater than or equal to 7%. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety. See Figure 43–1 for initiation and adjustment of insulin. (A1c, hemoglobin A1c; CHF, congestive heart failure; GLP-1, glucagon-like peptide-1.) (From Ref. 27.)
Dietary Supplements
Many patients with diabetes may seek and utilize dietary supplements in the treatment of diabetes. Commonly used products include α-lipoic acid, omega-3 fatty acids, and chromium. Current clinical evidence regarding dietary supplements is limited and does not support the use of these agents as treatment. Nevertheless, patients will inquire and use dietary supplements. It is important that pharmacists respect the patient’s health beliefs, address their questions and concerns, and educate patients on the differences between dietary supplements and prescribed therapies.29
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 weight loss is therapeutic lifestyle change (TLC), which integrates a 500 to 1,000 kcal/day (about 2,100–4,200 kJ/day) reduction in calorie intake and an increase in physical activity.30 A slow but progressive weight loss of 0.45 to 0.91 kg (1–2 lb) 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 1,000 to 1,200 kcal/day (about 4,200–5,000 kJ/day) for women and 1,200 to 1,600 kcal/day (about 5,000-6,700 kJ/day) for men. Because 80% of patients with T2DM are overweight, this strategy works best for these patients.
Physical Activity
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 T2DM 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 housecleaning tasks are good exercises as well. Long-term goals are to perform at least 30 minutes of aerobic activity as many days a week as possible.22
Psychological Assessment and Care
Mental health and social state have been shown to have an impact on a patient’s ability to carry out DM management care tasks. Approximately one in four patients with DM experience episodes of major depression. Clinicians should incorporate psychological assessment and treatment into routine care. The ADA guidelines recommend psychological screening, which includes determining the patient’s attitudes regarding DM, expectations of medical management and outcomes, mood and affect, general and diabetes-related quality of life, and financial, social, and emotional resources. Patients demonstrating nonadherence, depression, an eating disorder, and/or cognitive functioning that impairs judgment should be referred to a mental health specialist familiar with DM.7
Immunizations
Influenza and pneumonia are common preventable infectious diseases that increase mortality and morbidity in persons with chronic diseases including DM.7 Yearly influenza vaccinations, commonly called flu shots, are recommended for patients with DM. Pneumococcal vaccination is also recommended for patients with DM as a one-time vaccination for most patients.
Pharmacologic Therapy
Oral and injectable agents are available to treat patients with T2DM who are unable to achieve glycemic control through meal planning and physical activity. Currently there are 10 classes of blood glucose lowering agents available for the treatment of diabetes: seven classes of oral agents and three injectable classes. Figure 43–1 shows a way to start insulin therapy for people with T2DM who are going to continue to take oral glucose lowering medications.27 Table 43–831–34 lists the oral agents, and Figure 43–2 displays the ADA Treatment Algorithm for Patients with T2DM.27 The various classes of blood glucose lowering agents target different organs and have different mechanisms of action. Each of these agents may be used individually or in combination with other medications that target different organs for synergistic effects.
Sulfonylureas
Sulfonylureas represent the first class of oral blood glucose lowering agents approved for use in the United States. These drugs are classified as being either first- 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.
Sulfonylureas enhance insulin secretion by blocking ATP-sensitive potassium channels in the cell membranes of pancreatic β-cells. This action results in membrane depolarization, allowing an influx 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.12
All sulfonylureas undergo hepatic biotransformation, with most agents being metabolized by the cytochrome P450 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.
Sulfonylureas’ blood glucose lowering effects can be observed in both fasting and postprandial levels. Mono-therapy with these agents generally produce a 1.5% to 2% decline in A1c concentrations and a 60 to 70 mg/dL (3.3–3.9 mmol/L) reduction in fasting blood glucose (FBG) levels. Secondary failure with these drugs occurs at a rate of 5% to 7% per year as a result of continued pancreatic β-cell destruction. One limitation of sulfonylurea therapy is the inability of these products to stimulate insulin release from β-cells at extremely high glucose levels, a phenomenon called glucose toxicity. Common adverse effects include hypoglycemia and weight gain. There may be some cross sensitivity in patients with sulfa allergy.
Nonsulfonylurea Secretagogues (Glitinides)
While producing the same effect as sulfonylureas, non-sulfonylurea secretagogues, also referred to as meglitinides, have a much shorter onset and duration of action. Glitinide secretagogues also produce a pharmacologic effect by interacting with ATP-sensitive potassium channels on the β-cells; however, this binding is to a receptor adjacent to those to which sulfonylureas bind.
The primary benefit of nonsulfonylurea secretagogues is in reducing postmeal glucose levels by about 40 mg/dL (2.2 mmol/L). These agents have demonstrated a reduction in A1c levels between 0.6% and 1%. Since they have a rapid onset and short duration of action, they are to be taken within 15 minutes of a meal.
Table 43–8 Oral Agents for the Treatment of T2DM
They also may be used in combination therapy with other drugs to achieve synergistic effects. Combinations with biguanides are most commonly seen.
Biguanides
The only biguanide approved by the FDA and currently available in the United States is metformin. Metformin was approved in the United States in 1995. This agent is thought to lower blood glucose by decreasing hepatic glucose production and increasing insulin sensitivity in both hepatic and peripheral muscle tissues; however, the exact mechanism of action remains unknown. Metformin has been shown to reduce A1c levels by 1.5% to 2% and FPG levels by 60 to 80 mg/dL (3.3–4.4 mmol/L) when used as monotherapy. The response to metformin can vary according to the baseline blood glucose levels. Larger effects can be seen in patients with a higher initial A1c level (e.g., greater than 10%) than in patients beginning therapy with a relatively lower value (e.g., less than 8%). Metformin lowers both fasting blood sugar (FBS) and postmeal blood glucose. The ADA treatment algorithm (Fig. 43–2) considers lifestyle modification and metformin as first-line therapy.27 Metformin does not affect insulin release from β-cells of the pancreas, so hypoglycemia is not a common side effect. Metformin has been shown to produce beneficial effects on serum lipid levels, and has become a first-line agent for T2DM 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%.31 Metformin is often used in combination with a sulfonylurea or a thiazolidinedione (TZD) for synergistic effects.
Metformin does not undergo significant 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 (124 μmol/L) in women and 1.5 mg/dL (133 μmol/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, and renal function should be assessed 48 hours after the procedure. If normal, therapy can be resumed.
Primary side effects associated with metformin therapy are GI 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.
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, thiazoli-dinediones have established a significant role in T2DM therapy. TZDs are known to increase insulin sensitivity by stimulating peroxisome proliferator-activated receptor gamma (PPAR-γ). Stimulation of PPAR-γ 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.
As monotherapy, both rosiglitazone and pioglitazone reduce FPG levels by 30 to 50 mg/dL (1.7–2.8 mmol/L), and the overall effect on A1c is a 1% to 1.5% reduction. Onset of action for TZDs 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 A1creductions to 2% to 2.5%.
Additional effects of TZDs are seen in the lipid profile. Both pioglitazone and rosiglitazone increase HDL cholesterol by 3 to 9 mg/dL (0.08–0.23 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 significant increase has been reported for pioglitazone.
TZDs may produce fluid retention and edema; 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 fluid 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. Periodic liver function tests should be performed at baseline and periodically. 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 three times the upper limit of normal in patients receiving a TZD, the medication should be discontinued.
The results of several recent studies have posed questions on the benefit or harm of using these agents. Both agents require a black box warning of increased risk of heart failure.35 Although the results of meta-analyses were not conclusive regarding possible cardiovascular risks related to rosiglitazone, the ADA no longer recommends the use of this agent.27
α-Glucosidase Inhibitors
Acarbose and miglitol are α-glucosidase inhibitors currently approved in the United States. An enzyme that is along the brush boarder of the intestine cells called α-glucosidase breaks down complex carbohydrates into simple sugars, resulting in absorption. The α-glucosidase inhibitors work by delaying the absorption of carbohydrates from the intestinal tract, which reduces the rise in postprandial blood glucose concentrations. As monotherapy, α-glucosidase inhibitors primarily reduce postprandial glucose excursions. FPG concentrations have been decreased by between 40 and 50 mg/dL (2.2–2.8 mmol/L); however, 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 GI side effects including flatulence (41.5%), abdominal discomfort (11.7%), and diarrhea (28.7%) have limited their use. GI side effects occur as the result of intestinal bacteria in the distal gut metabolizing undigested carbohydrates and producing carbon dioxide and methane gas. Low initial doses followed by gradual titration may minimize GI side effects. The α-glucosidase inhibitors are contraindicated in patients with short-bowel syndrome or inflammatory bowel disease. In addition, neither drug in this class is recommended for patients with a creatinine clearance of less than 25 mL/min.
Because GI motility is increased in prediabetes and newly diagnosed patients, the α-glucosidase inhibitors are particularly useful when used early in the disease.
Dipeptidyl Peptidase-4 Inhibitors
Sitagliptin, the first in a new class of diabetic drugs called dipeptidyl peptidase-4 (DPP-4) inhibitors, was approved in October 2006 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. These agents lower blood glucose concentrations by inhibiting DPP-4, the enzyme found in the intestinal K cells that degrades endogenous GLP-1 within 2 minutes of secretion. DPP-4 inhibitors increase the amount of endogenous GLP-1. The blood glucose lowering effect of the gliptins is primarily on postprandial levels. A modest reduction in FPG concentration can be observed because glucagon suppression will result in decreased hepatic gluconeogenesis. Because DPP-4 inhibitors can affect the regulation of GI motility, their greatest effects are noted in recently diagnosed T2DM, but they have been shown to be moderately effective in people with long-standing diabetes. Typical A1creductions are 0.6% to 0.8%. Common adverse effects include diarrhea, nasopharyngitis, upper respiratory tract infections, and headache. Hypoglycemia is not a common adverse effect with these agents because insulin secretion results from GLP-1 activation due to meal-related glucose detection and not from direct pancreatic β-cell stimulation. Dosage adjustments to 50 and 25 mg daily are recommended for patients with moderate (creatinine clearance 30–49 mL/min) and severe (creatinine clearance less than 30 mL/min) renal impairment, respectively. Renal function monitoring is recommended prior to initiation and periodically thereafter.
The U.S. Food and Drug Administration (FDA) is revising the prescribing information for sitagliptin and sitagliptin/metformin to include information on reported cases of acute pancreatitis in patients using these products after 88 postmarketing cases of acute pancreatitis, including two cases of hemorrhagic or necrotizing pancreatitis, were reported between October 2006 and February 2009 in patients taking sitagliptin.
A second agent, saxagliptin, was recently approved and dosing information can be found in Table 43–8.
Central Acting Dopamine Agonist
A quick release formulation of a central acting dopamine agonist, bromocriptine, has been approved by the FDA in May 2009 for the treatment of T2DM. It has the potential of being used as monotherapy or combination therapy with existing oral agents. Available evidence indicates that the therapy acts centrally to reset hypothalamic centers, regulating postprandial insulin-mediated glucose and lipid metabolism to thereby reduce postprandial hyperglycemia and hyperlipidemia. It should be taken 2 hours after waking in the morning with food. The initial dose used in clinical trials was 0.8 mg, titrated up weekly until a maximum dose of 1.6 to 4.8 mg daily is achieved. It will be available as a 0.8-mg tablet and is currently not on the market. The main side effects during clinical trials included headache and nausea. Several contraindications include hypotension, syncopal migranes, and women that are nursing.
Insulin
Insulin is the one agent that can be used in all types of DM with the most effectiveness for blood sugar control.33 Insulin is the primary treatment to lower blood glucose levels for patients with T1DM and injected amylin can be added to decrease fluctuations in blood glucose levels. An insulin treatment algorithm for T2DM is found in Figure 43–2.27
Insulin is available commercially in various formulations that vary markedly in terms of onset and duration of action. Insulin can be divided into two main classes, basal and bolus, based on their length of action to mimic endogenous insulin physiology. Most formulations are available as U-100, indicating a concentration of 100 unit/mL. Insulin is typically refrigerated, and most vials are good for 28 days at room temperature. Insulin detemir can be stored at room temperature for 42 days. Specific details of insulin products are listed in Table 43–9.32,33
The most common route of administration for insulin is subcutaneous injection using a syringe or pen device. Patients should be educated to rotate their injection sites to minimize lipohypertrophy, a build up of fat that decreases or prevents proper insulin absorption. Additionally, patients should understand that the absorption rate may vary among injection sites (abdomen, thigh, arm, and buttocks) due to differences in blood flow, with absorption occurring fastest in the abdomen and slowest in the buttocks. Differences in absorption of insulin based on site of injection do not appear to be significant when analog insulins such as aspart, detemir, glargine, glulisine, and lispro are administered.
Insulin syringes are distinguished according to the syringe capacity, syringe markings, and needle gauge, and length. 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.
Table 43–9 Insulin Agents for the Treatment of T1DM and T2DM
Bolus Insulins
Regular Insulin
Regular insulin is unmodified crystalline insulin commonly referred to as natural or human insulin. It is a clear solution that has a relatively short onset and duration of action and is designed to cover insulin response to meals. On subcutaneous injection, regular insulin forms small aggregates called hexamers that undergo conversion to dimers followed by monomers before systemic absorption can occur. 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 I V.
Rapid-Acting Insulin
Three rapid-acting insulins have been approved in the United States: aspart, glulisine, and lispro. 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 and is dosed prior to or with meals.
Basal Insulins
Intermediate-Duration Insulin
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, and is designed to cover insulin requirements in between meals and/or overnight. With the advent of the long-acting insulins, NPH insulin use has declined due to: (a) an inability to predict accurately when peak effects occur and (b) 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 first.
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.
Detemir binds to albumin in the plasma which gives it sustained action. Neither glargine nor detemir can be administered IV or mixed with other insulin products. Neither glargine or detemir produce peak serum concentrations, and both can be administered irrespective of meals or time of day.36
Combination Insulin Products
A number of combination insulin products are available commercially. NPH is available in combinations of 70/30 (70% NPH and 30% regular insulin) and 50/50 (50% NPH and 50% 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. Novolog mix 70/30 contains 70% insulin aspart protamine suspension and 30% insulin aspart. The lispro and aspart insulin protamine suspensions were developed specifically for these mixture products and will not be commercially available separately.
Insulin Pump Therapy
Insulin pump therapy consists of a programmable infusion device that allows for basal infusion of insulin 24 hours daily (Fig. 43–3), as well as bolus administration prior to meals and snacks. Currently there are seven commercially available insulin pumps in the United States. Insulin is delivered from a reservoir either by infusion set tubing or through a small canula. Most pump infusion sets are inserted in the abdomen, arm, or other infusion site by a small needle. Most patients prefer insertion in abdominal tissue because this site provides optimal insulin absorption. Infusion sets should be changed every 2 to 3 days to reduce the possibility of infection.
FIGURE 43–3. Insulin pump and placement.
Patients use a carbohydrate-to-insulin ratio to determine how many units of insulin are required. More specifically, an individual’s ratio is calculated to determine how many units of the specific insulin being used in the pump “covers” for a certain amount of carbohydrates to be ingested at a particular meal. The 450 rule or 500 rule is commonly used. 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 rapid-acting 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 T1DM are the most likely candidates to use these devices. Use of an insulin pump may improve blood glucose control, reduce wide fluctuations in blood glucose levels, and allow individuals to have more flexibility in timing and content of meals and exercise schedules. Insulin pump therapy is not for everyone and 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 GI tract in response to food that stimulates insulin secretion. It is thought that obese, insulin-resistant patients with T2DM have lower levels of incretin hormones. This may or may not be true. Exenatide (Byetta), is the first incretin mimetic approved by the FDA and is indicated as adjunct therapy in T2DM in which adequate blood glucose control has not been achieved with sulfonylureas, metformin, or both (Table 43–10).37 A1c reductions ranging from 0.5% to 1% have been observed with this agent, whereas FPG concentrations decrease by 8 to 10 mg/dL (0.44–0.56 mmol/L). Postprandial glucose values decline by 60 to 70 mg/dL (3.3–3.9 mmol/L).
Table 43–10 Noninsulin Injectable Agents for the Treatment of Diabetes
Exenatide lowers blood glucose levels by: (a) producing glucose-dependent insulin secretion; (b) reducing postmeal glucagon secretion which decreases postmeal glucose output; (c) increasing satiety which decreases food intake; and (d) regulating gastric emptying which allows nutrients to be absorbed into the circulation more smoothly. Serum levels peak approximately 2 hours after subcutaneous administration. Exenatide 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 exenatide is used in combination with a sulfonylurea, and the dose of the sulfonylurea may need to be reduced or discontinued once blood glucose control improves. Hypoglycemia is not encountered when used as 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 exenatide. The extent and rate of absorption of orally administered drugs may be affected with concomitant use of exenatide; however, no clinical significance has been established to date.
Exenatide is available in 5 and 10 mcg injectable prefilled 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 are then increased after a month to 10 mcg if the patient’s blood glucose is improving and nausea is limited. Exenatide can be given up to 60 minutes before a meal, but practical use indicates that injection 15 to 20 minutes before a meal may decrease nausea. An average weight loss of 1.4 to 2.3 kg (3–5 lb) commonly occurs with the 5 mcg dose, whereas a weight loss of 2.3 to 4.6 kg (5–10 lb) is observed with the 10 mcg dose.
Amylin
Pramlintide acetate was approved for use in the United States in March 2005 (Table 43–10).35 This agent is a synthetic analog of human amylin, which is a naturally occurring neuroendocrine peptide that is cosecreted by the β-cells of the pancreas in response to food. Amylin secretion is completely deficient in patients with T1DM, or relatively deficient in patients with T2DM. Pramlintide is given by subcutaneous injection before meals to lower postprandial blood glucose elevations. Pramlintide generally results in an average weight loss of 1 to 2 kg (2.2–4.4 lb).
Pramlintide is indicated as combination therapy with insulin in patients with types 1 or 2 DM. It has been shown to decrease 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. Some practitioners will not decrease the premeal insulin dose this much because of fear of loss of glucose control. Primarily, the kidneys metabolize pramlintide, 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 efficacy 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 GI motility, such as anticholinergic agents, or drugs that slow the absorption of nutrients such as α-glucosidase inhibitors. A disposable pen formulation is now on the market and available as SymlinPen 60 for patients with T1DM and SymlinPen 120 for people with T2DM. The number of days the pen will last will vary depending on the daily dose. The amount of medication is 1.5 mL in the SymlinPen 60 and 2.7 mL in the SymlinPen 120.
Treatment of Concomitant Conditions
Glucose Control and Cardiovascular Health
The results of three trials have recently been released showing the relationship between glucose control and cardiovascular health. The Action to Control Cardiovascular Risk in Diabetes (ACCORD),38 Action in Diabetes and Vascular Disease (ADVANCE),39 and Veterans Affairs Diabetes Trial (VADT)40 examined if cardiovascular risks could be decreased or prevented with intensive glucose lowering. Other variables were evaluated in these trials, but the results indicated a decrease in cardiovascular events with tighter glycemic control.
At the same time, there was an increase in mortality reported in the ACCORD trial, but not in the ADVANCE or VADT trials. Additionally, these studies demonstrated that controlling blood pressure and cholesterol in these patients were beneficial. For more detailed results of these trials, the reader is referred to the references indicated above.
Coronary Heart Disease
Nearly two-thirds of patients with DM will die of coronary heart disease (CHD). 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 81 mg aspirin daily unless contraindicated.
Hyperlipidemia
The National Cholesterol Education Program Adult Treatment Panel III guidelines classify the presence of DM to be of the same risk equivalence as CHD.16 The primary target for lipid-lowering treatment of 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 a HMG-CoA reductase inhibitor, commonly called a statin, is often required to achieve these goals. After LDL cholesterol goals are reached, triglyceride and HDL goals also should be achieved. Treatments including niacin or fibrate therapy may be used to reach these secondary goals. However, caution should be used with statin and fibrate combination therapy because a higher risk of adverse events has been reported (refer to Chap. 12: Dyslipidemias).
Hypertension
Uncontrolled blood pressure plays a major role in the development of macrovascular events and nephropathy in patients 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 beneficial effects on renal function. Low-dose thiazide diuretics also can be used as either first- or second-line therapy.
The most common use of thiazide diuretics for patients with DM is in synergistic combination with other agents. Another choice of treatment is β-blockers which can also be used as either first- or second-line therapies. While β-blockers may mask the symptoms of hypoglycemia, it is generally believed that the benefit of β-blockers outweighs the low risk of hypoglycemia in patients with T2DM. In order to achieve blood pressure goals, most patients require combination therapy with two or three antihypertensive agents.
Treatment of Acute Complications
Hypoglycemia
Hypoglycemia, or low blood sugar, can be defined clinically as a blood glucose level of less than 50 mg/dL (2.8 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 (16.7-22.2 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 (3.9 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 (e.g., sulfonylureas and insulin), exercising when insulin doses are reaching peak effect, or inadequately adjusted drug therapy in patients with impaired renal or hepatic function. 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 (approximately 120 mL) of orange juice, 8 oz (approximately 240 mL) of skim milk, or three to six glucose tablets. In patients receiving an α-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 α-glucosidase inhibitors.
For those patients whose blood glucose levels have dropped below 50 mg/dL (2.8 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. It is important to contact emergency medical personnel in this particular situation. The patient should be rolled onto his or her side to prevent aspiration, as many patients receiving the glucagon injection will vomit.
Diabetic Ketoacidosis
DKA is a reversible but potentially life-threatening medical emergency that results from a relative or absolute deficiency 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 T1DM on initial presentation, it can occur in adults as well as with patients who have T2DM. 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. Nonspecific symptoms include lethargy, headache, and weakness.
Hallmark diagnostic criteria for DKA include hyper-glycemia (greater than 250 mg/dL, 13.9 mmol/L), ketosis (anion gap greater than 10), and acidosis (arterial pH less than or equal to 7.25). Typical fluid deficit is 6 L or more, and major deficits of serum sodium and potassium are 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 not recommended when the pH is greater than or equal to 7.1. Regular insulin at 0.1 to 0.2 unit/kg/h by continuous IV infusion is the preferred treatment in DKA to regain metabolic control rapidly. Once plasma glucose values drop below 250 mg/dL (13.9 mmol/L), the insulin infusion may be decreased, and dextrose 5% to 10% can be added to the IV fluids. 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 (11.1 mmol/L), a bicarbonate level of greater than or equal to 10 mEq/L (10 mmol/L), and a venous pH of greater than 7.3. See Table 43–11 for the management of DKA.41,42
Table 43–11 Management of DKA
1. Confirm diagnosis (increased plasma glucose, positive serum ketones, metabolic acidosis)
2. Admit to hospital; intensive-care setting may be necessary for frequent monitoring or if pH less than 7 or unconscious
3. Assess: Serum electrolytes (K+, Na+, Mg2+, Cl–, bicarbonate, phosphate), acid–base status—pH, HCO3–, PCO2, β-hydroxybutyrate, renal function (creatinine, urine output)
4. Replace fluids: 2–3 L of 0.9% saline over first 1–3 hours (5–10 mL/kg/h); subsequently, 0.45% saline at 150–300 mL/h; change to 5% glucose and 0.45% saline at 100–200 mL/h when plasma glucose reaches 250 mg/dL (14 mmol/L)
5. Administer regular insulin: IV (0.1 unit/kg) or IM (0.4 unit/kg), then 0.1 unit/kg/h by continuous IV infusion; increase 2- to 10-fold if no response by 2–4 hours. If initial serum potassium is less than 3.3 mmol/L (3.3 mEq/L), do not administer insulin until the potassium is corrected to greater than 3.3 mmol/L (3.3 mEq/L)
6. Assess patient: What precipitated the episode (e.g., nonadherence, infection, trauma, infarction, cocaine)? Initiate appropriate workup for precipitating event (cultures, chest x-ray, ECG)
7. Measure capillar y glucose ever y 1–2 hours; measure elec trol y tes (espe cially K+, bicarbonate, phosphate) and anion gap every 4 hours for first 24 hours
8. Monitor blood pressure, pulse, respirations, mental status, and fluid intake and output every 1–4 hours
9. Replace K+: 10 mEq/h when plasma K+ less than 5.5 mEq/L (5.5 mmol/L), ECG normal, urine flow and normal creatinine documented; administer 40–80 mEq/h when plasma K+ less than 3.5 mEq/L (3.5 mmol/L) or if bicarbonate is given
10. Continue above until patient is stable, glucose goal is 150–250 mg/dL (8.3–14 mmol/L), and acidosis is resolved. Insulin infusion may be decreased to 0.05–0.1 unit/kg/h
11. Administer intermediate or long-acting insulin as soon as patient is eating. Allow for overlap in insulin infusion and subcutaneous insulin injection
Cl, chloride; HCO3, serum bicarbonate; IM, intramuscular; K, potassium; Mg, magnesium; Na, sodium; PCO2, partial pressure of carbon dioxide in the arterial blood.
From Refs. 41, 42.
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 T2DM. 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 than 320 mOsm/kg. The extreme hyperglycemia and large fluid deficits 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 20 to 74 years of age in the United States. Retino-pathy is staged as either nonproliferative or proliferative.
Nonproliferative 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 T2DM. This complication generally presents as pain, tingling, or numbness in the extremities. The feet are affected more often than the hands and fingers. 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-inflammatory 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
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 T2DM patients. For children with T1DM, 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 collection for measurement of the urine albumin/creatinine ratio. The desirable value is less than 30 mcg of albumin per mg of creatinine.
Microalbuminuria is defined as between 30 and 300 mcg of albumin per mg of creatinine. The presence of micro-albuminuria is a strong risk factor for future kidney disease in T1DM patients. In T2DM patients, micro albuminuria 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 T2DM 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 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 flow 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 flow 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 flow, 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 monofilament can detect areas of neuropathy. Treatment consists of glycemic control, preventing infection, debriding dead tissues, applying dressings, treating edema, and limiting ambulation. Untreated foot problems may develop gangrene, necessitating surgical intervention.
Patient Encounter, Part 2: Follow-Up Visit
EP comes in 1 week later for more education and brings in his blood glucose readings for you to download and review with him. See below. Readings are in units of mg/dL (mmol/L)
Are his blood glucose readings within target? What questions would you ask EP? Has a pattern been established?
You ask EP to remove his shoes and socks and you perform a foot screening. Why did you do this? Why is it important to record the results of the foot screening?
Does EP need to be referred to any specialists? If so, what type?
What nonpharmacologic interventions would you recommend for EP?
Are his blood pressure and lipids under control? Would you make any adjustments to therapy, and if so, specifically what?
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 (7.8 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 absorb 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.
When transferring someone from IV insulin drip to subcutaneous insulin, basal insulin should be administered several hours before the drip is discontinued to prevent loss of glycemic control. IV drip protocols are institution specific and will not be discussed. Hospitals may apply to receive a Certificate of Distinction for Inpatient Diabetes Care sponsored by the Joint Commission and the ADA.43
Sick Days
Patients should monitor their blood glucose levels more frequently during sick days because it is common for illness to increase blood glucose values. Patients with T1DM should check ketones when their blood glucose levels are greater than 300 mg/dL or higher. This may need to be done every 1 to 2 hours and additional insulin coverage may be necessary to prevent DKA.39 Sugar and electrolyte solutions such as sports drinks may be used by T1DM patients to prevent dehydration, electrolyte depletion, and hypoglycemia. Insulin treated patients with longstanding T2DM may also require ketone testing on sick days. Patients with T2DM may require sugar-free products if blood glucose levels are elevated consistently. Patients should be advised to eat smaller meals if possible during sick days to decrease nausea and maintain blood glucose control. 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 Encounter, Part 3: Follow-Up
It has been 3 years since EP was diagnosed with diabetes. His weight is now 123 kg (270 lb) and additional information can be found below about today’s visit.
Fasting glucose: 190 mg/dL (10.5 mmol/L); BP: 142/84 mm Hg; BUN: 13 mg/dL (4.64 mmol/L); creatinine: 0.9 mg/dL (80 μmol/L); AST/SGOT: 19 IU/L (0.34 μKat/L); ALT/SGPT: 20 IU/L (0.33 μKat/L); TSH: 1.26 microunits/mL (1.26 mU/L); total cholesterol: 236 mg/dL (6.1 mmol/L); LDL: 152 mg/dL (3.93 mmol/L); HDL: 29 mg/dL (0.75 mmol/L); triglycerides: 223 mg/dL (2.52 mmol/L); A1c: 10.6%; body fat: 48%; waist circumference: 48 inches (122 cm).
Blood Glucose Results (Units of mg/dL [mmol/L])
Current Meds:
• Metformin 1,000 mg (take one tablet twice daily to lower blood sugars)
• Glipizide 10 mg (take two tablets 30 minutes before breakfast daily to lower blood sugars)
• Diovan 320 mg (take one tablet daily to lower blood pressure)
• Chlorthalidone 25 mg (take one tablet daily to lower blood pressure)
• Simvastatin 80 mg (take one tablet daily to lower cholesterol)
• Cymbalta 60 mg (take one capsule once daily for peripheral neuropathy)
Meal History: EP says he is following his meal plan of 2,200 calories (9,205 kJ) (60 g carbohydrates at each meal and 30 g for bedtime snack). He also says he is limiting saturated fat to 17 g/day and sodium to 2,000 mg/day.
Physical Activity: Started walking 4 days/week for 30 minutes at moderate intensity
Plan—Next Steps
What are your treatment goals for EP regarding blood glucose, blood pressure, and lipids?
What therapeutic options would you consider if you determine that lifestyle or stress is not the cause of the changes in his results?
When would you want to see EP back in the office?
Patient Encounter, Part 4: Insulin Therapy
EP comes in 3 months later to assess the effectiveness of the changes that you suggested. His blood glucose, blood pressure, and lipids have been doing better. It is now 8 years since he was diagnosed, and he brings his readings in. He is discouraged because, although he has been taking his medication, following his meal plan, and is still physically active, he weighs 109 kg (240 lb). What therapeutic changes would you make and how would you teach EP to use the therapy suggested?
Fasting glucose: 180 mg/dL (10 mmol/L); BUN: 13 mg/dL (4.64 mmol/L); creatinine: 1 mg/dL (88 μmol/L); AST/SGOT: 26 IU/L (0.43 μKat/L); ALT/SGPT: 26 IU/L (0.43 μKat/L); TSH: 1.26 microunits/mL (1.26 mU/L); total cholesterol: 180 mg/dL (4.65 mmol/L); LDL: 98 mg/dL (2.53 mmol/L); HDL: 46 mg/dL (1.19 mmol/L); triglycerides: 130 mg/dL (1.47 mmol/L); A1c: 8.6%; body fat: 42%; waist circumference: 42 inches (107 cm)
Blood Glucose Results (units of mg/dL [mmol/L])
Current Medications
• Metformin 1,000 mg (take one tablet twice daily to lower blood sugars)
• Glipizide 10 mg (take two tablets 30 minutes before breakfast daily to lower blood sugars)
• Byetta 10 mg (inject twice daily to lower blood sugars)
• Diovan 320 mg (take one tablet daily to lower blood pressure)
• Chlorthalidone 25 mg (take one tablet daily to lower blood pressure)
• Lipitor 40 mg (take one tablet daily to lower cholesterol)
• Tricor 145 mg (take one tablet daily to lower cholesterol)
• Cymbalta 60 mg (take one capsule once daily for peripheral neuropathy)
Meal History: EP says he is following a meal plan of 2,000 calories (8,368 kJ) (60 g carbohydrates at each meal and 20 g for bedtime snack). He also says he is limiting saturated fat to 15 g/day and sodium to 2,000 mg/day.
Physical Activity: Increased walking to 5 days/week for 45 minutes at moderate intensity.
Plan—Next Steps
What are your treatment goals for EP regarding blood glucose, blood pressure, and lipids?
Are his readings within target? What questions would you ask EP? Has a pattern been established?
What therapeutic options would you consider if you determine that lifestyle or stress is not the cause of the changes in his results?
Should insulin therapy be considered for EP?
What type of insulin and dose would you recommend, and how would you transition EP to insulin?
What does EP need to know about insulin therapy before he leaves, and when should he return?
• 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 chafing; and monitoring blood glucose values as directed. Weekly appraisals of weight and blood pressure are also advised.
• Until A1c levels are at goal, quarterly visits with the patient’s primary health care provider are recommended. Table 43–7 summarizes the specific ADA goals for therapy. The practitioner should review SMBG data and a current 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.
Abbreviations Introduced in This Chapter
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 specific times of day or specific 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 (Table 43–7). What therapy goals are not being met? 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 modifications, appropriate monitoring, and drug therapy:
• Causes of DM complications and how to 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(s) should be reported to the physician?
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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