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Defeating Diabetes

Treatment for Diabetes

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The ADA categorizes patients demonstrating IFG or IGT as having prediabetes.

The categorization thresholds of glucose status for FPG determination and the OGTT

are listed in Table 43-6. 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 peri-phera 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.

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, 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 Aic (Aic) 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 Aic 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). 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). 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 un-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 Aic

Glucose interacts spontaneously with hemoglobin in red blood cells to form glyc-osylated derivatives. The most prevalent derivative is A. Greater amounts of glyc-osylation 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. 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 Aic to eAG is: eAG = 28.7 x Aic - 46.726 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 ^-hydroxybu-tyric 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





Less than

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Home tests for P-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 non-diabetics. 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 ti trated 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 43-2 summarize updated treatment algorithms for T2DM. Algorithms from AACE for T2DM can be found at 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.

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.


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 pmol/L); GFR (Modified Diet in Renal Disease [MDRD]) 90.8; AST/SGOT: 19 IU/L (0.32 pKat/L); ALT/SGPT: 20 IU/L (0.33 pKat/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 x 10 years; history of elevated cholesterol x 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, hyperbi-lirubinemia, 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.

Start with bedtime mtermediate-act*ig insulin or bedtime or morning long-acting insulin (can initiate with 10 units or 0.2 units per Kg)

Check lasting glucose (fingerstkfc) usually daily and increase dose, typicaly by 2 units every 3 days until fasting levels are consistently in target range (3.9-7.2 mmol/L 70-130 mg/dL). Can increase dose m larger increments, eg. by 4 units every 3 days, if fastmg glucose is greater than 10 mmol/L (180 mg/dL)

H hypoglycemia occurs, or fasting glucose level less than 3.9 mmol/L (70 mg/dL). reduce bedtime dose by 4 units or 10%— whichever is greater

A1C greater than or equal to 7% after 2-3 months

Continue regimen. Check A,c every 3 mo

If fasting BG is in larger range (3.9-7.2 mmoVL (70-130 mg/dLJ). check BG before lunch, dinner, and bed Depending on BG results, add second injection as below. Can usually begin with 4 units and adiust by 2 units every 3 days until BG is in range

Pre! unch BG out of range: Add rapid-acting insulin at breakfast'

Predmner BG out of range: Add NPH insulin at breakfast or rapid-acting at lunch

Prebed BG out of range: Add rapid-acting insulin at dinner

A,c greator than or equal to 7% after 3 months

Rech eck premeal BG levels and if out of range, may need to add another injection. If AlC continues to be out of range, check 2 hours postprandial levels and adjust preprandial rap*d-actmg irvsuhn

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. "Premixed 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. (Aic, hemoglobin Aic; 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. 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 Aic every 3 months until Aic less than 7% and then at least every 6 months. The interventions should be changed if Aic greater than or equal to 7%. a Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. ^Insufficient clinical use to be confident regarding safety. See Figure 43-1 for initiation and adjustment of insulin. (Aic, hemoglobin Aic; CHF, congestive heart failure; GLP-1, glucagon-like peptide-1.) (From Ref. 27.)

FIGURE 43-2. Algorithm for the metabolic management of T2DM; reinforce lifestyle interventions at every visit and check Aic every 3 months until Aic less than 7% and then at least every 6 months. The interventions should be changed if Aic greater than or equal to 7%. a Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. ^Insufficient clinical use to be confident regarding safety. See Figure 43-1 for initiation and adjustment of insulin. (Aic, hemoglobin Aic; 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 a-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 in-

crease in physical activity. 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 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 psycho logical 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


Influenza and pneumonia are common preventable infectious diseases that increase mortality and morbidity in persons with chronic diseases including DM. Yearly influenza vaccinations, commonly called flu shots, are recommended for patients with DM. Pneumococcal vaccination is also recommended for patients with DM as a onetime 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 contin-

27 3134

ue to take oral glucose lowering medications. Table 43-8 lists the oral agents,

and Figure 43-2 displays the ADA Treatment Algorithm for Patients with T2DM. 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 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 ^-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.

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 sulfonylur-eas 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 ^-cell destruction. One limitation of sulfonylurea therapy is the inability of these products to stimulate insulin release from ^-cells at extremely high glucose levels, a phenomenon called glucose toxicity. 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. Gl-itinide secretagogues also produce a pharmacologic effect by interacting with ATP-sensitive potassium channels on the ^-cells; however, this binding is to a receptor adjacent to those to which sulfonylureas bind.

The primary 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


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They also may be used in combination therapy with other drugs to achieve synergistic effects. Combinations with biguanides are most commonly seen.


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 Aic 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 Aic 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 post-meal blood glucose. The ADA treatment algorithm (Fig. 43-2) considers lifestyle

modification and metformin as first-line therapy. Metformin does not affect insulin release from ^-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 prnol/ L) in women and 1.5 mg/dL (133 p,mol/L) in men. Additionally, therapy with metformin should be withheld in patients undergoing radiographic procedures in which a nephrotoxic dye is used. Therapy should be withheld the day of the procedure, 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.


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-y). Stimulation ofPPAR-y 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 Aic 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, nonsulf-onylurea secretagogue, metformin, or insulin with a thiazolidinedione can improve A1c reductions 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). Piogl-itazone has been shown to decrease serum triglycerides by 10% to 20%, whereas no substantial effect is observed with rosiglitazone. LDL cholesterol concentrations in crease 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 piogl-itazone, 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 27

the use of this agent. a-Glucosidase Inhibitors

Acarbose and miglitol are a-glucosidase inhibitors currently approved in the United States. An enzyme that is along the brush boarder of the intestine cells called a-gluc-osidase breaks down complex carbohydrates into simple sugars, resulting in absorption. The a-glucosidase inhibitors work by delaying the absorption of carbohydrates from the intestinal tract, which reduces the rise in postprandial blood glucose concentrations. As monotherapy, a-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, Aic 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 ofintestinal 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 a-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 a-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 gluconeogen-esis. 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 A1c reductions 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 P-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 is the one agent that can be used in all types of DM with the most effectiveness for blood sugar control. 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 43-227

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

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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 di-mers 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 glar-gine 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.

Diabetic Pump Ratio
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). 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.


Pramlintide acetate was approved for use in the United States in March 2005 (Table

43-10). This agent is a synthetic analog of human amylin, which is a naturally occurring neuroendocrine peptide that is cosecreted by the ^-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 Aic 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 hy-poglycemia. 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 a-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 Cardi-

ovascular Risk in Diabetes (ACCORD), 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.


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 al

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