CONTINUING MEDICAL/PHARMACY EDUCATION
`
`Therapeutic Options for the Management
`of Type 2 Diabetes Mellitus
`
`Liza Takiya, PharmD, CDE, BCPS; and Sweta Chawla, PharmD
`
`AUDIENCE
`This activity is designed for primary care physicians, phar-
`macists, pharmacy directors, managed care organization
`medical directors and administrators, and payers for health
`services.
`
`GOAL
`To explain the economic and societal impact of type 2
`diabetes mellitus on the American population and
`describe new pharmacologic therapies for type 2 diabetes.
`
`LEARNING OBJECTIVES
`1. Describe the economic impact of diabetes mellitus on
`the US healthcare expenditure.
`2. Define the diagnostic criteria for diabetes mellitus.
`3. Differentiate diabetes mellitus from impaired fasting
`glucose and impaired glucose tolerance.
`4. Identify the goals of the treatment and the complica-
`tions of diabetes.
`5. Discuss the mechanism of action, contraindications,
`side effects, and monitoring parameters of rosiglita-
`zone, pioglitazone, metformin, miglitol, nateglinide,
`insulin glargine, insulin aspart, and inhaled insulin.
`
`CONTINUING MEDICAL EDUCATION CREDIT
`This activity has been planned and produced in accordance with
`the Essential Areas and Policies of the Accreditation Council for
`Continuing Medical Education. The Johns Hopkins University
`School of Medicine is accredited by the Accreditation Council for
`Continuing Medical Education to sponsor continuing medical edu-
`cation for physicians. The Johns Hopkins University School of
`Medicine takes responsibility for the content, quality, and scientific
`integrity of the CME activity.
`The Johns Hopkins University School of Medicine designates
`this educational activity for a maximum of 1.0 hour in category 1
`credit toward the AMA Physician’s Recognition Award. Each
`physician should claim only those hours of credit that he/she
`actually spent in the educational activity.
`This CME activity was produced under the supervision of Tabb
`Moore, MD, Associate Professor, Johns Hopkins University School
`of Medicine.
`Drs Takiya and Chawla have not received financial support for
`consultation, research, or evaluation and do not have a financial
`interest relevant to this article. The authors have indicated that this
`article does not reference unlabelled/unapproved uses of drugs.
`Program released November 30, 2002; program expires
`November 30, 2004.
`CONTINUING PHARMACY
`EDUCATION CREDIT
`This course has been approved for a total of two (2)
`contact hours of continuing education credit (0.2
`CEUs) by the University of Tennessee College of Pharmacy. The
`University of Tennessee College of Pharmacy is approved by the American
`Council on Pharmaceutical Education as a provider of continuing pharma-
`ceutical education. ACPE Program Number: 064-999-02-209-H-01. This
`course expires on November 30, 2004.
`
`From the Department of Clinical Pharmacy, University of the
`Sciences in Philadelphia, Penn (LT); and Arnold and Marie Schwartz
`College of Pharmacy and Health Sciences, Long Island University,
`Brooklyn, NY (SC).
`Address correspondence to: Liza Takiya, PharmD, CDE,
`University of the Sciences in Philadelphia, 600 South 43rd Street,
`Philadelphia, PA 19104. E-mail: l.takiya@usip.edu.
`
`The incidence of diabetes mellitus is steadily increasing
`in the United States. Currently the United States spends
`approximately $100 billion in healthcare costs annually for
`the management of diabetes. Most of the costs are attrib-
`uted to hospitalizations and treatment of diabetes compli-
`cations. Preventing these complications with tight glycemic
`control is the key to reducing morbidity, mortality, and
`healthcare costs secondary to diabetes mellitus. Recently,
`the American College of Endocrinology also stressed earli-
`er screening for diabetes and endorsed lowering the goal
`percent of hemoglobin glycosylation to 6.5%. These strate-
`gies help identify patients with diabetes at an earlier stage
`and in turn prevent more complications. Better control of
`diabetes is now feasible with the recent approval of 8 new
`antidiabetic products. Pioglitazone and rosiglitazone are
`agents with a novel mechanism of action. Metformin XR,
`insulin aspart, and miglitol are agents that are similar to
`previously marketed products, but have different pharma-
`cokinetic or pharmacodynamic properties. Metformin/gly-
`buride is the first combination product for the treatment of
`diabetes. Nateglinide represents the first agent in a new
`class of antidiabetic agents and insulin glargine is a novel
`insulin preparation. All of the agents have unique charac-
`teristics that may render them useful in specific patient
`populations.
`
`(Am J Manag Care 2002;8:1009-1023)
`
`T he term diabetes mellitus, from the Latin for
`
`“sweet urine,” is used to describe a series of
`metabolic disorders that are characterized
`by glucose intolerance. Diabetes mellitus (DM) is
`a chronic disease that affects approximately 16
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`CONTINUING MEDICAL/PHARMACY EDUCATION
`
`million Americans, with an estimated 90% diagnosed
`with type 2 DM.1 Although DM has no known cure,
`recently a number of advancements in treatment
`have been developed. Outcomes from the Diabetes
`Control and Complications Trial and the United
`Kingdom Prospective Diabetes Study (UKPDS) trials
`coupled with new drug therapies have provided prac-
`titioners with new treatment approaches.
`
`EPIDEMIOLOGY
`
`The Centers of Disease Control (CDC) recently
`declared diabetes an “emerging epidemic” because of
`the steady rise in incidence rates. In past years the
`annual incidence rate was steady at about 2 to 3 per
`1000 people; however, in 2000 the incidence rate
`increased to 6 per 1000 people. This rise is attributed
`to many causes such as the increase in the life
`expectancy of Americans, increase in overall popula-
`tion, and the increased incidence of obesity and
`sedentary lifestyle. Approximately 800 000 new
`cases of DM are documented yearly, with the highest
`prevalence rate among patients older than 65 years.1
`The disease has no gender predilection; however, in
`the United States, African Americans, Latin Americans,
`and Native Americans have the highest incidence of
`DM.1 If left unmanaged, DM results in devastating
`consequences. It is the number one cause of adult
`blindness in the United States and the second most
`common cause of end-stage renal disease.2 Diabetes
`is also associated with other comorbid conditions
`including hypertension, dyslipidemia, myocardial
`infarction, ischemic stroke, lower extremity amputa-
`tions, and peripheral/autonomic neuropathy.
`The management of diabetes is associated with
`approximately $100 billion in healthcare costs annu-
`ally, accounting for 13% of total US healthcare
`expenditures.3 Of the $100 billion, $44 billion is
`spent on direct medical costs: approximately half of
`the costs are dedicated to treatment of the condition
`itself and the other half to treatment of the chronic
`complications.4 Not only does the management of
`diabetes have a significant impact on direct medical
`costs, it also accounts for significant morbidity and
`indirect medical costs. In 1997, the American
`Diabetes Association (ADA) estimated that DM was
`associated with approximately $37.1 billion in dis-
`ability costs and $16.9 billion secondary to mortali-
`ty.3 Studies have demonstrated that by using
`intensive therapy regimens for diabetic patients, the
`overall cost of healthcare may decrease by reducing
`the treatment costs of chronic complications.4
`
`PATHOPHYSIOLOGY
`
`Of the 16 million people with diabetes in the
`United States, approximately 90% to 95% have type
`2 DM.1 Type 2 DM is a chronic metabolic disorder of
`abnormal glucose homeostasis resulting from inade-
`quate insulin action and insulin secretion. Unlike
`type 1 DM, type 2 DM is believed to stem from a dual
`effect of (1) insulin resistance and (2) secondary β-
`cell failure. Insulin resistance is a phenomenon by
`which insulin receptors found on peripheral muscle
`cells are unable to bind or recognize serum insulin
`properly, resulting in a compensatory increase in
`pancreatic production of insulin. Due to inadequate
`functioning insulin receptors and insulin activity,
`intracellular uptake of serum glucose is poor. This
`continuum results in further hyperglycemia and
`hyperinsulinemia. This phenomenon varies greatly
`from type 1 DM in which the primary defect is β-cell
`production of insulin. Type 1 DM is an autoimmune
`disorder in which the β cells in the pancreas are
`destroyed and therefore the pancreas is unable to
`produce insulin.
`
`DIAGNOSIS
`
`Diabetes may be diagnosed from results of 3 blood
`tests: fasting blood glucose, random blood glucose, or
`oral glucose tolerance test (OGTT). The ADA rec-
`ommends screening all patients over age 45 every 3
`years, and younger patients with significant risk
`factors. The American College of Endocrinology and
`the American Association of Clinical Endocrinology
`support these recommendations, and specifically
`state that all high-risk patients should be screened
`beginning at age 30. Screening entails acquiring fast-
`ing blood glucose levels. The diagnosis of DM can be
`made with any combination of 2 of the following
`results: fasting blood glucose concentration of 126
`mg/dL or higher, random blood glucose concentra-
`tion of more than 200 mg/dL with hyperglycemic
`symptoms, or 2-hour OGTT of more than 200
`mg/dL.5 Although glycosylated hemoglobin (HbA1c)
`is recommended as a monitoring parameter for DM,
`it is not recommended as a diagnostic test because
`patients with normal HbA1c levels may have abnor-
`mal fasting or random blood glucose
`levels.
`Therefore, the HbA1c test has limited sensitivity to
`detect patients with diabetes.
`Many patients may not have clinically defined
`DM, but may have “prediabetes” with either an
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`Therapies for Type 2 Diabetes
`
`Table 1. Diagnostic Criteria for Diabetes Mellitus*
`
`Euglycemia
`Impaired fasting glucose
`Impaired glucose tolerance
`Diabetes mellitus
`
`Fasting Plasma
`Glucose†, mg/dL
`
`Random Plasma
`Glucose, mg/dL
`
`2 Hour Plasma Glucose
`Post-OGTT‡,
`mg/dL
`
`< 110
`110–125
`< 110
`≥ 126
`
`< 140
`< 140
`140–199
`≥ 200§
`
`< 140
`< 140
`140–199
`≥ 200
`
`*Data from Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.5
`†Fasting is defined as no caloric intake for at least 8 hours.
`‡Oral glucose tolerance test (OGTT) consists of a glucose load of 75 g anhydrous glucose dissolved in water.
`§Random plasma glucose ≥ 200 mg/dL with patient exhibiting symptoms of hyperglycemia.
`
`impaired fasting glucose or impaired glucose toler-
`ance. Because each of these conditions increases the
`risk of developing diabetes, prompt lifestyle modifi-
`cations are indicated for these patients. Table 1 out-
`lines diagnostic criteria for impaired fasting glucose,
`impaired glucose tolerance, and DM.
`
`CLINICAL FEATURES
`
`Many patients with type 2 DM may be asympto-
`matic at the time of diagnosis since because hyper-
`glycemic symptoms do not occur until the blood
`glucose level is significantly elevated. Patients with
`type 2 DM tend to be overweight, possibly secondary
`to the propensity for hyperinsulinemia. Also, tradi-
`tionally, type 2 DM was thought to occur in patients
`older than 40 years; recently, however, the inci-
`dence of type 2 DM among children has risen, possi-
`bly secondary to the increase in sedentary lifestyle
`and poor dietary habits. Symptoms of uncontrolled
`blood glucose levels such as fatigue, headache, and
`polyphagia are mainly a result of lack of cellular
`energy. Polyuria is a result of osmotic diuresis sec-
`ondary to glucose spilling in the urine, whereas poly-
`dipsia is a result of dehydration secondary to
`polyuria. Acute changes in vision such as blurred
`vision are a result of an increase in osmotic pressure
`in the retinal cavity.
`Long-term complications of DM include a variety
`of macrovascular and microvascular complications.
`Paresthesias and neuropathy are a result of neuronal
`damage due to chronic hyperglycemia. Nephropathy
`and retinopathy are a result of increased pressure in
`the renal and retinal arteries. Myocardial infarction,
`ischemic stroke, and peripheral vascular disease are
`
`a result of poor control of dyslipidemias, and
`changes in endothelial lining. Fortunately, all of the
`devastating long-term complications may be pre-
`vented with good glycemic control. The UKPDS6
`demonstrated that intensive treatment strategies
`utilizing insulin, oral sulfonylureas, or metformin
`can decrease the risk of any diabetes-related end
`point including angina, myocardial infarction, heart
`failure, stroke, renal failure, amputation, retinopa-
`thy, blindness, or sudden death due to hypoglycemia
`or hyperglycemia by 12%. This 10-year study also
`demonstrated that by decreasing HbA1c by 11%,
`(from 7.9% to 7.0%) the risk of microvascular com-
`plications (retinopathy, nephropathy, and neuropa-
`thy) decreases by 25%.6
`
`TREATMENT APPROACH
`
`Effective management of the disease requires a
`partnership between the patient and the healthcare
`professional. The healthcare professional must
`aggressively treat and educate, and the patient must
`adhere to appropriate nonpharmacologic, pharma-
`cologic, and self-care measures. Successful treat-
`ment of diabetes is achieved by adopting a holistic
`approach. Diabetes can affect the medical, social,
`and financial aspects of a person’s life, therefore
`each aspect should be discussed with the patient.
`The goal for managing diabetes is to achieve opti-
`mal blood glucose control to prevent or minimize
`complications. Based on the recent update from
`the American College of Endocrinology and the
`American Association of Clinical Endocrinologists,7
`“optimal glycemic control” is defined as HbA1c less
`than 6.5% with fasting blood glucose levels between
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`CONTINUING MEDICAL/PHARMACY EDUCATION
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`80 and 110 mg/dL and postprandial blood glucose
`levels less than 140 mg/dL.7 Because recent studies
`have supported the relationship between lowering
`HbA1c and risk reduction of macrovascular and
`microvascular complications, these goals are more
`aggressive than traditional goals. By achieving these
`goals it has been found that the risk of microvascular
`and macrovascular complications of DM is reduced by
`14% to 25%.7 Many other preventive measures such as
`vaccination for pneumonia and influenza, treatment
`with aspirin and angiotensin-converting enzyme
`inhibitors, ophthalmology visits, and podiatry visits,
`should also be considered in patients with diabetes.
`Nonpharmacologic treatments including dietary
`changes and physical activity are the cornerstones of
`therapy for DM. However, many patients are unable
`to achieve optimal glycemic control with nonphar-
`macologic measures alone. Due to the lack of options
`and cost, oral sulfonylurea agents were traditionally
`considered the first-line treatment option for type 2
`DM. Monotherapy with sulfonylureas provides fair
`glycemic control with minimal side effects and at
`relatively low cost; however, they are also known
`to cause hyperinsulinemia. Hyperinsulinemia is
`associated with the “metabolic syndrome,” which
`is characterized by obesity, hypertension, and dys-
`lipidemias resulting in a possible increased risk in
`cardiovascular deaths. These effects of hyperinsu-
`linemia are independent of the effect of hyper-
`glycemia seen in diabetes. Many of the newer
`therapeutic options do not induce hyperinsulinemia,
`and therefore are becoming first-line therapy.
`
`NEW THERAPEUTIC OPTIONS
`
`Since 1999, 8 new products have been available
`for the treatment of diabetes. Each agent is unique
`in its pharmacokinetic or pharmacodynamic proper-
`ties. A brief discussion of each of the new products
`follows. Table 2 summarizes the pharmacologic and
`clinical efficacy of the individual products as well as
`the cost comparisons of each product.
`
`Thiazolidinediones
`The thiazolidinediones, or more commonly called
`“glitazones,” enhance insulin sensitivity at the level
`of the skeletal muscle, hepatic, and adipose tissue.
`These agents stimulate peroxisome proliferator-acti-
`vated receptor-γ (PPAR-γ), which enhances the repli-
`cation of the glucose transporter, GLUT-4, allowing
`extracellular glucose to move intracellularly, thereby
`lowering overall blood glucose levels. Because the
`
`glitazones act at the molecular level, peak glucose-
`lowering effect is seen 10 to 14 weeks after initiation
`of therapy. Also, glitazones do not stimulate insulin
`production, therefore hyperinsulinemia does not
`result, and when used as monotherapy the risk of
`hypoglycemia is minimal.
`Along with improving glycemic control, glitazones
`are also currently being studied for their use in poly-
`cystic ovarian syndrome (PCOS), because hyperin-
`sulinemia is a characteristic of PCOS. Because these
`agents stimulate ovulation in premenopausal amen-
`orrheic women, it is important to counsel patients
`on proper contraception methods.
`PPAR-γ is also responsible for lipid metabolism.
`Consequently, the thiazolidinediones are found to
`increase low-density lipoprotein cholesterol (LDL-C),
`high-density lipoprotein cholesterol (HDL-C), and
`total cholesterol levels by 5% to 15%, and decrease
`triglyceride levels by 5% to 15%.9-11 In a 26-week
`study, statistically significant increases in total cho-
`lesterol, LDL-C, and HDL-C were found in rosiglita-
`zone treatment groups at 4 mg daily and 8 mg daily
`when compared with baseline levels and when com-
`pared with metformin monotherapy. No significant
`difference in triglyceride levels was found between or
`within groups.11 Pioglitazone also showed similar lipid
`effects when compared with placebo. Overall,
`pioglitazone was found to significantly increase in
`HDL-C, LDL-C, and total cholesterol levels, and to
`decrease triglyceride levels when compared with
`baseline values.9,10,12 These results are clinically rele-
`vant because patients with diabetes traditionally have
`low HDL-C and high triglyceride levels. Therefore the
`thiazolidinediones may improve the lipid profile of
`diabetic patients; however, it is important to note that
`they may also increase LDL-C. Along with the effects
`on cholesterol levels and insulin sensitivity, PPAR-γ is
`also found to stimulate adipocyte replication, causing
`weight gain.13 Although the weight gain is minimal
`(about 5 to 10 pounds), more studies are needed to
`determine the clinical effect of the weight gain.10,13,14
`Given the high prevalence of obesity in type 2 DM,
`even minimal weight gain could be considered a sig-
`nificant adverse effect.
`Treatment with these agents as monotherapy
`or in combination with metformin, sulfonylureas,
`or insulin has traditionally been well tolerated.
`Occurrences of adverse events are comparable to
`placebo with the exception of edema. In fact,
`thiazolidinediones as metformin have less hypo-
`glycemic effect compared with other antidiabetic
`agents. Common adverse events include upper
`respiratory infection and headache. In addition,
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`

`Therapies for Type 2 Diabetes
`
`Table 2. Comparisons of Selected Antidiabetic Agents*
`
`Drug Product
`
`Glyburide (Micronase/ Diabeta)
`
`Metformin (Glucophage/Gluco-
`phage XR)
`
`Metformin/Glyburide (Glucovance)
`
`Miglitol (Glyset)
`
`Nateglinide (Starlix)
`
`Pioglitazone (Actos)
`
`Rosiglitazone (Avandia)
`
`Mechanism
`of Action
`
`Absolute
`Contraindication
`
`Stimulates β-cell
`to enhance insulin
`secretion from
`pancreas
`
`Inhibits hepatic
`gluconeogenesis
`and enhances
`insulin sensitivity
`
`Pregnancy,
`type 1 diabetes,
`sulfa allergy
`
`Men SCr > 1.5 mg/dL,
`women SCr > 1.4 mg/dL;
`acute/uncompensated
`heart failure, sepsis,
`hypoxia
`
`Pregnancy, type 1
`Inhibits hepatic
`diabetes, sulfa allergy,
`gluconeogenesis.
`Stimulates β-cell
`men SCr > 1.5 mg/dL,
`to enhance insulin women SCr > 1.4 mg/dL,
`secretion from
`acute/uncompensated
`pancreas
`heart failure, sepsis,
`hypoxia
`
`Maximum HbA1c
`Lowering (%)
`(Monotherapy)
`
`1.0-1.5
`
`Cost ($)†
`(AWP for
`30-day supply)
`
`46.30 (generic)
`
`Equivalent
`Doses
`
`10 mg
`twice daily
`
`1.0-1.5
`
`1000 mg
`twice daily
`
`89.53;
`78.80 (XR)
`
`1.0-2.0
`
`500/5 mg
`(2 tablets)
`twice daily
`
`93.99
`
`Inhibits α-glucosi-
`dase enzymes
`in order to delay
`carbohydrate
`metabolism and
`absorption
`
`Stimulates β-cell
`to enhance insulin
`secretion from
`pancreas
`
`Stimulates PPAR-γ
`to enhance
`synthesis of glucose
`transporters
`
`Stimulates PPAR-γ
`to enhance
`synthesis of glucose
`transporters
`
`Gastrointestinal obstruction,
`inflammatory bowel
`disease
`
`0.5-1.0
`
`100 mg
`3 times daily
`
`62.81
`
`Type 1 diabetes, pregnancy
`
`0.5-1.0
`
`120 mg
`3 times daily
`
`86.40
`
`Class III/IV heart failure,
`liver failure
`
`1.0-1.5
`
`45 mg daily
`
`154.29
`
`Class III/IV heart
`failure, liver failure
`
`1.0-1.5
`
`8 mg daily
`
`142.40
`
`Aspart (NovoLog)
`
`Insulin analog
`
`Lispro (Humalog)
`
`Insulin analog
`
`Insulin NPH (Novolin)
`
`Insulin analog
`
`Glargine (Lantus)
`
`Insulin analog
`
`No absolute
`contraindications
`
`No absolute
`contraindications
`
`No absolute
`contraindications
`
`No absolute
`contraindications
`
`Depends on
`dose
`
`1 vial
`(1000 units)
`
`Depends on
`dose
`
`1 vial
`(1000 units)
`
`Depends on
`dose
`
`1 vial
`(1000 units)
`
`Depends on
`dose
`
`1 vial
`(1000 units)
`
`45.31
`
`45.11
`
`24.34
`
`43.95
`
`*Data from Cardinale.8
`†Generic cost of medications are provided when available.
`HbA1c indicates hemoglobin A1c ; AWP, average wholesale price; SCr, serum creatinine; PPAR-γ, peroxisome proliferator-activated recep-
`
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`CONTINUING MEDICAL/PHARMACY EDUCATION
`
`edema and anemia have been associated with the
`thiazolidinediones.11,14–16 Due to the risk of develop-
`ing a fluid overload status, these agents are not rec-
`ommended in patients with New York Heart
`Association class III or IV heart failure. Recently,
`exacerbation of congestive heart failure has been an
`increased concern for patients treated with the thi-
`azolidinediones. Patients should be warned and
`should be prompted to seek medical attention if
`they develop edema, shortness of breath, weight
`gain, fatigue, or weakness. Decreases in hemoglobin
`and hematocrit levels have also been associated
`with the first 4 to 8 weeks of therapy and may be
`related to the increase in fluid volume. The risk of
`developing anemia is mild; however, hemoglobin
`levels should be monitored during the initial months
`of treatment. Present clinical trials have not identi-
`fied hepatotoxicity as a common adverse effect,
`however, the glitazones are contraindicated in
`patients with liver disease. In addition, monitoring
`liver function at baseline, every other month for the
`first year, and every 6 months thereafter is required
`when using these agents. Lastly, like most oral
`
`Reference
`
`Phillips et al18
`
`Fonesca et al11
`
`Wolffenbuttel et al19
`
`Aronoff et al9
`
`Einhorn et al10
`
`Kipnes et al20
`
`Patients, No.
`
`Duration,
`Wk
`
`959
`
`483
`
`593
`
`408
`
`249
`
`478
`
`26
`
`26
`
`24
`
`24
`
`16
`
`16
`
`Table 3. Comparison of Clinical Trials of Currently Marketed Thiazolidinediones
`
`antidiabetics, the glitazones are not recommended
`in pregnant patients and are classified as pregnancy
`category C.15
`Troglitazone was the first member of this class of
`drugs to be approved; however, in March, 2000 it
`was withdrawn from the market because it was
`associated with idiosyncratic hepatotoxicity.17
`Currently 2 thiazolidinediones are on the market:
`rosiglitazone (Avandia; SmithKline Beecham, Phila-
`delphia, Penn), and pioglitazone (Actos; Takeda
`Pharmaceuticals America, Inc, Lincolnshire, Ill).
`Currently, no direct head-to-head trials have com-
`pared pioglitazone and rosiglitazone. However,
`many studies have been conducted to demonstrate
`the efficacy of both agents within similar cohorts.
`Rosiglitazone Maleate (Avandia). Rosiglitazone
`is the second member of the thiazolidinedione class
`that was approved by the US Food and Drug Admin-
`istration (FDA) in 1999 as monotherapy or in com-
`bination with metformin in conjunction with diet
`and exercise to lower blood glucose levels in
`patients with type 2 DM.15 Rosiglitazone is available
`as 2-, 4-, and 8-mg tablets and may be adminis-
`tered with
`or
`without food to a
`maximum dose of
`8 mg/day at once-
`or
`twice-daily
`dosing. The pri-
`mary
`route of
`elimination
`is
`through the kid-
`ney; however, no
`dose adjustment
`is required
`for
`patients with renal
`i m p a i r m e n t .
`Currently no clini-
`cally
`significant
`drug interactions
`have been associat-
`ed with rosiglita-
`zone.15
`R o s i g l i t a z o n e
`has been evaluated
`as monotherapy
`and in combination
`with metformin or
`sulfonylureas
`in
`multiple, 26-week-
`long, trials. Results
`from these studies
`have consistently
`
`Drug Regimen and
`HbA1c Reduction
`
`Rosiglitazone 4 mg qd: −0.8 %*
`Rosiglitazone 2 mg bid: −0.9%*
`Rosiglitazone 8 mg qd: −0.1%*
`Rosiglitazone 4 mg bid: −1.5%*
`Met 2.5 g qd/Ros 4 mg qd: −1.0%*
`Met 2.5 g qd/Ros 8 mg qd: −1.2%*
`Sulfonylurea/Ros 2 mg qd: −0.59%†
`Sulfonylurea/Ros 4 mg qd: −1.03%†
`Pioglitazone 15 mg qd: −1.0%*
`Pioglitazone 30 mg qd: −1.0%*
`Pioglitazone 45 mg qd: −1.6%*
`Met/Pioglitazone 30 mg qd: −0.83%‡
`Sulfonylurea/Pio 15 mg qd: −0.8%§
`Sulfonylurea/Pio 30 mg qd: −1.2%§
`
`*P < .001 when compared with placebo.
`†P < .05 when compared with sulfonylurea alone.
`‡P < .01 when compared with metformin alone.
`§P < .05 when compared with placebo.
`HbA1c indicates hemoglobin A1c; qd, every day; bid, twice a day; Met, metformin; Ros, Rosiglitazone; Pio,
`pioglitazone.
`
`1014
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`THE AMERICAN JOURNAL OF MANAGED CARE
`
`NOVEMBER 2002
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`MPI EXHIBIT 1077 PAGE 6
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`

`

`Therapies for Type 2 Diabetes
`
`rosiglitazone significantly
`that
`demonstrated
`reduces HbA1c and fasting plasma glucose levels in
`patients with type 2 DM.11,18,19 When used as
`monotherapy, rosiglitazone has demonstrated a
`reduction in HbA1c at all dosage ranges (4-8 mg/day).
`Clinically significant decreases in HbA1c were
`observed at the maximal dosing of 8 mg/day.
`Interestingly, the 4 mg twice-daily dose had a greater
`effect on HbA1c than the 8 mg daily dose. In a 26-
`week study with 959 patients, rosiglitazone demon-
`strated a dose-dependent reduction in HbA1c when
`compared with placebo18 (Table 3). In addition,
`combination therapy with rosiglitazone shows simi-
`lar significant improvements. In a 26-week study
`483 patients who were already stabilized on met-
`formin 2.5 g daily were randomized to either contin-
`uing metformin 2.5 g daily or receiving metformin
`2.5 g daily in combination with rosiglitazone at
`either 4 or 8 mg daily.11 Results showed a significant
`drop in HbA1c with either combination (Table 3).
`Rosiglitazone in combination with sulfonylureas
`has an additive effect. During a 24-week, multicenter
`study, 593 patients were randomized to receive sul-
`fonylurea monotherapy, or a sulfonylurea in combina-
`tion with rosiglitazone at either 2 or 4 mg daily.20 The
`sulfonylurea/rosiglitazone combinations were associat-
`ed with dose-dependent decreases in HbA1c in com-
`parison with sulfonylurea-monotherapy19 (Table 3).
`Pioglitazone Hydrochloride (Actos). Pioglitazone
`is the newest thiazolidinedione approved by the FDA
`as monotherapy or in combination with a sulfony-
`lurea, metformin, or insulin for the improvement of
`glycemic control in patients with type 2 DM when
`diet and exercise is insufficient. Pioglitazone is
`available in 15-, 30-, and 45-mg tablets and can be
`taken without regard to meals. The drug is metab-
`olized primarily hepatically, and to date no clini-
`cally significant drug interactions have been
`documented. However, the cytochrome P450 iso-
`form CYP3A4 is partially responsible for metabo-
`lism. Patients on multiple hepatically metabolized
`drug regimens should be monitored for possible
`drug interactions.21
`Pioglitazone is effective as monotherapy or in
`combination with sulfonylureas, metformin, or
`insulin.21 In a 6-month study, 408 patients were ran-
`domized to either placebo, or pioglitazone 7.5, 15,
`30, or 45 mg daily.9 All doses of pioglitazone reduced
`HbA1c significantly when compared with placebo;
`however, higher doses had a greater effect on HbA1c
`(Table 3). When stratifying patients between those
`who were naïve to therapy and those who were pre-
`viously treated with drug therapy, the glucose-lower-
`
`ing effect was dramatically greater in those patients
`who were naïve to therapy at all doses.8 Maximum
`HbA1c lowering was found 10 to 14 weeks after initi-
`ation of therapy.
`Similar, statistically significant glycemic lowering
`has been demonstrated when pioglitazone is used in
`combination with either metformin or sulfonylureas.
`In a 16-week, double-blind study, 249 patients were
`randomized to either metformin alone or metformin
`plus pioglitazone 30 mg daily.10 At week 16, the
`pioglitazone group statistically significantly lowered
`HbA1c by 0.83%.9 (Table 3). In another 16 week trial,
`placebo or pioglitazone at 15 or 30 mg was used in
`combination with a stable regimen of a sulfonylurea
`in 478 patients.20 The most common sulfonylurea
`used was either glyburide (55%) or glipizide (37%). A
`statistically significant dose-dependent decrease in
`HbA1c and fasting plasma glucose concentrations was
`found between the 2 pioglitazone doses and both sta-
`tistically significantly decreased HbA1c when com-
`pared with placebo (Table 3).
`Overall, the data supports the use of rosiglitazone
`and pioglitazone as monotherapy or in combination
`with other antidiabetic agents to improve glycemic
`control. Although no trials have compared rosiglita-
`zone and pioglitazone head to head, neither agent
`seems to provide a large benefit over the other. As a
`class, they enhance glycemic parameters by lower-
`ing HbA1c by about 1.5 points, and have potential
`beneficial effects on lipid parameters.
`
`Metformin (Glucophage, Glucophage XR,
`Glucovance)
`Approval of metformin has changed treatment
`strategies for type 2 DM. Although traditionally sul-
`fonylureas were considered first-line therapy for
`patients with type 2 DM, metformin is now preferred
`in certain patient populations. Metformin primarily
`affects glucose levels by inhibiting hepatic gluconeo-
`genesis; however, it also increases peripheral glucose
`uptake, and decreases intestinal absorption of glu-
`cose.22 Because metformin does not stimulate fur-
`ther insulin production, and therefore does not
`cause hyperinsulinemia, this agent is now favored
`over sulfonylureas, especially in the obese popula-
`tions. The UKPDS 34 study demonstrated the use of
`metformin in overweight (> 120% ideal body weight)
`patients over a 10-year period. When compared with
`sulfonylureas and insulin therapy, metformin had an
`overall lower incidence of weight gain in obese dia-
`betics patients.23
`Overall, metformin achieves tight glycemic con-
`trol without weight gain when compared with sul-
`
`VOL. 8, NO. 11
`
`THE AMERICAN JOURNAL OF MANAGED CARE
`
`1015
`
`MPI EXHIBIT 1077 PAGE 7
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`

`

`CONTINUING MEDICAL/PHARMACY EDUCATION
`
`fonylureas and significantly reduces HbA1c by 1 to
`1.5 percentage points with continued therapy.
`Also, although minor, metformin beneficially affects
`the lipid profile by decreasing LDL-C by 1.0% to
`1.5% and increasing HDL-C levels by 4% to 5%.
`However, contraindications to metformin limit its
`use. Metformin is associated with lactic acidosis.
`Although the incidence of lactic acidosis is low, it
`should be used cautiously in patients with condi-
`tions that may predispose them to acidosis such as
`heart failure, pulmonary congestion, and respiratory
`distress.23 It should be discontinued in patients with
`hypoxemia, metabolic acidosis, sepsis, and acute
`heart failure or class IV heart failure.23 It is absolute-
`ly contraindicated in patients with elevated serum
`creatinine levels (> 1.5 mg/dL in men, > 1.4 mg/dL
`in women), and should be used cautiously in
`patients with impaired renal function. Serum creati-
`nine, therefore, should be monitored periodically.23
`Metformin must also be discontinued for 48 hours
`after any procedure using iodinated contrast dyes to
`prevent cases of lactic acidosis.23
`Metformin is currently available in 3 different for-
`mulations: immediate-release (Glucophage; Bristol-
`Myers Squibb, Princeton, NJ), extended-release
`(Glucophage XR; Bristol-Myers Squibb), and in a com-
`bination formulation with glyburide (Glucovance;
`Bristol-Myers Squibb). All metformin products have
`similar indications, contraindications, and precau-
`tions. Although the immediate-release formulation
`has been on the market for more than 7 years, the
`others are new.
`Metformin/Glyburide (Glucovance). Glucovance
`is the first combination oral hypoglycemic product.
`The combination formulation of metformin and gly-
`buride was approved by the FDA in July 2000.
`Although combination therapy (> 1 agent) is rou-
`tinely necessary for adequate glycemic control, n