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RELEASE DATE: JULY 31, 2008 EXPIRATION DATE: JULY 30, 2010 ESTIMATED TIME TO COMPLETE: Jointly sponsored by the Duke University School of Medicine and Jespersen & Associates, LLC This CME activity is supported by an educational grant from GlaxoSmithKline.


Signposts and Pathways: Multidimensional Care for Patients with Type 2 Diabetes

Editorial Board Activity Medical Director Ann J. Brown, MD, MHS Department of Medicine/Division of Endocrinology Duke University School of Medicine Durham, North Carolina Authors Tracy L. Setji, MD Department of Medicine/Division of Endocrinology Duke University Medical Center Durham, North Carolina Katherine C. Pereira, MSN, FNP Department of Medicine/Division of Endocrinology Duke University Medical Center Durham, North Carolina M. Angelyn Bethel, MD Department of Medicine/Division of Endocrinology Duke University Medical Center Durham, North Carolina Angela F. Jarman Department of Medicine/Division of Endocrinology Duke University Medical Center Durham, North Carolina

Cover Photography by Amy S. Phillips

Jointly Sponsored by the Duke University School of Medicine and Jespersen & Associates, LLC This CME activity is supported by an educational grant from GlaxoSmithKline.

CME Information Disclaimer

Statement of Need Based upon a review of the literature, clinicians need an updated, evidence-based, comprehensive guide to caring for patients with, and at risk for developing, type 2 diabetes mellitus. This includes prevention, screening, diagnosis, and therapeutic interventions for diabetes, along with an understanding of the psychosocial impact of diabetes. ”Signposts and Pathways: Multidimensional Care for Patients with Type 2 Diabetes” is designed to provide healthcare providers with the most current information on diabetes.

Target Audience This monograph is intended for healthcare professionals who are involved in the primary care of patients with, and at risk for developing, type 2 diabetes mellitus. This may include family physicians, general internists, nurse practitioners, and physician assistants.

Learning Objectives At the conclusion of this activity, participants should be able to: • Diagnose prediabetes and diabetes • Identify patients at high risk of developing type 2 diabetes and discuss evidence-based methods to prevent progression to diabetes • Evaluate for and recognize complications of type 2 diabetes, including psychiatric manifestations • Develop an appropriate care plan that emphasizes lifestyle therapy (diet and exercise) and includes the current FDA-approved medications for type 2 diabetes as well as investigational therapies • Successfully monitor patients’ treatment plans and goals


The information provided at this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.

Faculty Disclosure The following authors and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity: Ann J. Brown, MD, MHS; Tracy L. Setji, MD; Katherine Pereira, MSN, FNP; Angela Jarman, BA; Anna Robinson Brodeur, BA. The following authors and/or planning committee members have indicated they have relationships with industry to disclose relative to the content of this CME activity: M. Angelyn Bethel, MD, has indicated she is a speaker for Merck, Aventis Pharmaceutical. She is a co-investigator for Sanofi-aventis, Novartis.

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Duke University School of Medicine and Jespersen & Associates, LLC. The Duke University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Unapproved Use Disclosure

Credit Designation

Duke School of Medicine requires CME faculty (authors) to disclose to attendees when products or procedures being discussed are off-label, unlabeled, experimental, and/or investigational (not FDA-approved); and any limitations on the information that is presented, such as data that are preliminary or that represent ongoing research, interim analyses, and/or unsupported opinion. Faculty may discuss information about pharmaceutical agents that is outside of U.S. Food and Drug Administration approved labeling. This information is intended solely for continuing medical education and is not intended to promote off-label use of these medications. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information.

Instructions on How to Receive CME Credit

The Duke University School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

To receive CME credit for reviewing this self-study activity, participants must review the materials on accreditation information (learning objectives, disclosures, etc),


review the entire self-study monograph, complete the self-assessment and evaluation form, and mail the evaluation form to: Duke Office of CME 3100 Tower Boulevard, Suite 1300 Durham, North Carolina 27707

Questions About CME Credit:

Questions About the Monograph:

For continued study and additional information, please visit the accompanying CME-accredited web module with interactive case studies on Type 2 Diabetes: www.ja-online.com/dukediabetes

Office of Ann J. Brown, MD, MHS Box 3611, DUMC Durham, North Carolina 27710 Telephone: (919) 684-4139

Duke Office of CME Telephone: (919) 401-1200 E-mail: [email protected]

Contents CME Information...................................................................................................................................................................................................2 Introduction............................................................................................................................................................................................................4 Epidemiology..........................................................................................................................................................................................................4 Epidemiology of Adolescent Diabetes....................................................................................................................................................4 Pathogenesis of Type 2 Diabetes ....................................................................................................................................................................4 Risk Factors.............................................................................................................................................................................................................5 Screening and Diagnosis.....................................................................................................................................................................................5 Type 2 Diabetes............................................................................................................................................................................................5 Gestational Diabetes Mellitus...................................................................................................................................................................6 Prevention of Type 2 Diabetes..........................................................................................................................................................................7 Lifestyle...........................................................................................................................................................................................................7 Pharmaceutical Agents...............................................................................................................................................................................7 Summary of Diabetes Prevention...........................................................................................................................................................10 Complications......................................................................................................................................................................................................10 Microvascular Complications.................................................................................................................................................................10 Macrovascular Complications.................................................................................................................................................................11 Psychosocial Complications.................................................................................................................................................................... 12 Management of Type 2 Diabetes................................................................................................................................................................... 13 Glycemic Control........................................................................................................................................................................................ 13 Exercise..................................................................................................................................................................................................................14 Medical Nutrition Therapy....................................................................................................................................................................... 15 Diabetes Education and Care Models................................................................................................................................................... 16 Pharmaceutical Agents......................................................................................................................................................................................18 Future Outlook.................................................................................................................................................................................................... 24 References........................................................................................................................................................................................................... 25 Continuing Medical Education Assessment............................................................................................................................................... 28 Continuing Medical Education Assessment Answers............................................................................................................................. 29 Continuing Medical Education Activity Evaluation Form........................................................................................................................ 30 Continuing Medical Education Credit Attestation Form......................................................................................................................... 32




The prevalence of type 2 diabetes has doubled since 1980, a trajectory that places it alongside the plague, typhoid, and influenza in the alarming category of epidemics. Yet, unlike these infectious disease epidemics, diabetes is a chronic condition that requires long-term management and the associated and persistent demands of time, money, and energy. As a result, healthcare providers and a growing number of their patients are facing—together—a long-term relationship with each other and with diabetes. This relationship requires stamina, innovation, and trust. This monograph is meant to assist with the challenges of caring for patients with diabetes by providing information about prevention, early detection, and multifaceted therapy for diabetes. It is appropriate for all providers but is written for those who provide primary diabetes care, and in this capacity, coordinate care over time.

The vast majority of patients with diabetes—over 90%— have type 2 diabetes. This form of the disease is characterized by insulin resistance and dysfunction of the insulin-producing pancreatic beta cells. Type 2 diabetes begins when the body develops a resistance to insulin and no longer utilizes it effectively. At this stage, insulin levels are elevated and blood glucoses are normal. Over time, the chronically overproducing pancreas loses its ability to produce sufficient amounts of insulin to regulate blood sugar, and blood sugars rise. In the early stages this may be detected as prediabetes (either impaired glucose tolerance or impaired fasting glucose), before progressing to type 2 diabetes. Type 1 diabetes, in contrast, results from autoimmune destruction of the beta cells and is much less common than type 2. Type 1 diabetes will not be specifically addressed in this monograph.

Over the past several years, exciting changes have occurred in the medical options for treating patients with diabetes. Incorporating all of these changes into the already complex care of individuals with diabetes can be challenging. This monograph is intended to provide a practical approach to managing patients with type 2 diabetes, based on existing evidence in the medical literature. It includes information about the pathogenesis of and risk factors for diabetes, as well as screening and preventive strategies. It also addresses several classes of complications common in patients with diabetes, including mental health issues. The sections on diabetes management include discussions of lifestyle therapy and provide an extensive review of pharmacologic treatment options.

Epidemiology of Adolescent Diabetes


In 2007, the Centers for Disease Control and Prevention (CDC) estimated that 23.6 million people—or 8% of the U.S. population—have diabetes.1 Diabetes is a particular concern for aging Americans. Among those aged 60 years or older, it is estimated that nearly one in four has diabetes.1 Patients with diabetes are at a markedly increased risk of micro- and macrovascular complications, including renal failure, blindness, neuropathy, and cardiovascular disease. Based on death certificate data from 2006, diabetes was the seventh leading cause of death in the United States.1 Perhaps more compelling, though, are data showing that diabetes more than doubles one’s risk of developing cardiovascular disease,2 which is the most common cause of death for all adults. Thus, death certificate data may underestimate the real impact of diabetes on mortality.3 Data from the Framingham Heart Study estimate that men and women aged 50 or older with diabetes live 7.5 and 8.2 fewer years, respectively, than those without diabetes.2 The costs associated with diabetes and its complications are also staggering. The CDC estimated the total economic impact of diabetes in 2007 at $174 billion, $116 billion of which was for direct medical costs.1 4

Although the prevalence of diabetes rises with age, it is increasingly affecting adolescents. In 2007, approximately 186,300 people aged 20 and younger in the United States had diagnosed diabetes (0.2% of all people in this age group).1 Historically, juvenile-onset diabetes has been synonymous with type 1, because the vast majority of childhood diabetes diagnoses were type 1. This assumption is changing, though, as the prevalence of type 2 diabetes among adolescents is increasing at a remarkable rate. This is a public health concern as those diagnosed with diabetes before age 20 may have a life expectancy that is 15 to 27 years shorter than average.4 To answer some of the many questions about adolescent diabetes, the CDC and the National Institutes of Health (NIH) funded a large, multicenter study, known as SEARCH for Diabetes in Youth.5 The study includes more than 5 million subjects, which represents 6% of all American children aged 0 to 19 years; this is the largest and most racially and geographically diverse study cohort involved in a youth diabetes study to date.6 The SEARCH for Diabetes in Youth Study estimated a prevalence rate of 0.18% for all U.S. youth aged less than 20 years.7 This rate is slightly deceptive, though, in that it varies substantially by age. Among those aged 0 to 9 years, the prevalence rate is 0.08%, which is consistent with estimates that type 1 diabetes still accounts for more than 80% of diabetes cases in this age group.7 Adolescents, however, are increasingly developing type 2 diabetes—a disease usually diagnosed in adults aged 40 years or older.7, 8 Among those 10 to 19 years old, the prevalence rate is 0.28%, much higher than in younger children.

Pathogenesis of Type 2 Diabetes

Insulin resistance is generally the first abnormality detected in individuals with type 2 diabetes.9 In healthy individuals, pancreatic beta cells can compensate for insulin resistance by producing more insulin, thus main-


taining normoglycemia. This compensation occurs in part by increasing beta-cell mass, an expansion resulting from increases in nutrient supply, the activity of various growth factor signaling pathways, and glucagon-like peptide 1 (GLP-1) signaling.10 Insulin resistance does not necessarily lead to type 2 diabetes. As long as beta-cell compensatory mechanisms are adequate, normoglycemia is maintained. It is only when pancreatic beta cells can no longer produce enough insulin to maintain normoglycemia that hyperglycemia develops. The mechanisms that lead to beta-cell failure are complex and include both genetic and acquired defects.10 Molecular mechanisms postulated as possible initiators of diabetes include mitochondrial dysfunction, dysregulation of triglycerides and free fatty acid cycling, and disordered AMP-activated protein kinase/malonyl-CoA signaling. Once hyperglycemia develops, the elevated glucose levels have a toxic effect on beta-cell function. This effect, known as glucotoxicity, results in damage to beta cells and further pancreatic insufficiency. Though a discussion of the mechanisms of glucotoxicity is beyond the scope of this monograph, for a comprehensive review, please see the article by Prentki and Nolan.10

Risk Factors

There are several well-recognized risk factors for developing type 2 diabetes. These include body mass index (BMI), age (60 years or older), ethnicity, family history of diabetes, and personal history of prediabetes, gestational diabetes, polycystic ovary syndrome, high blood pressure (140/90 mm Hg or higher), sedentary lifestyle, cardiovascular disease, low HDL, and high triglycerides.11 When evaluating patients for type 2 diabetes risk, it is important to note that risk rises in proportion with the number of risk factors present. A few of these risk factors will be specifically discussed here. Obesity may be the most common risk factor for developing diabetes, and is thought to be a major driver of the diabetes epidemic. Rates of obesity have doubled since the late 1970s, with 34% of U.S. adults aged 20 and over now being obese (BMI > 30).12 Prevalence rates of obesity are highest in people ages 40 to 59 (about 40.0% of men and 41.1% of women).12 Ethnicity is an important contributor to diabetes risk. NonHispanic white adults in the United States have the lowest risk of developing diabetes. Compared to non-Hispanic whites, non-Hispanic blacks and Mexican Americans are 1.8 and 1.7 times as likely to have diabetes, respectively.13 American Indians, especially in the southern United States, have a very high prevalence rate of diabetes; approximately 26.7% of adults in this area are affected. When data on American Indians and Alaska Natives are combined and compared with non-Hispanic whites, these

populations are 2.2 times more likely to develop diabetes. The overall risk of developing diabetes among Asian Americans and Pacific Islanders is not known throughout the United States. However, in California, Asian Americans are 1.5 times more likely; in Hawaii, Asian Americans and Pacific Islanders are 2 times more likely to develop diabetes than non-Hispanic whites.13 Family history of diabetes among first-degree relatives is also an important risk factor. Data from the Framingham Offspring Study suggest that children with a parental history of diabetes have an odds ratio for developing type 2 diabetes of 1.87 (95% CI, 1.28-2.72).14 The health of one’s parents may even be important before birth. Children of women with gestational diabetes mellitus (described below in ”Screening and Diagnosis”) are at increased risk of developing insulin resistance, obesity, and type 2 diabetes.15 Therefore, the intrauterine metabolic environment may play a role in susceptibility to type 2 diabetes later in life. There is also an association between low birth weight and increased risk of developing type 2 diabetes.16 A recent study found that very low birth weight (600-1,500 g) was associated with insulin resistance and impaired carbohydrate metabolism in young adults.17 For women, reproductive health impacts diabetes risk. A history of gestational diabetes or delivery of a baby weighing > 9 lb increases risk of developing type 2 diabetes later in life. Although 90% of cases of gestational diabetes initially resolve following delivery of the infant,18 up to 70% of women with a history of gestational diabetes subsequently develop type 2 diabetes.19 Women with polycystic ovary syndrome (PCOS), which is characterized by oligo/anovulation and hyperandrogenism, are at a markedly increased risk of developing metabolic complications related to insulin resistance.20 In addition to an increased risk of gestational diabetes,21 approximately 40% of women with PCOS develop prediabetes or type 2 diabetes by the age of 40.22 Because several characteristics are associated with an increased risk of developing type 2 diabetes, effective prevention relies on the recognition of those at increased risk of developing diabetes and working with patients to implement proven preventive strategies.

Screening and Diagnosis Type 2 Diabetes Screening for type 2 diabetes is recommended by the American Diabetes Association (ADA) in all individuals 45 years or older.11 If a patient is overweight (see Table 1 for classification according to body mass index) and has another risk factor for diabetes (as described previously), screening should begin earlier. If initial screening is negative, testing should be repeated every three years. The most commonly used screening test is fasting plasma



TABLE 1. Classification of Body Mass Index Body Mass Index (kg/m2) Underweight

< 18.5






> 30

Source: Department of Health and Human Services; Centers for Disease Control & Prevention. About BMI for adults. http://www.cdc.gov/nccdphp/dnpa/bmi/adult_BMI/about_adult_BMI.htm. Accessed June 23, 2008.

glucose. However, a 75 g oral glucose tolerance test (OGTT) can also be used, and may offer the advantage of earlier detection of diabetes, or prediabetes. This is because many patients with early diabetes will first show abnormalities in their carbohydrate metabolism after ingesting glucose, effectively a metabolic ”stress test.” Thus, the two-hour glucose level during the OGTT is often elevated before fasting glucose becomes impaired. The diagnoses of prediabetes and diabetes have evolved over the past decade (see Table 2). The term ”prediabetes” now includes patients with impaired fasting glucose (IFG) (fasting plasma glucose of 100-125 mg/dL) and/or impaired glucose tolerance (IGT) (two-hour glucose of 140-199 mg/dL during a 75 g OGTT). Diabetes is diagnosed when patients meet any one of the following criteria: (1) casual plasma glucose > 200 mg/dL accompanied by symptoms of diabetes; (2) fasting plasma glucose > 126 mg/dL; or (3) a two-hour glucose > 200 mg/dL during a 75 g oral OGTT.11 If the diagnosis of diabetes is equivocal or if glucose levels are close to the cutoff values, repeat testing should be performed on a different day to confirm the diagnosis.

can be confusing because the screening and diagnostic criteria differ from those of type 2 diabetes. The decision to screen a woman for GDM depends on her estimated risk of developing type 2 diabetes. According to current ADA recommendations, women who are low risk do not need to undergo screening for GDM; women who are at average risk should undergo screening between 24 and 28 weeks; and women who are at high risk should undergo screening at the time of pregnancy confirmation, or as early in the pregnancy as possible. If the initial screen in a high-risk woman is normal, she should be retested between 24 and 28 weeks of gestation.11

Gestational Diabetes Mellitus

To be considered low risk, a woman must meet all of the following criteria: younger than 25 years of age, normal pre-pregnancy weight, no history of abnormal glucose tolerance or poor obstetric outcome, low-risk ethnic background, and no family history of diabetes among her first-degree relatives. A woman is considered high risk if she is obese, has a history of GDM, has evidence of glucose in her urine, or has a strong family history of diabetes; another group that has recently been identified as having an increased risk of developing GDM is women with PCOS.21 Women are considered average risk if they do not meet criteria for either high or low risk.

Gestational diabetes mellitus (GDM) refers to diabetes that is diagnosed in a woman during pregnancy; it occurs in approximately 7% of all pregnancies.11 Diagnosing GDM

A two-tiered approach for screening and diagnosing GDM is most commonly used. The first tier consists of

Table 2. Classification of Prediabetes, Type 2 Diabetes, and Gestational Diabetes

Fasting (mg/dL)

Prediabetes 75 g OGTT

Type 2 Diabetes 75 g OGTT

Gestational Diabetes 100 g OGTT

100-125 (IFG)

> 126

> 95

1-hour (mg/dL) 2-hour (mg/dL)

> 180 140-199 (IGT)

> 200

3-hour (mg/dL) IFG: Impaired Fasting Glucose

> 155 > 140

IGT: Impaired Glucose Tolerance

Note: For the diagnosis of prediabetes or diabetes, one of the two criteria above must be met. For the diagnosis of gestational diabetes, two of the four above criteria must be met. Source: Standards of medical care in diabetes—2008. Diabetes Care. 2008;31 Suppl 1:S12-54.



screening with a nonfasting 50 g OGTT.11 The cutoff values used for the one-hour glucose following ingestion of the 50 g glucose solution vary. If 140 mg/dL is the glucose threshold, approximately 80% of women with GDM will be identified. If 130 mg/dL is the threshold, the sensitivity will increase to 90%; however, the falsepositive rate will also increase. If a woman fails the 50 g OGTT screen, she should undergo a diagnostic three-hour 100 g OGTT. To diagnose GDM with the 100 g OGTT, two or more of the following plasma glucose levels must be reached: fasting > 95 mg/dL, one-hour > 180 mg/dL, two-hour > 155 mg/dL, and three-hour > 140 mg/dL (see Table 2). In patients at high risk for GDM, providers may choose to skip the 50 g glucose screening test and perform only the diagnostic three-hour 100 g OGTT. In women with a history of gestational diabetes, current recommendations suggest a repeat OGTT six weeks postpartum for reclassification of glycemic status.11 If the OGTT is normal, patients should be retested at least every three years. If the OGTT is consistent with prediabetes, patients should be retested annually and counseled about preventive strategies.

Prevention of Type 2 Diabetes

The ADA guidelines note that up to 70% of individuals with the prediabetic states of IFG or IGT will eventually develop diabetes.23 (See definitions of IFG and IGT under ”Screening and Diagnosis.”) The risk for cardiovascular disease is only moderately elevated with IFG and IGT, but that risk increases sharply with the onset of type 2 diabetes. Thus, identifying people at risk for diabetes and employing interventions to prevent the progression to diabetes are imperative. Clinical trials investigating the effects of lifestyle interventions as well as pharmaceutical agents have demonstrated that the progression from prediabetes to diabetes can be delayed and/or prevented. These interventions are discussed next.

Lifestyle Several large, randomized studies have examined the relationship between lifestyle modification, which includes diet and exercise, and the prevention of diabetes (see Table 3). The Da Qing IGT and Diabetes Study randomized 577 patients with impaired glucose tolerance (IGT) from a population-based screening program in northern China.24 The study randomized these high-risk participants to one of four interventions: diet only, exercise only, diet and exercise, or control. After a six-year followup, the incidence of diabetes was significantly lower in all of the intervention groups compared to control (incidence of diabetes in the diet-only group was 44%; exercise-only group 41%; diet and exercise group 46%; and control group 68%; p < 0.05 for each intervention vs. control). The study was underpowered to evaluate differences between the intervention groups; it does, however,

demonstrate the positive impact lifestyle interventions can have in preventing diabetes in high-risk adults. A second trial, the Finnish Diabetes Prevention Study (DPS), found similar effects of lifestyle modification on diabetes incidence. The researchers enrolled 522 patients with either IFG or IGT from a screening population in which a first-degree relative was already diagnosed with type 2 diabetes. The participants were randomized to either a control group or an intervention group. The control group received general information about diet and exercise. The intervention group received detailed recommendations: 5% weight reduction, < 30% daily fat intake, < 10% daily saturated fat intake, increased fiber intake, and moderate exercise for 30 minutes daily. After four years, the cumulative incidence of diabetes in the intervention group was 11% compared with 23% in the control group (HR 0.4, 95% CI, 0.3-0.7, p < 0.001).25 The reduction in the incidence of diabetes was associated with a relatively small absolute weight loss and correlated with the ability of patients to reach the diet and exercise goals of the study. The third and most recent study, the Diabetes Prevention Program (DPP), evaluated the effect of lifestyle interventions on the incidence of diabetes.26 This study randomized a diverse group of 3,234 overweight patients in the United States with IFG and IGT to one of three interventions: standard lifestyle recommendations plus placebo, standard lifestyle recommendation plus metformin, or intensive lifestyle modification. Patients in the intensive lifestyle modification group were instructed to exercise at least 150 minutes a week, and to lower their intake of fat and calories; these changes were designed to yield a 7% weight loss. Patients in this group received one-on-one counseling on diet, exercise, and behavioral modification. Over the three-year study, these patients reduced their risk of progressing to type 2 diabetes by 58%.26, 27 Lifestyle change was even more effective in those aged 60 and older; they reduced their risk by 71%.26 Those who received standard lifestyle recommendations plus metformin, as discussed in the following section, experienced a 31% reduction in the incidence of diabetes. Based on these results, modest lifestyle interventions help high-risk individuals prevent type 2 diabetes. In other words, diet modification and exercise work. Taken together, these studies suggest that decreasing weight by as little as 5% to 7% and exercising the equivalent of walking 150 minutes per week can lead to substantial reductions in diabetes risk (see Table 3).

Pharmaceutical Agents Although a healthy lifestyle is important in preventing diabetes and should form the basis of every therapeutic intervention, recent trials have shown that medications



Table 3. Summary of Randomized Clinical Trials for Diabetes Prevention in Subjects with Impaired Glucose Tolerance Trial (n)


Mean Follow-up (years)

New DM (%)



Da Qing

Standard lifestyle


Diet alone


Exercise alone


Diet + exercise



Finnish DPS

Standard lifestyle


Intensive lifestyle


Standard lifestyle + placebo


Standard lifestyle + metformin


Intensive lifestyle













11 2.8







42 32


Rosiglitazone 6


25 11


9 6


Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20(4):537-544 2. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-1350. 3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403. 4. Chiasson JL, Josse RG, Gomis R, et al; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359(9323):2072-2077. 5. Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368(9541):1096-1105. 6. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27(1):155-161.

can be useful additions to preventive therapy. There have been four major trials published that evaluated the use of pharmaceutical agents in the prevention of diabetes; one additional trial is ongoing. Each of these is discussed next, and the results are summarized in Table 3.

Metformin As discussed earlier, the Diabetes Prevention Program (DPP) evaluated metformin in combination with standard lifestyle advice for the prevention or delayed onset of diabetes. In fact, this is the only study to date that has evaluated metformin for this purpose. Results showed that metformin was more effective than placebo, but only about half as effective as intensive lifestyle interventions (31% compared with 58%) in reducing the incidence of diabetes. Patients in the metformin group experienced more adverse gastrointestinal events than either placebo or lifestyle interventions. Serious adverse events, however, 8

such as hospitalization and death, occurred at low rates and were unrelated to treatment group. The ADA recently released a consensus statement endorsing the use of metformin for diabetes prevention in certain individuals.23 These guidelines take into account data from eight major clinical trials published between 1997 and 2006, all of which showed reductions in the development of diabetes, ranging from 25% to 60%. According to the ADA guidelines, patients who have both IFG and IGT, and at least one additional characteristic may benefit from adding metformin 850 mg twice daily to lifestyle therapy.23 Those characteristics include age less than 60 years, BMI of 35 kg/m2 or greater, glycated hemoglobin > 6.0%, family history of diabetes in firstdegree relatives, elevated triglycerides, or reduced HDL cholesterol. Glycated hemoglobin should be monitored semiannually in patients treated with metformin. Patients


with both IFG and IGT but none of the characteristics listed previously should receive lifestyle therapy alone. Patients who have either IFG or IGT, but not both, should also receive lifestyle therapy alone.

Acarbose Acarbose has also been studied for its utility in preventing diabetes in high-risk individuals. Like metformin, it has been shown to delay the onset of diabetes. It is an alphaglucosidase inhibitor designed to inhibit glucose uptake at the brush border of the small intestine, thus decreasing postprandial hyperglycemia. In the Study to Prevent NonInsulin-Dependent Diabetes Mellitus (STOP-NIDDM), 32% of patients with prediabetes treated with acarbose progressed to diabetes, compared with 42% in the placebo group, resulting in a 25% relative risk reduction.28 In addition, posthoc analyses showed that patients randomized to acarbose also had a reduced risk of ”any cardiovascular event,” including myocardial infarction, angina, cardiovascular death, congestive heart failure, stroke, and peripheral vascular disease (HR 0.51, 95% CI, 0.28-0.95, p = 0.03).29 This analysis was limited, however, by the small number of such events (15 in the acarbose group and 32 in the placebo group, of a total of 1,439 participants) and by the lack of adjustment for testing multiple hypotheses. The trial also had a higher than expected rate of discontinuation (24% overall), and patients randomized to acarbose often could not be titrated to the maximum daily dose due to gastrointestinal side effects. While acarbose may be an effective pharmacologic intervention to prevent diabetes, gastrointestinal side effects may limit its clinical utility.

Thiazolidinediones Thiazolidinediones (TZDs), which bind to peroxisome proliferator-activated receptors (PPAR), enhance peripheral insulin sensitivity through a series of mechanisms that enhance the transcription of insulin-responsive genes. These PPAR agonists improve several markers of insulin resistance, including free fatty acids, adipocytokines (such as tumor necrosis factor alpha), resistin, and adiponectin, making TZDs a potentially attractive option for preventing or delaying the onset of type 2 diabetes. The DPP initially included a troglitazone arm in its design, but the treatment was discontinued after the death of one participant in this arm and increasing concerns about its potential liver toxicity.30 Troglitazone was ultimately removed from the market due to acute liver toxicity. Despite the short exposure time in the trial, troglitazone was associated with a significant (75%) reduction in the progression to diabetes. Adequate collection of adverse events was not possible due to the early discontinuation of the treatment group. The most extensive evaluation of TZDs for diabetes prevention was done in the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial.31 This study evaluated the effects of rosiglitazone and

ramipril on progression from IGT to type 2 diabetes. Of the patients with IGT who participated in the study, those treated with rosiglitazone had a 60% reduction in the primary composite outcome of diabetes or death. However, rosiglitazone’s salutary effect on diabetes prevention was accompanied by an increased rate of congestive heart failure compared to nonusers. The FDA has amended package labeling for the drug, which notes potential heartrelated risks.32 For additional discussion of the effects of TZDs on cardiovascular endpoints, see the section on ”Pharmaceutical Agents” for treating diabetes. Finally, those randomized to rosiglitazone experienced weight gain (2.2 kg) compared to those randomized to placebo.

Meglitinides The meglitinides, repaglinide and nateglinide, are short-acting insulin secretagogues that work similarly to the sulfonylureas. They are structurally similar to the nonsulfonylurea moiety of glyburide and work by closing the ATP-dependent potassium channel in the pancreatic beta cell, causing increased insulin secretion. Like acarbose, meglitinides are primarily designed to decrease postprandial hyperglycemia. Although no trials to determine their effect on diabetes prevention have been completed, one is underway. Similar to the DREAM trial, the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is evaluating the effects of an oral antidiabetic (nateglinide) and an antihypertensive (valsartan) on progression from IGT to type 2 diabetes.33 Enrolled patients are either at high risk for or have existing cardiovascular disease, in addition to having IGT. The study will also evaluate the effect of therapy on cardiovascular events. Results from this multinational trial are due in late 2009.

Orlistat Orlistat is a medicine that inhibits gastrointestinal lipase and thus blocks the absorption of fat. It is commonly used to supplement diet and exercise in patients trying to lose weight. The XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) trial demonstrated that treatment with 120 mg orlistat before each meal resulted in a 37% reduction in the risk of developing diabetes among nondiabetic patients in comparison to a placebo over four years.34 Greater weight loss was also seen in the group treated with orlistat (-5.8 kg) compared to placebo (-3.0 kg). In contrast to the studies discussed, this one included both patients with normal glucose tolerance (79% of participants) and patients with either IFG or IGT (21% of participants). Subsequent analyses suggested that the decreased risk of developing diabetes in this trial was attributable to the decreased cumulative incidence of diabetes among those who had baseline IFG and IGT, whereas participants with normal baseline carbohydrate metabolism did not benefit from orlistat. Orlistat



is a relatively safe medication, though its use may be limited by gastrointestinal side effects; it is now available over the counter in the United States in 60 mg capsules.

Summary of Diabetes Prevention Although at least four oral pharmaceutical agents have been associated with delayed progression to diabetes (see Table 3), none are currently FDA-approved for treatment of patients with prediabetes. The ADA, however, has recently endorsed the use of metformin therapy in addition to lifestyle interventions in some patients, as described above. The decision to use metformin should be made on an individual basis, taking into account the risks and benefits of the therapy in each patient. Although the evidence suggests that the onset of diabetes can be delayed, there is no evidence that the overall risk of developing diabetes or complications is reduced. Thus, a drawback of pharmacologic treatment for prediabetes may be the exposure of an asymptomatic population to the risks of pharmacologic therapy without a clear benefit. Consequently, lifestyle interventions remain first-line therapy for patients with prediabetes.

Treatment for microalbuminuria consists of good glycemic and blood pressure control. The treatment goal for blood pressure is < 130/80 mm Hg and is discussed in further detail following (see “Hypertension”). In patients with microalbuminuria, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are first-line therapy because they reduce protein excretion. Even if blood pressure is normal, ACE inhibitors or ARBs should be considered in patients with microalbuminuria. If a patient has nephropathy, the ADA also recommends that protein be restricted in the diet. Patients with nephropathy should be counseled by a nutritionist to design a balanced meal plan consisting of 0.8 g/kg of protein per day.11 Reducing dietary protein intake and taking measures to reduce urinary protein excretion slow progression of nephropathy and renal failure.



Microvascular Complications Microvascular complications—such as nephropathy, retinopathy, and neuropathy—are relatively common in patients with type 2 diabetes. Though common, they can be prevented or delayed with aggressive treatment. For instance, the U.K. Prospective Diabetes Study (UKPDS) demonstrated a 25% reduction in microvascular complications (fatal or nonfatal renal failure, retinopathy requiring photocoagulation, and vitreous hemorrhage) with tight glycemic control compared to conventional therapy.35 Tight blood pressure control reduced microvascular complications by 37%.36 Preventing these complications and slowing their progression are thus major treatment goals (see Table 4).

Nephropathy Approximately 20% to 40% of patients with diabetes will develop nephropathy.11 Risk factors include hypertension, poor glycemic control, and race/ethnicity; African American, Hispanic, and Native Americans are at increased risk compared to non-Hispanic whites. Early detection along with aggressive glucose and blood pressure control help prevent the development and progression of nephropathy. Patients with type 2 diabetes should be screened for nephropathy at the time of their initial diagnosis.11 This is done by measuring the albumin:creatinine ratio in a spot urine collection. The ratio is considered normal if it is less than 30 mcg/mg creatinine; microalbuminuria if it is 30 to 299 mcg/mg creatinine; and albuminuria if it is 300 or more mcg/mg creatinine. For diabetic patients with negative screens, it is recommended that the albumin:creatinine ratio be repeated on an annual basis.


For diabetic patients with positive screens, repeat testing should be done to confirm diagnosis (up to three times within a three- to six-month period). Patients with two positive tests should be treated for microalbuminuria.

One in five patients with type 2 diabetes has retinopathy at the time of their initial diabetes diagnosis. This suggests a fairly long preclinical duration of diabetes, during which time hyperglycemia is present but undetected; this causes retinal vascular damage. Further, more than 60% of patients with type 2 diabetes eventually develop retinopathy.37 Retinopathy is essentially a form of vascular disease—a consequence of vascular occlusion in the vessels supplying the retina. Retinal ischemia leads to macular edema (swelling of the retina that occurs as a result of fluid leaking from the blood vessels within the macula) and proliferation of new blood vessels, the hallmark of proliferative retinopathy. Retinopathy and/or macular edema can lead to vision changes and eventually blindness. Retinopathy is classified in the one of the following categories: mild nonproliferative, moderate to severe nonproliferative, or proliferative. Patients should be screened for retinopathy at the time of their diabetes diagnosis and on an annual basis thereafter. Early therapy with laser photocoagulation has been shown to reduce visual loss.37 As with nephropathy, good glycemic and blood pressure control are essential in preventing the development and/or progression of retinopathy.

Neuropathy Longstanding diabetes and poor glycemic control both raise one’s risk of developing neuropathic complications. Peripheral diabetic neuropathy may lead to foot ulcers that do not heal and, in severe cases, amputations. Regular foot examinations are essential for patients with diabetes. Annual screening examinations should include a


Table 4. Summary of Recommendations for Screening and Preventing Complications Frequency of Checking




Blood glucoses

Fasting and pre-meal 70-130 mg/dL (lower in pregnancy) Postprandial < 180 mg/dL (lower in pregnancy)

Every office visit

Blood pressure

< 130/80 mm Hg

Foot examination if known neuropathy

Prevention and early detection and treatment of foot lesions


Glycated hemoglobin

< 7.0%, less stringent if elderly or history of significant hypoglycemia; every 6 months if A1c is at goal


Ophthalmology examination

Detect and treat retinopathy at earliest stage

Microalbumin:creatinine ratio

Microalbumin:creatinine < 30 mcg/mg creatinine


LDL < 100 mg/dL (consider < 70 mg/dL if patient has cardiovascular disease) HDL > 40 mg/dL in men, > 50 mg/dL in women; triglycerides < 150 mg/dL

Statin therapy

Consider in all patients >40 yrs old with type 2 diabetes, particularly if LDL is > 100 mg/dL or they have other risk factors for cardiovascular disease

ACE inhibitor or ARB therapy

Consider in patients with microalbuminuria/ nephropathy and/or elevated blood pressure

Aspirin therapy

Consider in all patients with type 2 diabetes who are over age 40 or have other risk factors for cardiovascular disease


Influenza vaccine annually. Pneumococcal vaccine should be given to all adults with diabetes; revaccination should be considered if it has been > 5 years and patient is 65 years or older or has another indication for repeat vaccination.

Smoking cessation

All patients should be counseled regarding the risks of smoking

Source: Standards of medical care in diabetes—2008. Diabetes Care. 2008;31 Suppl 1:S12-54.

neurological assessment with the 10 g monofilament, assessment of pedal pulses, and evaluation for skin or bone deformities.11 Additional testing for vibration, temperature, pinprick sensation, and Achilles reflexes may help to detect underlying abnormalities. All patients should be counseled to actively manage their foot care by doing daily foot inspections at home, choosing proper footwear, and performing daily skin and nail care. For patients with known neuropathy, examination of their feet should be performed at each visit. Referral to a foot care specialist should also be considered. If there is any

evidence of peripheral vascular disease, ankle-brachial index should be obtained and a referral for further vascular evaluation should be considered.

Macrovascular Complications Type 2 diabetes is a cardiovascular risk equivalent. Therefore, preventing cardiovascular events requires not only intensified glucose control but also aggressive management of hypertension and dyslipidemia. Combination therapy is often required to reach treatment targets for both conditions.



Hypertension Blood pressure control is the cornerstone of preventing cardiovascular events. A large body of evidence shows that improving blood pressure control reduces both mortality and morbidity from cardiovascular disease in patients with and without diabetes. A number of antihypertensive therapies have been demonstrated to reduce cardiovascular events, including diuretics, beta blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs).38-42 The choice of antihypertensive regimen should be dictated by the patient’s degree of hypertension and other comorbidities. For instance, beta blockers and calcium channel blockers may be a good choice for patients with angina, as they have been associated with antianginal effects and a possible atherosclerotic benefit.43, 44 In patients with heart failure, diuretics, ACE inhibitors, and beta blockers are beneficial.45, 46 For diabetic patients with prior myocardial infarction, beta blockers may prevent a second heart attack, and should not be withheld despite the theoretical risk of worsening glucose control.47 Calcium channel blockers and diuretics also appear beneficial in stroke prevention.40, 48 ACE inhibitors and ARBs are useful in preserving renal function in patients with diabetic nephropathy, as discussed previously.40, 49, 50 To achieve the ADA-recommended target blood pressure of < 130/80 mm Hg for patients with diabetes, combination therapy is generally required.

Dyslipidemia Lipid abnormalities are common in patients with type 2 diabetes and increase the risk of cardiovascular disease. Although lifestyle interventions aimed at increasing physical activity and weight loss can help to improve cholesterol levels, most patients will require medical therapy. Pharmacologic interventions that lower LDL cholesterol and triglycerides while raising HDL cholesterol can reduce cardiovascular disease mortality in patients with diabetes. The primary target of lipid pharmacotherapy is to lower LDL. Two landmark trials, the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS), have shown that treatment with a hydroxymethylglutaryl(HMG)-CoA reductase inhibitor (statin) produces a significant reduction in cardiovascular events.51, 52 The HPS found that a 30% reduction in LDL, regardless of baseline LDL levels, resulted in a 25% decreased rate of cardiovascular events. Therefore, current recommendations suggest an LDL target of < 100 mg/dL and consideration of statin therapy in all patients over age 40 with type 2 diabetes. More recent trials in high-risk patients with known cardiovascular disease show that even more aggressive therapy, targeting LDL levels of < 70 mg/dL, may be beneficial.53, 54 Although the ADA recommendations include goals for reduced triglycerides (< 150 mg/dL) and increased HDL (> 40 mg/dL in men and > 50 mg/dL in women), there


are few prospective clinical studies to guide pharmacologic therapies for these targets. The most effective pharmacologic agents for lowering triglycerides and raising HDL are fibrates and niacin. Prospective fibrate studies evaluating mortality and cardiovascular endpoints have yielded mixed results. Most recently, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study randomized patients with diabetes who were not receiving statin therapy to fenofibrate or placebo.55 After five years of follow-up, fenofibrate use resulted in favorable changes in total cholesterol, LDL, and HDL. However, event outcomes were varied. The primary outcome of ”coronary events” was not different between the groups. However, fenofibrate users had a 24% reduction in nonfatal myocardial infarction, p = 0.01; 11% reduction in total cardiovascular disease events, p = 0.035. Fenofibrate therapy was also associated with a nonsignificant trend toward increased total mortality, and coronary heart disease mortality. Similarly, the largest study of niacin therapy for triglyceride lowering demonstrated a modest decrease in myocardial infarction, but no difference in all-cause mortality after five years.56 Many patients require combination therapy, either with a statin and fibrate or with a statin and niacin, to reach lipid targets. However, both combinations are associated with increased risk of elevated transaminase levels, myositis, and rhabdomyolysis. The true risk of such combinations has not been adequately quantified in prospective, randomized trials, but it is likely greater in patients using high doses of statins. There are no data from randomized clinical trials evaluating cardiovascular event reductions with combination lipid-lowering therapy.

Psychosocial Complications Depression

Depression has not been considered a traditional complication of diabetes, but strong evidence supports such a relationship. Individuals with diabetes are twice as likely to have depression as those without diabetes.57 A meta-analysis of 21,351 patients in 42 studies revealed a 25% overall prevalence of depression in those with diabetes versus 11.4% in those without diabetes.57 Additionally, women may be more susceptible than men; one study found that 28% of women and 18% of men with diabetes had depression.57 Depression can adversely affect metabolic control.58 Several studies have shown that the presence of severe depressive symptoms is strongly associated with poor diabetes self-care behaviors.59 One study of 367 individuals with diabetes in a primary care setting found that depressed patients were twice as likely to be nonadherent with oral medication regimens and were less likely to follow dietary recommendations.60 This lack of self-care may result in increased financial burden. In this study, healthcare costs in those with severe depres-


sion were 86% higher than those without depression.60 Thus, there is a clear connection between depression and poor patient outcomes. Several studies have examined the effect of depression treatment on glycemic control; results have been mixed. Lustman and colleagues conducted an eight-week placebo-controlled, double-blind trial in 60 patients with type 1 or type 2 diabetes and depression.61 Patients were randomized to either fluoxetine or placebo. Glycated hemoglobin and symptoms of depression were measured at the beginning and end of the trial. As expected, the fluoxetine group had significant improvement in depressive symptoms compared to placebo. There was a trend toward lower glycated hemoglobin in the fluoxetine group, but it was not statistically significant.61 Lustman and colleagues also examined the effects of buproprion therapy on diabetes self-care behaviors, BMI, and depression in a 34-week open-label treatment trial.62 Previously, other studies had argued that treatment of depression resulted in improved attention to self-care behaviors and weight loss and that these explained the improved glycemic control. This study, however, found that 10 weeks of acute phase depression treatment with buproprion improved glycated hemoglobin, independent of improvement in self-care behaviors or change in BMI. The improvement in glycated hemoglobin was sustained over a 24-week maintenance treatment phase. Thus, this study suggests that treating depression may improve glycemic control, independent of other factors. More recently, Georgiades and colleagues administered cognitive behavioral therapy to 90 subjects with diabetes and depression over a 12-month period.63 The study sought to determine if changes in depressive symptoms were related to changes in glycemic control. Although the patients reported significant reduction in depressive symptoms over the course of the study, there was no associated improvement in glycemic control or fasting blood glucose.

When depression is severe, attention to diabetes may become a low priority for many patients. It is important for clinicians to be aware that one in four patients with diabetes may have depression and that it can be responsive to therapy. It is not clear from available studies whether depression treatment results in improved glycemic control, but this is an important question that deserves further study. Screening for symptoms of depression should be a routine part of caring for those with diabetes.

Management of Type 2 Diabetes

Healthy diet, physical activity, and attention to mental health are integral parts of effective diabetes management. Despite the clear importance of lifestyle therapies, they are often underutilized. The National Health and Nutrition Examination Survey (NHANES III) showed that 31% of people with type 2 diabetes reported no regular physical activity and an additional 38% reported less than the recommended level of activity. Nearly two-thirds of the survey participants ate fewer than the recommended five servings of fruits and vegetables daily and consumed higher than recommended portions of fat and saturated fat.64 Maintenance of both a healthy diet and regular physical activity are clearly daunting challenges for many patients. These challenges emphasize the importance of finding ways to support patients in integrating healthy lifestyle choices into their daily routine, which will aid in the achievement of glycemic targets (see Table 5).

Glycemic Control Glycated Hemoglobin

Glycated hemoglobin, also called glycosylated hemoglobin, hemoglobin A1c, or HbA1c, is formed by the nonenzymatic attachment of glucose to alpha- and beta-chains of hemoglobin A. In normoglycemic individuals, glycated hemoglobin values generally range between 4.0% and 5.9%, depending on the laboratory. In the presence of hyperglycemia, glycosylation of hemoglobin increases, resulting in higher glycated hemoglobin values.

Table 5. Glycemic Targets Parameter




< 7.0%, lower if patient is not having significant hypoglycemia

< 6.5%

Preprandial glucose*

70-130 mg/dL

< 110 mg/dL

Postprandial glucose*

< 180 mg/dL 1-2 hours after the beginning of a meal

< 140 mg/dL 2 hours after the beginning of a meal

*Nonpregnant individuals. 1. Standards of medical care in diabetes—2008. Diabetes Care. 2008;31 Suppl 1:S12-54. 2. American College of Endocrinology Consensus Statement on Guidelines for Glycemic Control. Endocrine Practice. January/February 2002;8 Suppl 1:5.



A patient’s level of glycated hemoglobin reflects the degree of glycemic control over the life span of a red blood cell (approximately 100-120 days), making it a useful marker of recent blood sugar levels.65 Thus, blood tests for HbA1c measure glycemic control over the previous two to three months, with lower values indicating better control. The level of glycation is easily measured, because hemoglobin is an abundant protein that can be easily sampled. It is important to note that conditions that result in increased turnover of red blood cells can result in falsely lowered glycated hemoglobin values. The ADA has issued guidelines on glycemic targets and optimal HbA1c levels for patients with type 2 diabetes.11 The ADA recommends a hemoglobin A1c level of less than 7.0% for most patients. Recent evidence has suggested that intensively lowering HbA1c below recommended levels may be associated with an increased risk of death in some patients. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was designed to determine whether intensively lowering blood sugar, blood pressure, and lipids would reduce the risk of cardiovascular events in type 2 diabetes patients at already high risk.66-69 The study enrolled 10,251 participants who were considered at especially high risk for heart disease, based on prior known cardiovascular disease, or at least two other risk factors for cardiovascular disease in addition to type 2 diabetes. Participants were randomized to either intensive or standard glycemic treatment groups, and either the lipid or blood pressure group. The intensive glycemic treatment group aimed for HbA1c levels similar to that of adults without diabetes (less than 6.0%). The standard treatment group targeted an HbA1c of 7.0% to 7.9%. In February 2008, the study’s Data Safety and Monitoring Board decided to stop the intensive treatment arm, due to a 20% higher death rate in this group than in the standard control group. The final results of the intensive intervention were recently reported in the New England Journal of Medicine. After one year of therapy, those randomized to the intensive glucose control group achieved a median HbA1c level of 6.4% and maintained that level of control throughout the remainder of the trial. The median HbA1c in those randomized to standard glycemic treatment was 7.5%. Those randomized to intensive control had higher rates of hypoglycemia (annual rate 3.1% vs. 1.0%) and weight gain (3.5 kg vs. 0.4 kg), compared to those randomized to standard treatment. Also of note, 27.8% of those in the intensive group gained >10 kg from baseline, compared with 14.1% of those in the standard group. There was no significant difference in the primary outcome (composite of nonfatal myocardial infarction or stroke, or death from cardiovascular cause) between the two groups. However, 257 participants in the intensive group died, compared with 203 in the standard treatment group (HR 1.22, 95% CI, 1.01-1.46, p = 0.04).69


In the same issue of the New England Journal of Medicine, an additional study evaluating the effects of intensive blood glucose control on vascular outcomes in individuals with type 2 diabetes was published, the ADVANCE trial— Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation. This study found that intensive glycemic control (mean HbA1c of 6.5% in intensive control arm vs. 7.3% in standard treatment arm) did not have a significant effect on major macrovascular events, death from cardiovascular cause, or death from any cause. However, it did yield a 21% relative reduction in the risk of new or worsening nephropathy, which in turn was largely responsible for an overall 10% relative reduction in the primary outcome of combined major macrovascular and microvascular events.70 These studies had a number of differences (rapidity of decline in HbA1c, amount of weight gain, and different pharmacologic treatment choices) that may explain the discrepant findings. Reviewing these differences is beyond the scope of this monograph, but they are summarized in editorials published along with the two trials.71, 72 Aggressive blood sugar control is an ongoing area of research, and more information is needed. The safety concerns highlighted by the ACCORD trial underscore the importance of adapting any treatment plan to the needs and risks of individual patients, and suggest that patients at especially high risk for cardiovascular disease are poor candidates for aggressive therapies that aim for blood glucoses in the normal, nondiabetic range.

Exercise Exercise is an important lifestyle therapy that provides multiple benefits. Exercise has been shown to improve insulin sensitivity through increased expression of GLUT-4, the major glucose transporter protein in skeletal muscle, cardiac muscle, and adipose tissue. Both muscle contraction and insulin recruit preformed GLUT-4 transporters to the cell surface, with the overall effect of enhanced glucose uptake. Endothelial function is also improved through exercise.73 Even as a sole intervention (without caloric reduction or weight loss), exercise can lower glycated hemoglobin by 0.66%.74 Exercise has also been shown to improve lipoprotein profiles.75 Specifically, exercise lowers LDL cholesterol and triglycerides and increases HDL cholesterol. Exercise improves cardiovascular fitness in general and overall well-being. In those with diabetes, regular exercise is associated with reduced mortality from cardiovascular events. Gregg and colleagues reviewed National Health and Nutrition Examination Survey (NHANES) data on 2,896 adults with diabetes.76 Those who walked at least two hours per week had a 39% lower all-cause mortality and a 34% lower cardiovascular disease mortality. Participants who walked at least three to four hours per week had additional reductions in mortality rate.


The ADA has established several exercise guidelines for patients with diabetes. They recommend at least 150 minutes per week of moderate intensity aerobic exercise (at 50%-70% of maximum heart rate) or 90 minutes per week of vigorous aerobic exercise (> 70% maximum heart rate). Ideally, patients should exercise at least three days per week, with fewer than two consecutive days without exercise. Multiple short bouts of aerobic activity—as little as 10 minutes three times per day—have also been shown to improve fitness and insulin resistance. The ADA also recommends that patients perform resistance (weight) training that targets all major muscle groups three times per week.11 Before initiating an exercise program, stress testing should be considered, particularly in sedentary individuals, those with other risk factors for cardiovascular disease, abnormal EKG, or other cardiac symptoms. Specific ADA recommendations for patients with diabetes complications are included in Table 6.

Medical Nutrition Therapy Medical nutrition therapy is another type of lifestyle therapy that is effective in patients with type 2 diabetes. Goals of medical nutrition therapy include lowering glucose levels, improving lipid levels, improving blood pressure levels, and preventing chronic complications of diabetes.77 It is important that medical nutrition therapy be individualized to each patient and his or her lifestyle in order to incorporate personally and culturally appropriate nutrition information into planning sessions. A registered dietician who is skilled in the treatment of diabetes should administer medical nutrition therapy.78 Specific challenges in achieving nutrition goals may include meals eaten outside of the home, food aversions, and family and ethnic preferences that may not coincide with nutritional guidelines. Specific

recommendations for dietary intake are summarized in Table 7. Many patients with type 2 diabetes may ask about the benefits of a low-glycemic index diet or a low-carbohydrate diet. Patients typically consider these diets either for weight-loss benefits or for improved glycemic control. Glycemic index (GI) refers to the effect that certain foods have on blood glucose levels; the measure was developed to account for the fact that some foods with the same carbohydrate content have different effects on blood sugar. Foods with a high GI produce a greater rise in postprandial glucose than those with a low GI.79 A food’s GI is an artificial value that is based on a comparison to white bread; white bread has been assigned a GI of 100 and all other foods are compared to this in their ability to raise blood glucose. Foods that are higher in soluble fiber tend to have lower GI values. A partial list of the GI of some common foods is included in Table 8. Theoretically, a low-GI diet will produce less variation in blood glucose and therefore yield a drop in HbA1c levels. A recent metaanalysis showed an average drop in HbA1c of 0.43% associated with low-GI diets.80 Because most studies to date have been relatively short in duration (averaging only 10 weeks), more long-term studies are needed to confirm this effect. Low-carbohydrate diets (popularly advocated by Dr. Atkins) usually contain 20 g or less of carbohydrates per day. These diets often allow unrestricted dietary protein and fat content. Research on the effects of low-carbohydrate diets in patients with diabetes has been limited by both short duration lengths and small sample sizes.81, 82 In the short term, low-carbohydrate diets may result in sig-

Table 6. ADA Exercise Recommendations for Patients with Complications from Diabetes Diabetes Complication

Exercise Recommendations

Severe peripheral neuropathy

Encourage non-weight-bearing exercise such as swimming, bicycling, or arm exercises

Autonomic neuropathy

Because of association with increased cardiovascular disease risk, undergo cardiac evaluation prior to exercise program

Microalbuminuria and nephropathy

No specific restrictions for isolated microalbuminuria or nephropathy


Proliferative diabetic retinopathy (PDR) or severe non-PDR, avoid vigorous aerobic or resistance exercise


If ketosis is present, exercise should be avoided (not typically seen in type 2 diabetes); usually no need to postpone exercise for hyperglycemia alone


Not frequently seen if patient is not on insulin or insulin secretagogue; if glucose is < 100 mg/dL, ingest 15-20 g carbohydrates

Source: Standards of medical care in diabetes—2008. Diabetes Care. 2008;31 Suppl 1:S12-54.



Table 7. Recommendations for Dietary Intake Dietary Component

Primary Source

Recommended Intake/ Percentage of Total Daily Energy Intake


Whole grains, fruits, vegetables, dairy

60% to 70% of calories should be divided between CHO and monounsaturated fat.


Meat, poultry, fish, eggs, milk, cheese, soy

15% to 20% in those with normal renal function


Saturated fat < 7% total calories Limit intake of trans fat Limit dietary cholesterol to < 200 mg/day

20% to 35%

Artificial Sweeteners


No more than 50 mg/kg body weight Average amount in one 12 oz can of soda: 200 mg Amount in one packet of sweetener: 35 mg


No more than 5 mg/kg body weight Average amount in one 12 oz can of soda: 70 mg Amount in one packet of sweetener: 5 mg

Legumes, nuts, whole grains, fruits, vegetables

14 g fiber/1,000 kcal


Source: Franz M, Bantle J, Beebe C, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care. 2002;25:148-198.

nificant improvement in HbA1c, triglycerides, and insulin sensitivity; however, long-term studies in patients with type 2 diabetes have not been conducted. It is unclear if the high fat content of these diets increases cardiac risk in patients with diabetes, who already have an established high risk of cardiovascular events. Low-carbohydrate diets are also lacking in many other elements of a healthy diet, including fiber, vitamins, minerals, and other nutrients.77 Fiber, in particular, is a key dietary component of reducing risk for diabetes. About 25 to 50 g of fiber per day is recommended. The ADA has recently approved low-carbohydrate diets for weight loss in those with diabetes.11 They do, however, stipulate that patients should not remain on the diet longer than one year and that providers should monitor lipid profiles, renal function, and protein intake in those with nephropathy. Patients who attempt a low-carbohydrate diet and are on insulin therapy or a sulfonylurea should also be counseled about possible hypoglycemia, as mealtime insulin needs may decrease drastically. Vitamin and Herb Therapy Many nutritional supplements claim to improve insulin sensitivity, but few have strong evidence to support their use. Among the more commonly touted supplements are Co-enzyme Q10 (CoQ10), selenium, zinc, chromium, and cinnamon. Studies on each of the supplements’ purported


benefits are limited. Most of the existing prospective studies have not shown clear benefit on glucose levels or HbA1c levels with these treatments.83

Diabetes Education and Care Models

Diabetes self-management education programs are an important part of comprehensive diabetes management. These programs, guided by national standards, support patients in successfully integrating medical and lifestyle therapies. Diabetes self-management education is recommended for all individuals at the time of diagnosis and as needed after diagnosis.78 The programs teach skills in self-management that help the patient and family to make informed healthcare choices, which can improve metabolic control, weight loss, and quality of life.84 The ADA recognizes self-management programs that are staffed by certified diabetes educators (CDEs) and include quality improvement as part of their program. CDEs are skilled at providing individualized patient education and can account for factors such as ethnicity, literacy, and patient age. CDEs are also experts in the application of healthcare learning and motivational techniques. Many patients receive formal diabetes education at the time of diagnosis. CDEs may also be useful for times of change, such as when planning conception, during pregnancy, and at initiation of insulin therapy.


Table 8. Glycemic Index of Common Foods Food Item

Glycemic Index

White bread, 10 g


White potato, 150 g

121 +* 16

White rice, 150 g


Apple, 120 g

52 + 3

Banana, 120 g


Strawberries, 120 g


Cola, 250 mL

83 + 7

Raisin Bran® cereal, 30 g

87 + 7

Cheerios® cereal, 30 g

106 + 9

Kidney beans, 150 g


Black beans, 150 g

28 + 4

Ensure®, 250 mL


Glucerna®, 237 mL


White spaghetti, 180 g

60 + 9

Orange juice, 250 mL

71 + 5

*+ reflects variation in food processing and manufacturing. Source: Foster-Powell K, Holt S, Brand-Miller J. International table of glycemic index and glycemic load values: 2002. Am J Clin Nutr. 2002;76:5-56.

Alternatives to traditional diabetes self-management education programs, however, also have a positive impact, especially those that incorporate community and social support. The REACH (Racial and Ethnic Approaches to Community Health) program is an example. African American and Latino adults with type 2 diabetes participated in a diabetes self-management curriculum every four weeks for four months. The program was designed around cultural relevance and delivered by community members who had been trained as family health advocates. Of the 151 participants, 111 completed the program and reported improved knowledge about the relationship between healthy diet, exercise, and glucose control. Significant behavioral changes also occurred, such as switching to whole-grain bread and reducing intake of regular soda. As a result of these behavior changes, participants’ glycated hemoglobin levels decreased from baseline, dropping from 8.4% to 7.6% at completion of the program.85 Like REACH, Project Dulce used a nontraditional approach to educate patients with diabetes. Project Dulce took a multidisciplinary approach that included community members as part of the diabetes care team. In the study, 153 underinsured high-risk patients received a team care intervention, which included a nurse case manager who worked closely with primary care providers. This group

was compared to 76 control patients, chosen because their baseline characteristics matched those of the intervention group. In addition, community health workers (promotoras) delivered peer education and empowerment classes. The intervention group met with the nurse case manager eight times over one year and attended monthly two-hour education classes with community health workers. The group that received the team care intervention had a significant drop in glycated hemoglobin, from 12.0% at baseline to 8.3% at study end.86 The usual care group had no change in glycated hemoglobin. Total cholesterol, LDL cholesterol, and triglycerides were also significantly reduced for the intervention group. Another study followed 367 patients whose diabetes was managed by a trained registered nurse. The nurse followed detailed treatment and medication adjustment algorithms and met with an endocrinologist weekly to review patient charts. At study entry, only 28% of participants had achieved glycated hemoglobin < 7.0% and 51% were at LDL goal of < 100 mg/dL. At the end of one year, 60% of the participants had achieved a glycated hemoglobin of < 7.0% and 82% had met an LDL goal of < 100 mg/dL.87 Moreover, the nurse-managed group had a significant drop in diabetes-related emergency department visits and hospitalizations when compared to the year prior to study



participation (94 emergency department visits vs. 46 at a cost of $129,176 compared with $24,630).88 Group care is another option for delivery of diabetes support. Group care incorporates routine diabetes care with education delivered in an interactive group setting instead of the traditional one-on-one office visit. Trento and colleagues conducted a four-year randomized controlled trial of group diabetes care.89 Fifty-six patients received group diabetes care for four years, while 56 patients in the control group received traditional office visits during the same period. The researchers followed several key indicators of metabolic health, including glycated hemoglobin, blood pressure, creatinine, microalbuminuria, total cholesterol, HDL cholesterol, and triglycerides. Among the participants in group care, glycated hemoglobin remained stable (7.4% at baseline and 7.0% after four years); whereas glycemic control worsened and glycated hemoglobin increased from 7.4% to 8.6% in the traditional care group. Patients who received group care also had improved BMI, diastolic blood pressure, and HDL cholesterol compared to controls. Overall, group care increased knowledge of diabetes and expressed quality of life. Follow-up analysis showed that patients with type 2 diabetes in group care had less fatalistic attitudes and higher internal control compared to controls. Further, internal control tended to be inversely related to insulin resistance as measured by homeostatic model assessment (HOMA), suggesting that elements of psychological well-being may correlate with insulin sensitivity.90 All of these nontraditional diabetes care interventions are successful and share a common theme of increased social support and more frequent interaction with a medical team. As the prevalence of type 2 diabetes climbs rapidly in this country and around the world, these alternative care models may represent the next level of effective medical care for this complex illness.

Pharmaceutical Agents

Over the past 10 years, the FDA has approved five new classes of medications for the treatment of diabetes, bringing the total to nine classes. There is no shortage of choices in the United States. Although many of the newer agents are less effective at lowering glycated hemoglobin than older diabetes medications (such as insulin, sulfonylureas, and metformin), their availability greatly increases the possible combination of therapies and allows for a tailored diabetes regimen. Many of the medications discussed here are also available in combination formulations, which may allow for better medication adherence and decreased cost to the patient.

Oral Agents Sulfonylureas Sulfonylureas, used since 1946, are oral hypoglycemic agents and have been available the longest. They cause insulin secretion by binding to ATP-sensitive potassium


channels in pancreatic beta-cell membranes. Sulfonylureas reduce glycated hemoglobin by 1.5% to 2.0%. Because they have been around for so long, this class of medication is generally less expensive than many alternatives. Potential side effects include hypoglycemia and weight gain. In the UKPDS, participants assigned to the sulfonylureas chlorpropramide and glibenclamide gained 2.6 kg and 1.7 kg more, respectively, than participants treated with conventional therapy.35 Hepatic or renal impairment are relative contraindications to sulfonylureas. Not all sulfonylureas are equal with respect to other possible side effects. For example, glyburide, known in Europe as glibenclamide, impairs the ability of myocardial tissue to adapt to episodes of transient ischemia, a phenomenon known as ischemic preconditioning.91 Though the consequences of this are unknown, this apparent adverse effect of glyburide has led some to question whether it is still a useful medication.92 Treatment with an alternative sulfonylurea, glimepiride, does not result in impairment of the myocardial tissue’s ability to adapt to transient episodes of ischemia.91

Biguanides Metformin has been approved for the treatment of diabetes in the United States since 1995, and biguanides have been available in other countries since 1957. Metformin decreases hepatic production of glucose and increases insulin sensitivity with an average improvement in glycated hemoglobin of 1% to 2%. Unlike sulfonylureas and insulin, metformin is not associated with weight gain93 and is, therefore, first-line treatment in overweight patients with type 2 diabetes.11 A recent Cochrane Review compared metformin with several other classes of diabetes medications, including sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, and insulin. The study found that metformin therapy resulted in greater glycemic and weight control, and improved dyslipidemia and diastolic blood pressure compared to the other diabetes medications.94 The most common side effect of metformin is gastrointestinal intolerance with symptoms that may include nausea, vomiting, diarrhea, abdominal bloating, flatulence, and anorexia. Gastrointestinal side effects are minimized with slow titration of the medication and by taking the medication with food (i.e., 500 mg with dinner for one week, then increasing to 500 mg with breakfast and dinner). Gastrointestinal symptoms resolve in most patients after a few weeks of therapy. If symptoms persist, extended release metformin is an option. Metformin is contraindicated in patients aged 80 or older, patients with a history of heart failure, or patients with renal dysfunction (creatinine greater than 1.4 in females or greater than 1.5 in males) because of the possible risk of lactic acidosis. Metformin should be held if contrast dye studies are performed.


Alpha-glucosidase Inhibitors Alpha-glucosidase inhibitors (AGIs) were approved by the FDA in 1995, about the same time as metformin. Alpha-glucosidase is a key enzyme in the hydrolysis and absorption of carbohydrates in the small intestine. By inhibiting alpha-glucosidase, this class of medication inhibits carbohydrate absorption, thereby reducing blood glucose especially after meals. AGIs have a modest effect on glycated hemoglobin.95 They do not have a significant effect on body weight. The main side effect associated with AGIs is gastrointestinal intolerance, including flatulence, diarrhea, and abdominal pain. As with metformin, these symptoms can be minimized by starting with a low dose and titrating slowly. Contraindications include severe renal and liver dysfunction and disorders of digestion or absorption. AGIs may be most effective in patients with fairly well-controlled diabetes but elevated postprandial sugars. Two agents in this class that are FDA-approved are acarbose and miglitol.

Thiazolidinediones The first thiazolidinedione (TZD), troglitazone, became available in 1997. TZDs are PPAR-gamma agonists, and enhance peripheral insulin sensitivity. Though hepatic toxicity was not initially known to be a problem with this medication, it was noted within about six months after it was approved by the FDA. The prevalence of severe hepatic toxicity was ultimately found to affect approximately one in 15,000 patients on the medication. Troglitazone was subsequently pulled from the market in 1999. That same year, two additional TZDs became available, rosiglitazone and pioglitazone. Both lower glycated hemoglobin by 1.0% to 1.5%, and neither of these medications has been associated with severe hepatic toxicity. However, drug labeling states that liver function tests should be monitored at baseline and periodically thereafter. Because they are known to increase edema and risk of congestive heart failure, these two agents are contraindicated in New York Heart Association class 3 and 4 heart failure. A recent study demonstrated that monotherapy with rosiglitazone was less likely to result in failure of therapy (15%) at five years, compared to monotherapy with metformin (21%) or glyburide (34%).96 Failure of therapy in this study was defined as fasting plasma glucose > 180 mg/dL. Further, the participants randomized to rosiglitazone maintained glycated hemoglobin at < 7.0% longer (60 months) than those randomized to metformin (45 months) or glyburide (33 months). Rosiglitazone may lead to greater durability of glycemic control by reducing the rate of loss of beta-cell function. However, participants randomized to rosiglitazone had an increase in edema compared to those receiving metformin and glyburide, and an increase in congestive heart failure compared to glyburide. Further, those randomized to rosiglitazone gained 4.8 kg of weight, compared with a

loss of 2.9 kg in the metformin group and an increase of 1.6 kg in the glyburide group. Thus, the cardiovascular side effects and weight gain need to be considered against the favorable glycemic durability seen with the medication. A recently published meta-analysis of the effects of rosiglitazone on death from cardiovascular causes has sparked controversy.97 This meta-analysis looked at 42 trials and found that the odds ratio for myocardial infarction was 1.43 (95% CI, 1.03-1.98) in the rosiglitazone group compared to controls. However, the investigators of this study acknowledged several flaws: many of the trials examined were small, short-term, and not designed to evaluate cardiovascular outcomes; there were very few adverse cardiovascular events or deaths to analyze; most trials did not adjudicate cardiovascular events; and the authors did not have access to original data or definitions of myocardial infarction used in the trials. Thus, the ability to interpret risk of cardiovascular events from this meta-analysis is limited. Other studies are prospectively evaluating cardiovascular risks with TZDs. The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial is specifically designed to investigate the effect of rosiglitazone on cardiovascular events. Although the study has not reached completion, an interim analysis reported that it has thus far shown no significant difference in ischemic cardiac events between the rosiglitizone users and the comparator group.98 However, patients randomized to rosiglitazone have had a significantly higher risk of congestive heart failure, reinforcing the need for caution when using this drug in patients at risk for congestive heart failure. The risks and benefits of rosiglitazone continue to be debated.99-101 Finally, results from a prospective trial utilizing pioglitazone, called the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE), demonstrated a trend toward benefit in the combined primary end point but it was not statistically significant.102 Until the evidence for cardiovascular risk with TZDs is clarified through clinical trials, the FDA has required that both rosiglitazone and pioglitazone labeling include black box warnings.103, 104 This cautionary language addresses the possibility of an increased risk of myocardial ischemic events with rosiglitazone, and the risk of heart failure with both drugs. These warnings also state that the risk for congestive heart failure is higher in older individuals, those with risk factors for congestive heart failure, those taking higher doses of the TZD, and those using the TZD in combination with insulin. These warnings emphasize the importance of close monitoring of patients using these medications.



Nonsulfonylurea Insulin Secretagogues (Meglitinides) Meglitinides were approved for use in 1997. They are approved for both monotherapy and combination therapy with metformin. On average, they decrease glycated hemoglobin by 0.5% to 1.0%. Like sulfonylureas, the meglitinides stimulate insulin release from the pancreatic beta cells by binding to ATP-sensitive potassium channels. However, they have a slightly different structure than sulfonylureas, resulting in a faster onset and shorter duration of action. Because of this, meglitinides are generally given just before meals to lower postprandial glucoses. They can be particularly helpful in patients who do not eat regularly because they can be taken at the time of a meal, and their hypoglycemic effects do not last as long as traditional sulfonylureas. Although hypoglycemia is still a possible side effect, their short duration and mealtime dosing reduces this risk. The drugs should be used cautiously in patients with hepatic impairment. They are not indicated in individuals with diabetic ketoacidosis or type 1 diabetes.

Dipeptidyl Peptidase IV Inhibitors (Gliptins) The FDA approved the first dipeptidyl peptidase IV (DPP-4) inhibitor, sitagliptin, in October 2006. A second DPP-4 inhibitor, vildagliptin, is undergoing testing. These medications work by inhibiting the enzyme DPP-4, which breaks down glucagon-like peptide-1 (GLP-1), thereby increasing the availability of GLP-1. GLP-1 is a gastrointestinal peptide that, in response to a glucose load, stimulates insulin secretion, promotes insulin synthesis, inhibits inappropriate glucagon secretion, increases beta-cell mass, slows gastric emptying, and promotes satiety.105 The effects of DPP-4 inhibitors on glycemic control are modest. Sitagliptin decreases glycated hemoglobin by 0.5% to 0.9%.106-109 Sitagliptin does not appear to have a significant effect on weight. Although hypoglycemia can be seen when sitagliptin is used with a sulfonylurea it does not cause hypoglycemia by itself. It is generally well tolerated with few side effects. One potential advantage of sitagliptin is that it is not contraindicated in patients with significant liver disease or congestive heart failure. Dose adjustment is advised for patients with renal impairment. Although this medication appears safe thus far, clinical experience with it is limited

Injectable Noninsulin Therapy Glucagon-like Peptide-1 Analogues Glucagon-like peptide-1 (GLP-1) analogues, or incretin mimetics, are another relatively new class of diabetes medication. One GLP-1 analogue, exenatide, was approved for use in 2005. Currently, it is approved for use with metformin, thiazolodinediones, and sulfonylureas. Like DPP-4 inhibitors, exenatide makes use of this gut peptide pathway by mimicking the action of GLP-1. Thus, exenatide responds to a glucose load by stimulating insulin secretion, increasing insulin synthesis, inhibiting inappropriate glucagon secretion, increasing beta-cell mass, slowing


gastric emptying, and promoting satiety.105 Exenatide also causes moderate weight loss. In one trial, participants randomized to exenatide 10 mcg twice daily lost 2.8 kg (+ 0.5 kg) in a 30-week period, compared to placebo.110 The reduction in glycated hemoglobin was -0.78% (+ 0.10%). These effects on weight and glycated hemoglobin appear to be progressive, based on the results of another openlabel study that lasted for 82 weeks. At the end of 82 weeks, there was a 5.3 kg (+ 0.8 kg) reduction in weight and a 1.3% (+ 0.1%) reduction in glycated hemoglobin.111 In addition to potential weight loss, another advantage of this medication is that its actions on insulin secretion are glucose-dependent. Thus, as with the gliptins, the risk of hypoglycemia with this medication is low. However, the risk of hypoglycemia increases if it is used with a sulfonylurea. A potential disadvantage is that exanatide requires subcutaneous injections twice daily, which may make the medication less desirable to some patients. Because the drug can cause nausea and vomiting, it may be intolerable to some patients. It should not be used in those with gastrointestinal abnormalities, such as gastroparesis. There have also been reports of pancreatitis with this medication, and patients should be counseled about this risk and the symptoms of pancreatitis.112 Dose adjustment is not needed for mild to moderate renal impairment, but exenatide is not recommended for patients with severe renal impairment.

Amylin Analogues Amylin analogues are another relatively new class of diabetes medication, and the first, pramlinitide, was approved by the FDA in 2005 for use by patients with diabetes on insulin therapy. Pramlinitide is an analog of amylin—a pancreatic peptide—that slows gastric emptying which promotes satiety, inhibits secretion of glucagon during hyperglycemia, and decreases total insulin demand.113 These effects result in more stable blood glucose levels. It is injected subcutaneously at mealtimes, along with preprandial insulin. Because pramlinitide lowers the total insulin demand, insulin doses should be decreased by 50% upon initiation of pramlinitide to help prevent hypoglycemia. It has modest effects on glycated hemoglobin and weight. It decreases glycated hemoglobin by 0.3% and may result in a slight decrease in weight (- 0.4 kg, compared with + 0.8 kg in controls).114 Nausea is a common side effect, though it tends to improve after the first few weeks. It is contraindicated in gastroparesis.

Insulin Therapies Subcutaneous Insulin The first synthetic ”human” insulin was approved by the FDA in 1982. Insulin therapy is very effective at controlling hyperglycemia, and there are multiple insulin regimens available. Insulin can be added to oral agents or used alone. In patients who are close to reaching blood glucose goals, adding long-acting insulin such as glargine and


Table 9. Onset and Duration of Insulin Therapies Type of Insulin

Onset of Action

Peak Action

Duration of Action

Rapid-acting insulin Lispro Aspart Glulisine

15-30 minutes

30-90 minutes

3-5 hours

Short-acting insulin Regular

30 minutes

1-4 hours

Up to 8 hours

Intermediate-acting insulin NPH

1-4 hours

4-14 hours (mean 5.5 hours)

Up to 24 hours, but generally 12-16 hours

60-120 minutes

Relatively flat (though detemir may have some peak 6-8 hours after injection)

Up to 24 hours, but detemir duration is somewhat dose dependent

Long-acting insulin Glargine Detemir

Source: Clinical Pharmacology. Available at http://clinicalpharmacology-ip.com/default.aspx. Accessed June 23, 2008.

detemir at bedtime, while continuing oral agents, may be enough to achieve target glucose levels. This is because basal insulin therapy suppresses hepatic glucose production overnight, thus lowering fasting morning sugars. In addition to basal insulin therapy, many patients will eventually need insulin therapy before meals. The following discussion classifies insulin based on onset and duration of action. Table 9 summarizes the onset and duration of action of insulin therapies.

peak action at four to fourteen hours, mean 5.5, and it can last up to twenty-four hours, but generally lasts 12 to 16 hours. An important use of NPH is in pregnant women since glargine and detemir are not FDA-approved for use in pregnancy, and there is little clinical experience with their effects on fetal outcomes. Thus, some authorities recommend using NPH for basal insulin coverage in pregnancy. In this setting, NPH provides basal insulin therapy when given every eight to twelve hours.

The rapid-acting insulin analogues—lispro, aspart, and glulisine—mimic pancreatic insulin secretion in response to food. These are taken immediately before eating and begin working within 15 to 30 minutes. They peak in 30 to 90 minutes, and the effects are generally gone after about three to five hours. They are available in vials as well as insulin pens, which may increase the ease of administrating multiple insulin injections. Lispro and aspart are both Pregnancy Category B; glulisine is Pregnancy Category C.

In nonpregnant individuals, the long-acting insulin analogs glargine and detemir provide advantages to NPH in basal insulin coverage. Because they do not peak, they deliver a more consistent dose of insulin over the course of 24 hours. This feature of more predictable delivery makes their hypoglycemia risk more manageable. Glargine and detemir should be given at the same time every day. These cannot be mixed in the same syringe with any other insulin. For this reason, they are often given at bedtime when patients are generally not taking any other insulin. However, they can be given at the same time as other insulin therapy as long as each insulin injection is given with a separate syringe. Detemir can be given once or twice daily. Detemir may be associated with less hypoglycemia than glargine, presumably because of decreased within-subject variability of detemir’s action.115

Regular insulin has a slower onset, later peak, and longer duration of action than short-acting insulin analogues. It is taken approximately 30 minutes before eating, peaks in one to four hours, and lasts up to eight hours. Regular insulin offers less flexibility around meals than short-acting insulin and necessitates that patients follow a more regular eating and activity schedule. Intermediate-acting insulin, such as NPH (Neutral Protamine Hagedorn), provides basal insulin therapy. If given in the morning, it may also cover the postprandial glucose increase after lunch. However, it does not cover postprandial glucose as well as short-acting insulin, and patients may be more prone to hypoglycemia from lingering effects. Its onset of action is one to four hours, with

A number of premixed insulin formulations are available. The main problem with these is titration. It is not possible to dose each component separately. Further, meal-timing flexibility is markedly decreased. However, these combinations can be more convenient for patients who have a very routine schedule, refuse more intensive insulin regimens, or are unable to administer insulin more frequently.



Adverse effects of insulin include weight gain and hypoglycemia. In the UKPDS trial, those randomized to insulin gained 4 kg over a 10-year period.35 Hypoglycemia can occur when insulin is used alone, but may be exacerbated when used with other agents that also lower blood glucose. Insulin clearance is dependent on kidney function, and insulin requirements will often drop as renal insufficiency progresses. When insulin therapy is added to an existing oral medication regimen, a low dose such as five to ten units of intermediate- or long-acting insulin—such as NPH, glargine, or detemir—is generally started and then titrated to reach a fasting morning glucose goal of less than 130 mg/dL. Starting patients with type 2 diabetes on multiple daily injection insulin therapy is more complex, and recommendations are summarized in Table 10. Patients starting on insulin should receive education regarding several key

points: proper administration of insulin, proper site rotation, recognition of hypoglycemia, and appropriate treatment of hypoglycemia. Table 11 details examples of 15 g carbohydrate portions used to treat hypoglycemia.

Injection-Site Issues The rate of insulin absorption depends in part on the location of injection. Generally, insulin injected into the abdomen is absorbed fastest, followed by insulin injected into the arms (see Figure 1). Insulin injected into the thighs or buttocks is absorbed the slowest. It is important to rotate the site of injection so that patients do not develop disorders of the subcutaneous fatty tissue, such as lipohypertrophy or lipoatrophy, which alter the rate of absorption.116 Insulin should be injected into the subcutaneous tissue (not muscle) at a 90-degree angle (see Figure 2). If a patient is very thin, a 45-degree angle may be needed to avoid intramuscular injection. Practitioners

Table 10. Initiation of Multiple Daily Insulin Injection Therapy in Patients with Type 2 Diabetes 1. Starting total daily dose of insulin should be between 0.2 and 0.8 units/kg, depending on body habitus, other signs of insulin resistance (i.e. Acanthosis nigricans), and level of hyperglycemia. 2. Approximately 40%-50% of the total daily dose should be given as basal therapy (i.e. NPH, glargine, or detemir). If the dose of basal therapy is correct, blood glucoses should remain fairly flat in the fasting state (i.e. overnight or at times when patient is fasting during the day). 3. Approximately 50%-60% of the total daily dose should be given as bolus therapy before meals (i.e. Lispro, aspart, or glulisine). Adjustment of bolus therapy should be based on postprandial glucose control (goal is < 180 mg/dL). An insulin:carbohydrate ratio can be very useful if patients are able to count carbohydrates. This allows for more flexibility with carbohydrate intake during meals. 4. If regular and NPH insulin are utilized, there are several methods available to decide doses. One simple method is to divide the total daily dose of insulin by 4, and give equal doses of regular insulin before meals and NPH at bedtime. For example, if a patient requires a total daily dose of 40 units of insulin per day, they are given 10 units of regular insulin before each meal and 10 units of NPH at bedtime. 5. Blood glucose should be checked at least before each meal and at bedtime. In addition, it is prudent to check a 3 am blood sugar with each change in basal therapy (NPH, glargine, or detemir) to detect evidence of hypoglycemia overnight.

Table 11. Fast-acting 15 g Doses of Carbohydrates to Treat Hypoglycemia 4 oz juice 4 oz sweetened cola 8 oz skim milk 5 hard candies 3 glucose tablets (each tablet contains 5 g of carbohydrates) 1 package of glucose gel (as marked on the container) Note: Plasma glucose should be retested in 15 minutes. Waiting after treatment is important because overtreating hypoglycemia can lead to hyperglycemia. If glucose is still low after waiting, retreat with another 15 g of carbohydrates. Source: Standards of medical care in diabetes—2008. Diabetes Care. 2008;31 Suppl 1:S12-54



should routinely examine areas around insulin injection sites for fat accumulation (lipohypertrophy) or fat loss (lipoatrophy). Both conditions, depicted in Figure 3, can alter insulin absorption, and thus cause erratic blood glucose levels.

Figure 1. Injection-Site Absorption

Most insulin injections are not painful. However, there are several common causes of painful insulin injection, including the insulin is not at room temperature, there are air bubbles in the syringe, the alcohol from the alcohol swab has not yet evaporated, the direction of the needle

Figure 3. Lipohypertrophy/Lipoatrophy Lipohypertrophy

(a) The abdomen, except for a 2-inch circle around the navel. (b) The top and outer thigh, but avoid the bony area above the knee. (c) The outer and upper arm, where there is the most fatty tissue.

Image provided and used with permission from Disetronic Medical Systems, Inc.


Original image by sanofi-aventis. Used with permission by sanofi-aventis.

Figure 2. Proper Injection Angle

Source: Aprile I, Pazzaglia C, Caputo D et al. J Neurol Neurosurg Psychiatry. (24 August 2006). Electronic letter available at: http://jnnp.bmj.com/cgi/eletters/77/12/1382. Image reproduced with permission from BMJ. Permission to use image granted by Jespersen & Associates.



was changed after penetrating the skin, or the needle was dull/reused.116 If patients are experiencing pain with injections, their technique should be evaluated. Inhaled Insulin Inhaled insulin was approved by the FDA in January 2006. It was an alternative pre-meal insulin with a peak action in about 30 to 90 minutes.117 A meta-analysis of 16 openlabel, mostly short-term trials found that overall patient satisfaction was higher with inhaled insulin than subcutaneous insulin.118 However, inhaled insulin was slightly less effective at lowering glycated hemoglobin compared to subcutaneous insulin. This difference was due to differences in glycated hemoglobin in the longer-term studies, but not generally seen in trials of 24 weeks or less. In addition, patients had a slight decrease in forced expiratory lung volume in one second (FEV1) in the first six months of therapy with inhaled insulin compared to subcutaneous insulin and oral hypoglycemic agents. This subsequently stabilized in the longer-term studies. Recently, the manufacturer of the only inhaled insulin currently on the market announced that it will discontinue production. This decision was based upon the lack of demand for the medicine, not safety issues.119 However, recent reports raise concerns for long-term risk of lung cancer with inhaled insulin use, and in April 2008 the company revised its product labeling to include data on lung cancer in inhaled insulin users.120

Summary of Pharmaceutical Agents Until the introduction of metformin in 1995 into the U.S. pharmacopeia of diabetes medications, drug therapy was limited. In the years since 1995, treatment options have increased dramatically, approaching an estimated market value of $10 billion by 2010. In addition, new metabolic pathways have been discovered, and engineered insulins have broadened the treatment options. On a practical level, these new options enhance flexibility. For example, long-acting basal insulin, such as glargine or detemir, can be combined with rapid-acting bolus (mealtime) insulin, such as lispro or aspart. Insulin can be taken via an insulin pen for convenience, and rapid-acting insulin can be administered whenever the patient is ready to eat.


Oral agents can be combined in multiple ways to better meet the individual needs of patients. Despite the increased flexibility and the FDA’s approval of new treatments, there is still room for improvement in the areas of drug efficacy, safety, and disease progression. Following safety issues raised by the ACCORD trial, more extensive experience with thiazolidinediones, and emerging lung cancer data with inhaled insulin, long-term safety data are becoming increasingly important. This will raise the safety bar for new therapies and is likely to lead to requirements for a long safety record for new drugs before they are recommended as first- or second-line therapies.

Future Outlook

Overall, the flexibility, convenience, and range of treatment choices have expanded to meet the growing demand caused by the type 2 diabetes epidemic in the United States. Over the next 20 to 30 years, this epidemic is forecast to worsen as more adults become elderly and at-risk children age into early adulthood. To better meet patient and provider needs, future studies should identify effective disease prevention strategies, and barriers to appropriate prescribing, care adjustment, and regimen adherence. Further, innovative approaches to treatment and long-term drug safety data will continue to be of importance. Despite many established classes of oral antidiabetic agents, there is still a need for a safe and efficacious agent that can halt or reverse long-term disease progression. Finally, supporting patients in managing their diabetes and finding individualized ways to help them build healthy practices into their daily routine are critical components of caring for patients with type 2 diabetes.

For continued study and additional information, please visit the accompanying CME-accredited web module with interactive case studies on Type 2 Diabetes: www.ja-online.com/dukediabetes


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Dluhy RG, McMahon GT. Intensive Glycemic Control in the ACCORD and ADVANCE Trials. N Engl J Med. 2008 Jun 12;358(24):2630-2633.


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Henriksen EJ. Invited review: effects of acute exercise and exercise training on insulin resistance. J Appl Physiol. 2002;93(2):788-796.


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Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA. 2001;286(10):1218-1227.


Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005-2016.


Kraus WE, Houmard JA, Duscha BD, et al. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med. 2002;347(19):1483-1492.


Gregg EW, Gerzoff RB, Caspersen CJ, Williamson DF, Narayan KM. Relationship of walking to mortality among US adults with diabetes. Arch Intern Med. 2003;163(12):1440-1447.


Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care. 2003;26 Suppl 1:S51-61.


Mensing C, Boucher J, Cypress M, et al. National standards for diabetes self-management education. Diabetes Care.2007 Jan;30 Suppl 1:S96-S103.


Foster-Powell K, Holt SH, Brand-Miller JC. International table of glycemic index and glycemic load values: 2002. Am J Clin Nutr. 2002;76(1):5-56.


Brand-Miller J, Hayne S, Petocz P, Colagiuri S. Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes Care. 2003;26(8):2261-2267.



MERIT-HF Study Group; effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001-2007.


Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD Study): randomised controlled trial. Lancet. 2005;366(9500):1849-1861.


The Coronary Drug Project Research Group; clofibrate and niacin in coronary heart disease. JAMA. 1975;231(4):360-381.


Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001;24(6):1069-1078.


Lustman PJ, Anderson RJ, Freedland KE, de Groot M, Carney RM, Clouse RE. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care. 2000;23(7):934-942.



Boden G, Sargrad K, Homko C, Mozzoli M, Stein TP. Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes. Ann Intern Med. 2005;142(6):403-411.


Gannon MC, Nuttall FQ. Effect of a high-protein, low-carbohydrate diet on blood glucose control in people with type 2 diabetes. Diabetes. 2004;53(9):2375-2382.


Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care. 2003;26(4):1277-1294.


Norris SL, Engelgau MM, Narayan KM. Effectiveness of selfmanagement training in type 2 diabetes: a systematic review of randomized controlled trials. Diabetes Care. 2001;24(3):561-587.


Two Feathers J, Kieffer EC, Palmisano G, et al. Racial and Ethnic Approaches to Community Health (REACH) Detroit partnership: improving diabetes-related outcomes among African American and Latino adults. Am J Public Health. 2005;95(9):1552-1560.


Philis-Tsimikas A, Walker C, Rivard L, et al. Improvement in diabetes care of underinsured patients enrolled in Project Dulce: a community-based, culturally appropriate, nurse case management and peer education diabetes care model. Diabetes Care. 2004;27(1):110-115.


Davidson MB, Castellanos M, Duran P, Karlan V. Effective diabetes care by a registered nurse following treatment algorithms in a minority population. Am J Manag Care. 2006;12(4):226-232.


Davidson MB, Ansari A, Karlan VJ. Effect of a nurse-directed diabetes disease management program on urgent care/emergency room visits and hospitalizations in a minority population. Diabetes Care. 2007;30(2):224-227.


Trento M, Passera P, Bajardi M, et al. Lifestyle intervention by group care prevents deterioration of type II diabetes: a 4-year randomized controlled clinical trial. Diabetologia. 2002;45(9):1231-1239.


Trento M, Passera P, Miselli V, et al. Evaluation of the locus of control in patients with type 2 diabetes after long-term management by group care. Diabetes Metab. 2006;32(1):77-81.


Lee TM, Chou TF. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab. 2003;88(2):531-537.


Riddle MC. Editorial: sulfonylureas differ in effects on ischemic preconditioning—is it time to retire glyburide? J Clin Endocrinol Metab. 2003;88(2):528-530.


UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes: UKPDS 34. UK Prospective Diabetes Study Group. Lancet. 1998;352(9131):854-865.


Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005(3):CD002966.


Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, De Grauw WJ. Alpha-glucosidase inhibitors for people with impaired glucose tolerance or impaired fasting blood glucose. Cochrane Database Syst Rev. 2006(4):CD005061.


Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427-2443.


Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-2471.


Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med. 2007;357(1):28-38.


Psaty BM, Furberg CD. The record on rosiglitazone and the risk of myocardial infarction. N Engl J Med. 2007;357(1):67-69.

100. Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med. 2007;356(24):2522-2524. 101. Nathan DM. Rosiglitazone and cardiotoxicity—weighing the evidence. N Engl J Med. 2007;357(1):64-66.

In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289. 103. Pioglitazone HCl (marketed as Actos, Actoplus Met, and Duetact) information. Department of Health and Human Services, U.S. Food and Drug Administration, ed.: Center for Drug Evaluation and Research; 2007. 104. Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl) information. Department of Health and Human Services, U.S. Food and Drug Administration, ed.: Center for Drug Evaluation and Research; 2007. 105. Drucker DJ. The biology of incretin hormones. Cell Metabolism. 2006;3(3):153-165. 106. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2632-2637. 107. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29(12):2638-2643. 108. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49(11):2564-2571. 109. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28(10):1556-1568. 110. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092-1100. 111.

Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes, Obesity & Metabolism. 2006;8(4):419-428.

112. Exenatide (marketed as Byetta) information. Department of Health and Human Services, U.S. Food and Drug Administration, ed.: Center for Drug Evaluation and Research; 2007. 113. Riddle M, Frias J, Zhang B, et al. Pramlintide improved glycemic control and reduced weight in patients with type 2 diabetes using basal insulin. Diabetes Care. 2007;30(11):2794-2799. 114. Ratner RE, Dickey R, Fineman M, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet Med. 2004;21(11):1204-1212. 115. Heise T, Nosek L, Ronn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53(6):1614-1620. 116. American Diabetes Association. Insulin administration. Diabetes Care. 2003;26 Suppl 1:S121-124. 117.

Rave K, Bott S, Heinemann L, et al. Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care. 2005;28(5):1077-1082.

118. Ceglia L, Lau J, Pittas AG. Meta-analysis: efficacy and safety of inhaled insulin therapy in adults with diabetes mellitus. Ann Intern Med. 2006;145(9):665-675. 119. Mack GS. Pfizer dumps Exubera. Nature Biotechnology. 2007;25(12):1331-1332. 120. Chaiken R. EXUBERA Labeling Update. Global Medical Cardiovascular and Metabolic Disease, ed.: Pfizer/FDA; 2008. http://www. fda.gov/medwatch/safety/2008/Exubera_DHCP.pdf. Accessed May 28, 2008.

102. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial



Continuing Medical Education Assessment

1. According to the CDC’s 2007 estimates, how many people of all ages are living with diabetes in the United States? a. 5 million b. 10 million c. 24 million d. 200 million 2. In the early stages of insulin resistance, insulin production by the beta cells of the pancreas is a. high. b. low. 3. All of the following are risk factors for type 2 diabetes except a. history of gestational diabetes. b. low HDL cholesterol and high triglycerides. c. age of 60 years or older. d. high LDL cholesterol. 4. Which ethnic group has the lowest risk for developing type 2 diabetes? a. Non-Hispanic whites b. Non-Hispanic blacks c. Mexican Americans d. American Indians and Alaska natives 5. The American Diabetes Association (ADA) has the following recommendations for screening individuals for diabetes: a. Screening should be done in all individuals age 45 and older. b. Consider screening before the age of 45 if the individual is overweight and has at least one other risk factor for diabetes. c. The most common and convenient screening test is a fasting plasma glucose. d. All of the above. 6. The following intervention(s) would be considered first intervention to prevent or delay the onset of type 2 diabetes: a. Walking 30 minutes a week and decreasing weight by 5% to 7% b. Metformin or any of the meglinitides c. Acarbose or orlistat d. Thiazolidinediones e. Any of the above


7. The UKPDS trial demonstrated that the following can reduce the incidence of microvascular complications from diabetes: a. Weight loss b. Tight blood pressure control c. Tight glycemic control d. More frequent glucose monitoring e. Both b and c 8. The following is true regarding diabetes and depression: a. Men with diabetes are more prone to depression than women with diabetes. b. Patients with diabetes are more likely to develop depression. c. Depression does not appear to have any affect on glycemic control in patients with diabetes. d. Research shows that treating depression in patients with diabetes clearly improves glycemic control. 9. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial results thus far a. show that patients in the intensive treatment arm had more significant weight gain than those in the conventional treatment arm. b. reveal a higher death rate in the intensive arm than the conventional treatment arm. c. show no difference in mortality between the intensive and conventional treatment arm. d. both a and b. 10. Exercise improves glycemic control through the following mechanisms: a. Lowering LDL cholesterol and increasing HDL cholesterol b. Improved endothelial function c. Enhanced glucose uptake by skeletal muscle and improved insulin sensitivity d. Improved cardiovascular fitness 11. The following is true regarding low-carbohydrate diets (with less than 20 g of carbohydrates daily): a. They are appropriate for all patients with diabetes. b. As long as a patient does not stay on the diet for longer than two years, the ADA approves the use of this diet for patients with diabetes. c. Patients on mealtime insulin may experience


20. The following insulin is most likely to cause hypoglycemia: a. Glargine insulin b. NPH insulin c. Detemir insulin

Continuing Medical Education Assessment Answers

8. b 7. e

2. a

6. a

1. c

13. d 12. d 11. c

20. b 19. a 18. a 17. c 16. d


3. d

15. e 14. b

15. The following medications have side effects of gastrointestinal intolerance, flatulence, diarrhea, and abdominal pain that can be minimized by a slow titration upward of dose: a. Metformin b. Sulfonylureas c. Alpha-glucosidase inhibitors d. A and b e. A and c

19. The following mealtime insulin is less flexible and demands a more regular eating and activity schedule: a. Regular insulin b. Lispro insulin c. Aspart insulin d. Glulisine insulin

9. d

14. The following drugs as monotherapy can have hypoglycemia as a side effect: a. Metformin b. Sulfonylureas c. Thiazolidinediones d. Alpha-glucosidase inhibitors

18. The following drug works by inhibiting DPP-4, the enzymes that breaks down glucagon-like peptide: a. Sitagliptin b. Pramlinitide c. Exenatide d. Metformin

10. c

13. Successful alternative approaches to traditional diabetes care have the following themes in common: a. Cultural relevance and social support b. More frequent interaction with the medical team c. Saving money by avoiding the multidisciplinary approach d. Both a and b e. A, b, and c

17. The following drug can help lower glucose levels fastest and has no dosing limit: a. Exenatide b. Metformin c. Insulin d. Sulfonylureas

4. a

12. The following patients would benefit from diabetes self-management education: a. A 52-year-old male with type 2 diabetes for the past 10 years who is now starting insulin therapy b. A 34-year-old female with new diagnosis of type 2 diabetes c. A 55-year-old female on multiple insulin injections who has just been promoted at work and now will be traveling out of the country several times a month d. All of these patients would benefit from diabetes self-management education

16. The following is true regarding the thiazolidinediones (TZDs): a. As monotherapy, one study demonstrated that they achieved glycemic control goals for longer durations than either metformin or sulfonylureas. b. Side effects include weight gain and edema. c. There is controversy about cardiovascular risk associated with this group of drugs. d. All of the above.

5. d

decreased insulin requirements and may be at greater risk for hypoglycemia as a result. d. Numerous long-term research studies clearly show benefit of this diet for patients with diabetes.


EVALUATION FORM Release Date: July 31, 2008; Expiration Date: July 30, 2010 1. Please indicate your profession: MD/DO





2. Please rate the projected impact of the following objectives: Not Applicable • Diagnose prediabetes and diabetes and successfully monitor patients’ treatment plans and goals

Knowledge Competence Performance Patient Outcomes

• Identify patients at high risk of developing type 2 diabetes and discuss methods to prevent progression to diabetes

Knowledge Competence Performance Patient Outcomes

• Evaluate and recognize complications of type 2 diabetes, including psychiatric manifestations

Knowledge Competence Performance Patient Outcomes

• Develop an appropriate care plan that emphasizes lifestyle therapy and includes the current medications and investigational therapies

Knowledge Competence Performance Patient Outcomess

No Impact

Moderate Impact

High Impact

3. What aspects of the monograph were exceptional?______________________________________________________________________ _ ___________________________________________________________________________________________________________________

4. What aspects of the monograph did not meet your expectations? Please explain:____________________________________________ _ ___________________________________________________________________________________________________________________

5. Do you feel the activity was scientifically sound and free of commercial bias* or influence? Yes No, please explain: _ _________________________________________________________________________________________________________ _________________________________________________________________________________________________________ *Commercial bias is defined as a personal judgment in favor of a specific product or service of a commercial interest.

6. Please indicate which of the following American Board of Medical Specialties/Institute of Medicine core competencies were addressed by this educational activity (select all that apply): Patient care or patient-centered care Interpersonal and communication skills Practice-based learning & improvement Professionalism System-based practice Interdisciplinary teams


Quality improvement Utilize informatics Medical knowledge Employ evidence-based practice None of the above


7. The content of this activity matched my current (or potential) scope of practice. Yes No, please explain:_ _________ ____________________________________________________________________________________________________________ 8. How will you change your practice as a result of attending this activity (select all that apply)? Create/revise protocols, policies, and/or procedures Change the management and/or treatment of my patients This activity validated my current practice Other, please specify: _ _________________________________________________________________________________ 9. Please indicate any barriers you perceive in implementing these changes. Cost Lack of time to assess/counsel patients Lack of experience Reimbursement/insurance issues Lack of opportunity (patients) Patient compliance issues Lack of resources (equipment) Lack of consensus of professional guidelines Lack of administrative support No barriers Other, please specify: _ _________________________________________________________________________________ 10. How will you address these barriers in order to implement changes in your knowledge and/or behavior?____________ _________________________________________________________________________________________________________ 11. Was the format of this activity appropriate to the content presented? Yes Somewhat If No or Somewhat, how might the format be improved? Check all that apply:

Include more case-based presentations Increase interactivity with attendees Add breakouts for subtopics


Add a hands-on instructional component Schedule more time for Q and A Other, describe:

12. What could improve this activity?_ _________________________________________________________________________ _________________________________________________________________________________________________________ 13. Based on your educational needs, please list any topics you would like to see addressed in future educational activities.________________________________________________________________________________________________ _________________________________________________________________________________________________________ 14. Other Comments: ________________________________________________________________________________________ _________________________________________________________________________________________________________ _________________________________________________________________________________________________________ _________________________________________________________________________________________________________ _________________________________________________________________________________________________________ _________________________________________________________________________________________________________



CME CREDIT ATTESTATION FORM Please return completed Evaluation Form and CME Attestation Form to: Duke Office of CME 3100 Tower Boulevard, Suite 1300 Durham, North Carolina 27707

Signposts and Pathways: Multidimensional Care for Patients with Type 2 Diabetes Please clearly PRINT information: First Name_________________________________ MI:______ Last Name___________________________________ Degree of Participant: MD



RN Other (please specify):___________________________________

Organization___________________________________ 7-digit Duke ID (if applicable):_______________________ Specialty:_______________________________________Email: _____________________________________________ Note: CME certificates will be issued via email approximately 6 weeks following the activity.

Mailing Address: __________________________________________________________________________________ City:_____________________________________________State:________Zip Code:___________________________ Telephone:_______________________________________Fax:_____________________________________________ Maximum number of AMA PRA Category 1 CreditsTM: 3.0 I certify that I have completed the Self-Study Monograph, Signposts and Pathways: Multidimensional Care for Patients with Type 2 Diabetes for a total of 3.0 credits.

I attest that the number of CME credits claimed above is accurate.

________________________________________________________ Signature


______________________________ Date