Current challenges in diabetes management

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Current Challenges in Diabetes Management LAWRENCE BLONDE, MD, FACP, FACE Director, Ochsner Clinical Research Unit, Section of Endocrinology, Diabetes and Metabolic Diseases Associate Residency Program Director, Department of Internal Medicine Ochsner Clinic Foundation New Orleans, Louisiana

The burden of diabetes on the health care system mandates efforts to more optimally treat those with the disease and to prevent its development in those at risk. Early and intensive intervention in patients with diabetes reduces the risk of microvascular and macrovascular complications and disease progression. Current challenges in diabetes management include: (1) optimizing the use of currently available therapies to ensure adequate glycemic, blood pressure, and lipid control and to reduce complications; (2) educating patients on diabetes self-management; (3) improving patient adherence to lifestyle and pharmacologic interventions; (4) reducing barriers to the early use of insulin; and (5) improving the delivery of health care to people with chronic conditions. (Clinical Cornerstone. 2005;7[Suppl 3]:$6-S17) Copyright © 2005 Excerpta Medica, Inc.

INTRODUCTION Diabetes mellitus (DM), one of the leading causes of morbidity and mortality in the United States, affects a substantial proportion of the US population. 1 In fact, 7% of the US population, or 20.8 million Americans, have DM, including 10.5% (10.9 million) of men and 8.8% (9.7 million) of women >20 years of age. Prevalence of the disease increases with age--20.9% of people >60 years of age, the fastest growing age segment in our society, have diabetes. Prevalence is also higher among virtually all nonwhite racial and ethnic populations, including African Americans, Asian Americans, Hispanics, and Native Americans. z Indeed, the lifetime risk of developing diabetes for an individual born in the year 2000 in the United States was recently estimated at 33% for men and 39% for women; for Hispanics, the estimated lifetime risk was even higher, with a rate of 45% for men and 53% for women) With increasing age, obesity, and racial and ethnic diversity, there will likely be a substantial increase in the population of US adults with diabetes. 4 The health care burden of diabetes is related to an increasing prevalence of obesity and overweight--2 key risk factors for the development of type 2 DM. The ageadjusted prevalence of obesity (body mass index [BMI] >30 kg/m 2) was 30.5% in the National Health and Nutrition

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The lifetime risk of developing diabetes for I

an individual born in the year 2000 in the United States was estimated at 33% for

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men and 39% for women.

Examination Survey (NHANES, 1999-2000) compared with 22.9% in NHANES III (1988-1994; P < 0.001). 5 The prevalence of overweight (BMI >25 kg/m 2) also increased significantly during this period, from 55.9% to 64.5% (P < 0.001), as did extreme obesity (BMI >40 kg/m2), which increased from 2.9% to 4.7% (P -- 0.002). 5 The incidence of type 1 DM is also increasing, although the reasons for this trend are not fully understood. Although it can occur at any age, type 1 DM is most often diagnosed in children or young adults and accounts for 5% to 10% of total diabetes cases. 6

E C O N O M I C B U R D E N OF DIABETES Diabetes is associated with numerous serious complications, including cardiovascular disease (CVD), retinopathy, nephropathy, and peripheral and autonomic neu-

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developing diabetes was found among and 53% for women.

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The annual cost of diabetes (estimated in

ropathy. The American Diabetes Association (ADA) reported that, in 2002, the estimated direct and indirect medical costs attributable to diabetes totaled $132 billion.4 Direct medical costs totaled $91.8 billion and comprised $23.2 billion for diabetes care, $24.6 billion for chronic complications attributable to diabetes, and $44 , billion for treatment of excess general medical care. Per capita medical expenditures totaled $13,243 for people with diabetes versus $2560 for people without diabetes. 4 Moreover, a relationship has been shown between worsening glycemic control and increasing health care costs. A study by Gilmer et al 7 suggested a relationship between medical costs and glycosylated hemoglobin (A1C) level. Relative to those with a baseline A1C of 6%, those with an A1C of 10% had 3-year medical costs that were 11% higher ($23,873 vs $26,408; P < 0.05).

2002 dollars) could rise from $132 billion to $156 billion by 2010 and $192 billion

Health Benefits There is ample evidence that early and aggressive treatment targeting hyperglycemia, hypertension, and dyslipidemia in patients with diabetes reduces the risk of both microvascular and macrovascular complications and disease progression. In the Steno-2 study,8 intensive therapy resulted in a 53% reduction in the composite CVD end point, a 58% reduction in the risk of retinopathy, a 61% reduction in the risk of nephropathy, and a 63% reduction in the risk of autonomic neuropathy in patients with type 2 DM and microalbuminuria. Similarly, in the epidemiologic analysis of the United Kingdom Prospective Diabetes Study (UKPDS), 9 which evaluated 3642 patients with type 2 DM, a lower A1C value was associated with a lower risk of myocardial infarction (MI) and cardiovascular (CV) death. Each 1% reduction in updated mean A1C was associated with a 14% reduction in the risk for MI and all-cause mortality, a 21% reduction in diabetes-related deaths, and a 37% reduction in microvascular complications. Any reduction in A1C was likely to reduce the risk of microvascular complications, with the lowest risk being in those with A1C values in the normal range (<6.0%). 9 Results of the UKPDS led to the adoption of lower goals for glucose control.

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Relative to those with a baseline A 1 C of !i

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HEALTH AND ECONOMIC BENEFITS OF GLYCEMIC CONTROL Both the economic burden of diabetes, as well as the adverse impact of compromised health to the affected persons, emphasize the importance of adequate prevention and management of this condition.

Hispanics, with a rate of 45% for men ii

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6%, patients with an A I C of 10% had 3-year medical costs that were I I% higher.

The burden of diabetes extends to the general US economy as well. Diabetes is associated with higher rates of lost work time, restricted workdays, disability, and premature mortality, resulting in a loss to the US economy estimated at about $40 billion. 4 The projected increase in the number of people with diabetes suggests that the annual cost of diabetes (estimated in 2002 dollars) could rise from $132 billion to $156 billion by 2010 and $192 billion by 2020. 4

Economic Benefits Improved glycemic control is also associated with substantial quality-of-life and health economic benefits. Favorable health economic outcomes include higher $7

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and other parameters. In addition, these associations have made recommendations for the prevention and management of diabetes complications and comorbidities. These recommendations are summarized in Table I ) 6-18

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In the UKPDS, any reduction in A I C was likely to reduce the risk of microvascular

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Glycemic Control The ADA, for example, recommends achieving an A1C goal of <7.0%) 6 whereas the AACE recommends a goal of <6.5%. 17 Maintenance of such glycemic levels will significantly reduce complications in both type 1 and type 2 DM. 17 Results from the UKPDS 9 demonstrated that there is no A1C threshold at which further lowering does not reduce the risk of complications until the normal range (<6.0%) is reached. The risks and benefits of a therapeutic AIC goal of <6.0% are being investigated in an ongoing study of patients with type 2 DM) 6 Of special note is the position of the Council for the Advancement of Diabetes Research and Education (CADRE) on A1C levels) 8 CADRE recommends trying to achieve an A1C level as close to the nondiabetic range (4.5% to <6%) as possible without the occurrence of unacceptable side effects (ie, hypoglycemia), although A1C goals may need to be higher for certain higher risk populations or for patients who experience frequent or severe hypoglycemic episodes.

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retained employment rates, greater productive capacity, less absenteeism, and fewer restricted activity days) ° Although intensive therapy increases treatment costs, it substantially reduces the cost of treating diabetes-related complications and increases the amount of time free of complications. For example, based on outcome data from the UKPDS triM, Gray et a111 determined that intensive therapy increased trial treatment costs by £695 (US $1138 in 1997) per patient but reduced the cost of complications by £957 (US $1597). Similarly, in the Diabetes Prevention Program (DPP), the cost per quality-adjusted life-year for lifestyle intervention was $8800 from a societal perspective but was estimated to delay the development of diabetes by 11 years. 12 Thus, the additional costs of intensive management are mitigated by the reductions in the costs of treating diabetes complications. Early glycemic control in patients with diabetes also provides residual long-term benefits in reducing vascular complications. During the Epidemiology of Diabetes Interventions and Complications study, an extended followup study of the Diabetes Control and Complications TriM, the reduction in the incidence of nephropathy, retinopathy, and hypertension between the previous intensive- and conventional-treatment groups continued to expand. This occurred despite the lack of a substantial difference in glycemic levels between the treatment groups after 5 years of follow-up. 13-15 The group that previously received intensive treatment also experienced a slower progression of vascular intima-media thickness and CVD.

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Results from the UKPDS demonstrated

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that there is no lower threshold of A I C

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above normal at which further lowering does not reduce the risk of complications.

Control of Blood Pressure Levels Hypertension is a common comorbidity of diabetes and contributes to an increased risk of CVD, as well as microvascular complications such as retinopathy and nephropathy.16 The benefit of reducing both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with diabetes has been established in randomized clinical trials. Based on clinical trial results, the ADA has recommended that blood pressure be maintained at <130/<80 mm Hg in patients with diabetes with the use of lifestyle modification (medical

G O A L S FOR DIABETES M A N A G E M E N T Several associations, including the ADA 16 and the American Association of Clinical Endocrinologists (AACE), 17 have developed guidelines for the prevention, classification, diagnosis, and treatment of diabetes, including specific targets for A1C, blood pressure, lipid levels, $8

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Measurement Glycemic control A 1C, % Fasting/preprandial, mg/dL 2-Hour postprandial, mg/dL

Blood pressure Systolic <130 mm Hg Diastolic <80 mm Hg

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ADA

AACE

ACE

ACP

IDF

CADRE

<7.0 90-130 < 180

-:6.5 < 110 < 140

s6.5 < 110 < 140

<6.5 -

s6,5 < 110 < 140

Lowest possible* -

X X

X X

X X

X X

X X

X X

Lipids LDL-C <100 mg/dL HDL-C >40 mg/dL (M) >50 mg/dL (W) Triglycerides <150 mg/dL

X

X

X

X

X

X

X X X

X X X

X X X

X X X

X X X

X X X

Cardioprotection Aspirin therapy, 1° or 2 ° prevention

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X

X

X

X

X

Smoking cessation

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X

X

X

X

X

ADA = American Diabetes Association; AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ACP = American College of Physicians; IDF = International Diabetes Federation; CADRE = Council for the Advancement of Diabetes Research and Education; A1C = glycosylated hemoglobin; X = agreement with stated measure; LDL-C = lowdensity lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; M = men; W = women. *CADRE recommends A1C targets as close to the nondiabetic range of 4.5% to 6.0% as possible without unacceptable side effects (ie, hypoglycemia); exceptions may need to be made for certain patients, such as those in higher risk populations, or for patients who continue to experience frequent or severe hypoglycemic episodes.

nutrition therapy and appropriately prescribed physical

disease; according to these guidelines, the primary goal

activity) and, if necessary, p h a r m a c o l o g i c therapy. 16

is an L D L - C level <100 mg/dL. 16 Although glycemic control and lifestyle measures may allow achievement of lipid targets, many patients will also need pharmacologic therapy to reach appropriate lipid levels. 21 For individuals <40 years o f age w h o have diabetes but not overt CVD, who are at increased risk for C V D due to other C V risk factors or long duration of diabetes, and who do not achieve lipid goals with lifestyle modification alone, the addition o f pharmacologic therapy to achieve the L D L - C target of <100 m g / d L is appropriate. For individuals >40 years of age who have diabetes and a total cholesterol level >135 mg/dL, but not overt CVD, the addition of a statin to the treatment regimen with the goal to reduce L D L - C by 30% to 40% is appropriate, regardless of baseline L D L - C levels. High-risk patients, such as those with acute coronary syndromes or previous CV events, may require more aggressive therapy to achieve the lower L D L - C target o f <70 mg/dL. 16 Other drugs, including nicotinic acid, ezetimibe, bile-acid sequestrants, and fenofibrate, may be used when needed to meet lipid goals. Lowering triglycerides and increasing high-density lipoprotein cholesterol (HDL-C) are also associated with a reduction in CV events.

For patients with S B P between 130 and 139 m m H g or D B P between 80 and 89 m m Hg, lifestyle modification should be considered first-line therapy. If after a m a x i m u m o f 3 months b l o o d pressure targets are not attained, therapy with angiotensin-converting e n z y m e inhibitors or angiotensin-receptor blockers should be added to the lifestyle measures. For patients with an SBP o f >140 m m Hg and/or a D B P o f >90 m m Hg, initial treatment should include drug therapy as well as lifestyle modification. T w o or m o r e antihypertensive agents are generally required to achieve these blood pressure targets.

Control of Dyslipidemia Dyslipidemia is associated with an increased risk for macrovascular events as well as the progression o f diabetic retinopathy and nephropathy. 19'2° Therefore, reducing levels of low-density lipoprotein cholesterol (LDL-C) is an integral part o f diabetes care. A D A guidelines reco m m e n d that people with diabetes have their lipids managed as aggressively as patients with established heart $9

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Aspirin Therapy Aspirin therapy (75-162 mg/d) is recommended as a secondary prevention strategy in individuals with diabetes and a history of CVD. 16 It is also recommended as a primary prevention strategy in those with type 1 or type 2 diabetes who are at increased CV risk, including individuals who are >40 years of age or who have additional risk factors such as family history of CVD, hypertension, smoking, dyslipidemia, or albuminutia. 16 All patients with diabetes who smoke should be encouraged to quit smoking. Smoking cessation counseling should be incorporated into the diabetes care plan. 16

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Failure of clinicians to adopt a treat-to-target approach

• Suboptimal use of currently available therapies - Failure to initiate oral combination therapy early - Reluctance to initiate insulin therapy because of its perceived complexity - Reluctance to intensify insulin therapy for fear of hypoglycemic episodes and weight gain - Belief that insulin therapy is not effective in type 2 diabetes • Suboptimal patient adherence to lifestyle measures - Diet and exercise plans • Suboptimal patient adherence to pharmacologic treatments - Oral therapy and insulin therapy • Lack of optimal systems of health care delivery

FACTORS IMPEDING OPTIMAL DIABETES CARE Although the glycemic, blood pressure, and lipid targets recommended in the ADA and AACE guidelines are achievable with currently available therapies, the majority of patients with diabetes do not achieve these goals. According to data from NHANES (1999-2000), 22 only 37% of participants achieved the target A1C goal of <7.0%, whereas 37.2% had an A1C level >8.0%. Only 35% achieved the ADA target SBP and DBP recommendations. More than half had total cholesterol levels of >200 mg/dL. In total, only 7.3% of adults with diabetes attained all the recommended targets: A1C <7.0%, SBP/DBP <130/<80 mm Hg, and total cholesterol <200 mg/dL. The National Diabetes Education Program (NDEP) calls these goals the ABCs of diabetes, z3 Koro et a124 compared glycemic control rates among patients with type 2 DM from NHANES III (1988-1994) with those from NHANES (1999-2000) and noted that glycemic control rates had actually declined from 44.5% to 35.8%. The results of a study on the state of diabetes health in 157,000 Americans in 39 states showed that two thirds of the individuals with type 2 DM had A1C levels above the AACE goal of <6.5%. 24 In each of the 39 states, more than half of the people studied had an A1C level above the AACE goal. 25 There are several factors, both physician related and patient related, for the failure of patients to achieve the glycemic goals recommended by various professional organizations (Table II). To effectively treat patients with type 2 DM, a fundamental change in the approach to diabetes management and attitudes toward the use of insulin is necessary.

• Need for new therapies Combination

Therapy

Delayed

Patients may be failing to achieve glycemic goals because clinicians may not be adopting a treat-to-target approach. Target glycemic goals can be achieved through early initiation of combination therapy (>2 agents from various antidiabetes medication classes) and persistent titration of dosages (ie, the treat-to-target approach), yet the use of available diabetes treatment options is suboptimal. Indeed, the use of combination therapy is often delayed. Brown et al26 conducted a population-based study using retrospective observational data from 7208 complete courses of treatment with nondrug therapy, sulfonylurea monotherapy, metformin monotherapy, and combination oral therapy between 1994 and 2002 among members of the Kaiser Permanente Northwest Region. They found that A1C levels averaged 9.6% before combination therapy was initiated. Moreover, patients remained on monotherapy for an average of 15 to 21 months after the first A1C >8.0%, the "take action" threshold previously recommended by the ADA.

Addition of Insulin Delayed The progression to more intensive treatments may also be delayed. A recent substudy of the UKPDS 27 suggested that early addition of insulin to oral therapy could safely maintain A1C at near-target levels in the first 6 years after diagnosis. However, clinicians are reluctant to initiate insulin therapy, even when patients fail to achieve or maintain a glycemic target of <7.0% with oral therapy alone. Koro et a124 found that use of insulin actually declined from 24% during the period 1988-1994 SlO

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(NHANES III) to 16% during the period 1999-2000 (NHANES), despite frequent failure of patients to achieve glycemic targets, yet the use of oral antidiabetic monotherapy increased. Whereas use of combination therapy with oral antidiabetic agents and insulin increased from 3% to 11%, overall, the data suggest a marked underutilization of insulin in patients whose glycemic control is not adequate. The 2001-2003 National Health Intervention Survey28 demonstrated similar results, with 16% of patients taking insulin alone and 12% taking insulin in combination with oral medications. The reluctance to add insulin therapy to the treatment regimen may be due to its perceived complexity, the belief that it is not effective in patients with type 2 DM, or fear of hypoglycemic episodes and weight gain. However, in the.,.UKPDS substudy previously discussed,27 the addition of a basal insulin to sulfonylurea therapy achieved the desired glycemic targets without a significant increase in hypoglycemic episodes or weight gain.

of Endocrinology (ACE) and AACE was held in early 2005 to address how health care professionals and patients can work together to achieve recommended glycemic goals.31 Experts from 9 countries reviewed the latest research and then developed strategies for health care professionals and their patients to: (1) overcome barriers to optimal diabetes care, (2) better manage diabetes, and (3) achieve glycemic goals. The major recommendations follow; specific details of these recommendations can be found at http://www.aace.corn/newsroom/ press/2005/index.php?r=20050201.

Patient N o n a d h e r e n c e to T r e a t m e n t R e g i m e n s Patients also may not achieve glycemic goals because of their failure to fully adhere to lifestyle measures and pharmacologic treatment regimens. In a survey29 of 125 primary care physicians, patient nonadherence to nonpharmacologic and pharmacologic therapy and lack of patient motivation were cited as significant obstacles to achieving optimal diabetes care. A systematic review 3° of adherence citing retrospective analyses showed that adherence to oral antidiabetic therapy ranged from 36% to 93% in patients remaining on treatment for 6 to 24 months. Prospective electronic monitoring studies 3° found that patients took 67% to 85% of the prescribed doses of their oral antidiabetic agents; adherence to insulin therapy among patients with type 2 DM was even lower, ranging from 62% to 64%.

Early Intervention to Delay or Prevent Progression in High-Risk Individuals Type 2 DM is a chronic disease characterized by insulin resistance in most affected individuals and at least a relative insulin deficiency in all affected individuals, which progress over the course of the disease. It is important, therefore, to identify persons with prediabetes and to intervene before the development of overt type 2 DM. Early glycemic control in diabetes has been shown to provide residual long-term benefits in reducing vascular complications.32 Furthermore, there is evidence that when current glycemic goals are achieved early, B-cells are preserved. 33 Another study, A Diabetes Outcome Progression Trial, 34 is an ongoing international multicenter study comparing the ability of a thiazolidinedione, metformin, and a sulfonylurea to preserve B-cell function in patients with newly diagnosed diabetes. Large, randomized controlled studies31 have shown that lifestyle and pharmacologic interventions can effectively prevent or at least delay the progression of IGT to type 2 DM. Data from the DPP 35 indicate that lifestyle measures in nondiabetic patients with elevated fasting and postload plasma glucose concentrations (risk factors for developing diabetes) are especially effective in preventing or delaying the development of diabetes. In the DPP, high-risk patients were randomized to treatment

Recommendations • Detect and treat impaired glucose tolerance (IGT) to prevent type 2 DM and potentially reduce CVD. • Adopt an uncompromising treat-to-target approach to achieve and maintain glycemic~goals in patients with diabetes. • Promote and teach the tools for diabetes selfmanagement.

O t h e r Factors Another barrier to effective diabetes management is the lack of optimal systems of health care delivery. Current health care systems are poorly structured to deliver health care for chronic conditions, and the services delivered are often fragmented. I M P L E M E N T I N G C U R R E N T GUIDELINES TO A C H I E V E GLYCEMIC C O N T R O L Clearly, outpatient management of diabetes is less than optimal. A conference organized by the American College SII

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Type 2 DM is a chronic disease characterized

by insulin resistance and at least a relative insulin deficiency, which progress over the

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with metformin, troglitazone, placebo, or intensive lifestyle intervention. The lifestyle intervention goals of 7% weight loss and >150 minutes of physical activity per week reduced the incidence of diabetes by 58% compared with placebo. The incidence of diabetes in the group receiving metformin was reduced by 31% compared with placebo. Similar risk reductions were obtained with lifestyle intervention in the Finnish Diabetes Prevention Study.36 In the DPP,37 during the mean 0.9 year of treatment before troglitazone was withdrawn, the diabetes incidence rate was 3.0 cases/100 person-years in the troglitazone arm, 5.1 cases/100 person-years in the lifestyle intervention arm, and 6.7 cases/100 person-years in the metformin arm, compared with 12.0 cases/100 personyears in the placebo arm. Troglitazone markedly reduced the incidence of type 2 DM in high-risk individuals due, in part, to improved insulin sensitivity with maintenance of insulin secretion; however, this action did not persist. During the 3 years after troglitazone withdrawal, the diabetes incidence rate in the troglitazone group was almost identical to that of the placebo group. Early glycemic control in patients with IGT may provide long-term benefits by reducing vascular complications. Although a-glucosidase inhibitors are not widely used in the United States for the treatment of diabetes, in a study of patients with IGT,38 reducing postprandial hyperglycemia with the a-glucosidase inhibitor, acarbose, was associated with a 49% relative risk reduction in the development of CV events and a 2.5% absolute risk reduction; the major reduction was in the risk of MI. In another study,39 acarbose therapy was also associated with a 34% relative risk reduction in the incidence of new cases of hypertension and a 5.3% absolute risk reduction.

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relative contributions of FPG and PPG to A1C is dependent on the A1C level. 4° At A1C levels >8.4%, the FPG contribution is greater than that of PPG; however, at lower A1C levels (<7.3%), the PPG contribution is greater. Many individuals with AIC levels between 6.0% and 7.0% have normal FPG levels but high 2-hour postchallenge plasma glucose levels, suggesting that lowering A1C will require treatment preferentially directed at lowering PPG levels. PPG excursions increase the risk of diabetic complications. In addition, experimental data have suggested mechanisms by which PPG spikes might cause oxidative stress and thereby adversely affect endothelial function.3° Thus, controlling both FPG and PPG is required to achieve A1C targets and reduce diabetic complications.

Individualize Treatment to Meet the Needs.~ of Each Patient Both glycemic targets and treatment regimens should be individualized to meet the needs and conditions of each patient.

Lifestyle Measures and Pharmacologic Treatment Although lifestyle measures (medical nutrition therapy and appropriately prescribed physical activity) alone may suffice to reach glycemic targets in some patients with type 2 DM, a combination of lifestyle measures and pharmacologic treatment is often required. In some patients, persistent titration of oral monotherapy may achieve the glycemic targets set by ACE/AACE and ADA. However, when A1C levels exceed the target set for an individual patient, despite a maximally effective dose of monotherapy, a second agent should be added in a timely manner and before the patient experiences treatment failure. In a study of patients with type 2 DM inadequately controlled with a sulfonylurea,41 combination therapy with glyburide and metformin provided significantly better glycemic control than monotherapy with either agent. Similarly, combination treatment with metformin and rosiglitazone was significantly more effective at reducing mean A1C and FPG levels and improving insulin sensitivity and 13-cell function than metformin alone.42 In this trial, 28% of patients being treated with combination therapy achieved A1C targets consistent with ACE/ AACE and ADA guidelines after 26 weeks. However, dose-dependent increases in body weight, total cholesterol, and LDL-C were observed more frequently in the

Both Fasting and Postprandial Glucose Must Be Controlled A1C is the measure of both fasting plasma glucose (FPG) and postprandial glucose (PPG) over time. The

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combination group. For patients whose A1C levels make it unlikely that they will achieve glycemic targets with monotherapy, initial treatment with a combination of 2 medications with complementary mechanisms of action may be required. 43

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When treatment with basal insulin plus oral agents does not attain or maintain glycemic goals, adding a rapidacting insulin (insulin lispro, insulin aspart, or insulin glulisine) before the meal with the highest PPG excursion is a logical next step and may be sufficient to achieve targets. If not, then rapid-acting insulin can be added before the next largest meal as well and, if necessary, before each meal. As prandial insulin is added, secretagogues are usually discontinued and the basal insulin dose may need to be adjusted. ACE/AACE has recently released road maps to help clinicians achieve glycemic goals. 46

Insulin Therapy The introduction of insulin therapy early in the course of type 2 DM is an opportunity to alter the course of diabetes progression. Early use of insulin therapy is often required for timely achievement of glycemic goals. In type 2 DM, targets may be achieved with basal insulin plus oral agents or with regimens combining basal and prandial (bolus) insulin; premixed insulin preparations also may be used in certain patients. Some patients with type 2 DM may present with symptomatic hyperglycemia that requires.-initial insulin therapy. After glucose levels improve, these patients may subsequently be able to maintain glycemic control with lifestyle measures and/or oral antidiabetic agents. In the Treat-to-Target Trial,44 a marked reduction in A1C was achieved with the addition of bedtime neutral protamine Hagedorn (NPH) insulin or insulin glargine to the treatment regimen of patients with A1C levels that remained >7.5% (mean A1C, 8.6%) despite the use of 1 oral antidiabetic agent. The 2 insulins were similarly effective in lowering glycemia; however, insulin glargine was associated with significantly less nocturnal hypoglycemia than NPH because of its flat time-action profile. Another study45 compared the addition of premixed biphasic insulin aspart (70/30) BID or insulin glargine to metformin and/or a thiazolidinedione. Although both groups of patients had a marked reduction in A1C, the patients receiving insulin aspart achieved lower A1C values than those receiving glargine. This was not surprising, since the patients who were being treated with insulin aspart were receiving a prandial as well as a basal treatment, whereas those being treated with glargine were only receiving a basal treatment. Although there were no episodes of severe hypoglycemia, almost half of the patients receiving the premixed insulin experienced hypoglycemic episodes, a rate almost 3 times that of the insulin glargine group. Because fear of hypoglycemia by both patients and physicians is a major obstacle to the use of insulin, the availability of newer insulin formulations with improved 24-hour time-action profiles should help increase appropriate use of insulin therapy.

Improving Adherence to Treatment Regimens to Achieve Glycemic Control Patient nonadherence to lifestyle measures and pharmacologic therapies is one of the most common reasons cited for failure to achieve glycemic goals. To help improve adherence and patient outcomes, initial and ongoing medical nutrition therapy and self-management education must be made available to all patients with diabetes. Ideally, these measures should be provided by nutritionists or registered dietitians and certified diabetes educators working in an ADA-recognized diabetes education program as a component of a team approach to the provision of diabetes care. One of the most important educational needs of people with diabetes is to learn how to correctly perform, interpret, and use the results of patient self-monitoring of blood glucose (SMBG). SMBG is an important educational tool for all patients. When performed accurately and with sufficient frequency, SMBG readings can help both patients and their health care team make informed decisions about lifestyle measures and adjustments in pharmacologic therapy. The readings can also provide ongoing feedback to patients about the success of their treatment program. Karter et a147 found that frequent SMBG was associated with clinically and statistically improved glycemic control regardless of diabetes type or therapy. Educational Resources Are Available There are many resources available to assist patients and their health care teams to better adhere to recommended lifestyle and pharmacologic diabetes treatments. The NDEP is a joint venture of the National Institutes of Health and the Centers for Disease Control and Prevention that partners with >200 public and private organizations to." (1) improve treatment and outcomes

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for people with diabetes, (2) promote early diagnosis, and (3) prevent the onset of diabetes. The NDEP focuses on programs and campaigns that provide patients and health care professionals with information that can help make diabetes treatment recommendations more available, easier to understand, and easier to use. This is done through resources and knowledge tools in 3 major campaign efforts: (1) Control Your Diabetes for Life48; (2) Be Smart About Your Heart: Control the ABCs (A1C, blood pressure, and cholesterol) of Diabetes23; and (3) Small Steps, Big Rewards: Prevent Type 2 Diabetes. 49 The Small Steps, Big Rewards: Prevent Type 2 Diabetes campaign was launched by the NDEP in conjunction with the investigators of the DPP. This initiative translates the results and key learnings from the DPP into a structured approach to help people with prediabetes implement lifestyle measures to achieve weight loss and enhanced physical fitness. The NDEP Web site provides evidence-based tools (eg, the Game Plan Toolkit) that patients and clinicians can download and use to individualize lifestyle modification programs and monitor results. The Game Plan Toolkit contains resources such as fat and calorie counters and an activity tracker. These tools were proven to be very effective in helping participants in the DPP achieve their goals of >7% weight loss and > 150 minutes of physical activity per week (30 minutes per day, 5 days a week at the intensity of brisk walking), resulting in a 58% decrease in the progression from prediabetes to type 2 diabetes. While the Small Steps campaign is focused on individuals with prediabetes, the information is likely to be helpful to patients with diabetes as well. The NDEP also has culturally specific resources to encourage patient adherence to lifestyle modifications. For example, the Latino/Hispanic work group of the DPP has developed a music CD, called Moviemento, to inspire movement and physical activity. The CD can be ordered from the DPP Web site, and several songs on the CD can be downloaded as MP3 files. NDEP program materials are available in multiple languages. The ADA also provides resources to help people with diabetes better adhere to lifestyle modifications and pharmacologic therapy, including the comprehensive Weight Loss Matters program. 5° The ADA Web site has a recipe of the day and a tip of the day, as well as news about diabetes and prediabetes. The ADA Doing Better Committee has launched Club Ped to promote physical activity. Individuals or groups can sign

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up online to track the number of steps they walk each day. Patients who meet their goals receive virtual rewards such as the next chapter of an online novel or a virtual pet who learns new tricks. The ADA Doing Better Committee also has a tool to help patients plan for their next physician visit. This tool helps patients track their medications, laboratory test results, and progress toward the diabetes management goals they have developed in collaboration with their clinician. The ADA also provides an interactive Web-based health-risk profiling tool, Diabetes Personal Health Decisions (Diabetes PHD), 51 that makes it easier for people with diabetes and those at risk for developing diabetes, heart disease, or stroke to better manage their health. Diabetes PHD allows users to create and submit an individual profile containing such health-related information as age, sex, height, weight, health history, and medications to be analyzed by Diabetes PHD. The user is then provided with a detailed risk profile. The user can modify various health variables, such as weight, blood pressure, and lipid levels, to see the effect these changes would have on their long-term risk for diabetes and CV complications. Diabetes T r e a t m e n t Recommendations

Treatment recommendations from ACE, ADA, and other professional health organizations are excellent resources for improving diabetes care and should be more widely implemented. These evidence-based guidelines are a necessary component of effective chronic disease management and should be made easily accessible at the point of care (ie, in examination rooms, on patient charts, on office computers, and on personal digital assistants). 3° Specialized clinical information systems (eg, electronic medical records, disease-specific patient registries, and databases) can help facilitate adherence to guidelines by providing all members of the health care team with timely access to data. Webbased resources (eg, www.betterdiabetescare.nih.gov) can help users design and implement more effective health care delivery systems for patients with diabetes. 3° Other valuable Web-based resources for diabetes care are listed in Table 111.30 CONCLUSIONS

Current challenges in diabetes management include: (1) optimizing the use of currently available diabetes therapies S14

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to ensure adequate glycemic, blood pressure, and lipid control and to reduce complications; (2) improving patient adherence to lifestyle changes and pharmacologic interven-

insulin to oral therapy regimens, as needed, can help pa-

tions; (3) reducing barriers to the early use of insulin;

self-management plan, adhering to recommended therapeu-

(4) educating patients about diabetes self-management;

tic interventions and monitoring fasting and postprandial blood glucose frequently. Widespread dissemination and

tients reach glycemic control and slow disease progression. Patients, in turn, must take an active role in their diabetes

and (5)improving the delivery of chronic health care. Physicians must adopt a treat-to-target approach, with persistent titration of oral medications and insulin to reach ACE/AACE and ADA glycemic goals. Early addition of

implementation of existing evidence-based treatment recommendations and intensive patient-centered education can help reduce the barriers to optimal diabetes care.

Web Address

Site Sites that publish, aggregate, or help translate practice guidelines

aace.com diabeteseducator.org

American Association of Clinical Endocrinologists American Association of Diabetes Educators American Diabetes Association Centers for Disease Control and Prevention Council for the Advancement of Diabetes Research and Education Lawson Wilkins Pediatric Endocrine Society

diabetes.org cdc.gov/diabetes cadre-diabetes.org lwpes.org ndep.nih.gov niddk.nih.gov

National Diabetes Education Program National Institute of Diabetes and Digestive and Kidney Diseases National Guideline Clearinghouse

guideline.gov idf.org tdh.state.tx.us/diabetes

TM

International Diabetes Federation Texas Diabetes Council Sites that provide information to help enhance adherence to treatment plans

American Association of Clinical Endocrinologists and American College of Endocrinology American Association of Clinical Endocrinologists Power of Prevention American Diabetes Association American Association of Diabetes Educators National Institute of Diabetes and Digestive and Kidney Diseases Lawson Wilkins Pediatric Endocrine Society MedlinePlus National Diabetes Education Program Nutrition.gov American Dietetic Association

aace.com powerofprevention.com diabetes.org diabeteseducator.org diabetes.niddk.nih.gov lwpes.org medlineplus.gov ndep.nih.gov nutrition.gov eatright.org/Public/Nutritionlnformation/92.cfm

Sites that can help clinicians answer clinical questions at the point of care

American Association of Clinical Endocrinologists and American College of Endocrinology American Diabetes Association Council for the Advancement of Diabetes Research and Education National Library of Medicine, PubMed Physicians' Information and Education Resource InfoPOEMS UpToDate

aace.com diabetes.org cadre-diabetes.org ncbi.nlm.nih.gov/entrez/query, fcgi pier.acponline.org infopoems.com uptodate.com

Adapted with permission. 3° SI5

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16. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(Suppl 1):$4-$36. 17. American Association of Clinical Endocrinologists. Medical Guidelines for the Management of Diabetes Mellitus: The AACE System of Intensive Diabetes SelfManagement-2002 Update. Endocr Pract. 2002;8(Suppl 1): 43-56. 18. Council for the Advancement of Diabetes Research and Education. CADRE's A1C Position. Curr Diabetes Pract. 2002; 1:1-8. Available at: http://www.cadre-diabetes.org/em/ pdf/newsletters/archive/CADRE-newsletter-01 .pdf. Accessed August 9, 2005. 19. Lyons TJ, Jenkins AJ, Zheng D, et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci. 2004;45:910-918. 20. Jenkins A J, Lyons TJ, Zheng D, et al. Lipoproteins in the DCCT/EDIC cohort: Associations with diabetic nephropathy. Kidney Int. 2003;64:817-828. 21. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(Suppl 1):$4-$36. 22. Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA. 2004;291:335-342. 23. National Diabetes Education Program. Awareness campaign: Be smart about your heart: Control the ABCs (A1C, blood pressure, and cholesterol). Available at: http://www.ndep.nih.govlcampaigns/BeSmart/BeSmart_ index.htm. Accessed December 15, 2005. 24. Koro CE, Bowlin S J, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes. Diabetes Care. 2004;27:17-20. 25. American Association of Clinical Endocrinologists. State of diabetes in America: A new report reveals America's diabetes health is in jeopardy. Available at: http://www. aace.com/newsroom/press/2005/index.php ?r=20050518. Accessed December 15, 2005. 26. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27:1535-1540. 27. Wright A, Burden AC, Paisey RB, et al. Sulfonylurea inadequacy. Efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UK Prospective Diabetes Study (UKPDS 57) [published correction appears in Diabetes Care. 2002;25:1268]). Diabetes Care. 2002;25:330-336. 28. NHIS Summary Health Statistics for US Adults: National Health Intervention Survey, 2003. Available at: http://www. cdc.gov/nchs/data/series/sr_l 0/sr 10225.pdf. Accessed December 7, 2005. 29. Cefalu WT, LeRoith D, and the Council for the Advancement of Diabetes Research and Education. Overcoming the barriers for achieving standards of diabetes care: The formation of CADRE. Diabetes Technol Thera. 2003;5: 385-392. 30. Cramer JA. A systematic review of adherence with medications for diabetes. Diabetes Care. 2004;27:1218-1224. 31. Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement. July 8, 2005. Available at: http://www.diabetsnpo. im.wustl.edu/resources/documents/ACE-Position StatementsDiabetes.pdf. Accessed December 7, 2005.

REFERENCES

1. American Diabetes Association. All About Diabetes. Diabetes Statistics. National Diabetes Fact Sheet, 2005. Available at: http://www.diabetes.org. Accessed December 6, 2005. 2. McBean AM, Li S, Gilbertson DT, Collins AJ. Differences in diabetes prevalence, incidence, and mortality among the elderly of four racial/ethnic groups: Whites, blacks, Hispanics, and Asians. Diabetes Care. 2004;27: 2317-2324. 3. Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003 ;290:1884-1890. 4. American Diabetes Association. Economic costs of diabetes in the U.S. in 2002. Diabetes Care. 2003;26:917-932. 5. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288:1723-1727. 6. National Diabetes Information Clearinghouse (NDIC). National diabetes statistics. Available at: http://diabetes. niddk.nih.gov/dm/pubs/statistics/. Accessed August 9, 2005. 7. Gilmer T, O'Connor PJ, Rush WA, et ai. Predictors of health care costs in adults with diabetes. Diabetes Care. 2005;28:59-64. 8. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393. 9. Stratton IM, Adler AI, Neil AW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ. 2000;321:405-412. 10. Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus. A randomized, controlled, double-blind trial. JAMA. 1998;280:1490-1496. 11. Gray A, Raikou M, McGuire A, et al. Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: Economic analysis alongside randomized controlled trial (UKPDS 41). BMJ. 2000;320: 1373-1378. 12. Herman WH, Hoerger TJ, Brandle M, et al. The costeffectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med. 2005; 142:323-332. 13. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290:2159-2167. 14. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563-2569. 15. Nathan DM, Lachin J, Cleary P, et al. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med. 2003;348:2294-2303. S16

h

32. The Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. JAMA. 2002; 287:2563-2569. 33. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic 13-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:2796-2803. 34. Viberti G, Kahn SE, Greene DA, et al. A Diabetes Outcome Progression Trial (ADOPT): An international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. Diabetes Care. 2002;25:1737-1743. 35. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 36. Lindstrom J, Eriksson JG, Valle TT, et al. Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: Results from a randomized clinical trial. J A m Soc Nephrol. 2003; 14:S108-S113. 37. Knowler WC, Hamman RF, Edelstein SL, et al. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes. 2005;54:1150-1156. 38. Chiasson J-L, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. The STOP-NIDDM Trial. JAMA. 2003;290:486--494. 39. Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Arch Intern Med. 2003;163:1306-1316. 40. The relationship of glycemic exposure (HbAlc) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes. 1995;44:968-983. 41. Blonde L, Rosenstock J, Mooradian AD, et al. Glyburide/metformin combination product is safe and efficacious in patients with type 2 diabetes failing sulphonylurea therapy. Diabetes Obes Metab. 2002;4:368-375.

42. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: A randomized controlled trial. JAMA. 2000;283:1695-1702. 43. Garber A, Donovan DS Jr, Dandona P, et al. Efficacy of glyburide/metformin tablets compared with initial monotherapy in type 2 diabetes. J Clin Endocrinol Metab. 2003;88:3598-3604. 44. Riddle MC, Rosenstock J, Gerich J, et al. The Treat-toTarget Trial. Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086. 45. Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes. Diabetes Care. 2005;28:260-265. 46. American Association of Clinical Endocrinologists. The road map for the prevention and treatment of type 2 diabetes. Available at: http://www.aace.com/meetings/ consensus/odimplementation/roadmap.pdf. Accessed December 15, 2005. 47. Karter A J, Ackerson LM, Darbinian JA, et al. Selfmonitoring of blood glucose levels and glycemic control: The Northern California Kaiser Permanente Diabetes Registry. Am J Med. 2001; 111:1-9. 48. NationalDiabetes Education Program. Awareness campaign: Control your diabetes for life. Available at: http://www. ndep.nih.gov/campaigns/ControlForLife/ControlForLife_ index.htm. Accessed December 15, 2005. 49. National Diabetes Education Program. Awareness campaign: Small steps, big rewards: Prevent type 2 diabetes. Available at: http://www.ndep.nih.gov/campaigns/ SmallSteps/SmallSteps_index.htm. Accessed December 15, 2005. 50. American Diabetes Association. Weight Loss & Exercise. Weight Loss Matters. Available at: http://www.diabetes. org/weightloss-and-exercise/weightloss.j sp. Accessed December 15, 2005. 51. American Diabetes Association. Diabetes Prevention. Diabetes PHD, Personal Health Decisions. Available at: http://www.diabetes.org/diabetesphd/default.j sp. Accessed December 15, 2005.

Address correspondence to: Lawrence Blonde, MD, FACP, FACE, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70115. E-mail: [email protected] SI7