SECTION 1: Type 2 Diabetes: An Overview

Introduction

This section reviews the epidemiology, burden of disease, pathophysiology, and current standards for the screening and diagnosis of type 2 diabetes. In addition, the overall status of diabetes care in the United States is discussed, illustrating the need for diabetes care to continually be a subject of concern and scrutiny for healthcare providers and payers.

Epidemiology of Type 2 Diabetes

Diabetes is an increasing problem around the world. In the United States, data from the Centers for Disease Control and Prevention (CDC) and the National Health and Nutrition Examination Survey (NHANES) show that the overall prevalence of diagnosed diabetes among adults increased from approximately 5% in 1990 to nearly 8% in 2006.¹ In addition, by 2006, 5% of adults had undiagnosed diabetes and 29.5% had prediabetes, yielding a total of more than 40% of US adults (>20 years of age) with a hyperglycemic condition.² Thus, even with the current interest in diabetes care, 40% of the diabetic population remains undiagnosed.² These data suggest that screening for diabetes has been inadequate. Early screening can enable important early intervention, even at the prediabetes stage.

Michael Bush:

Diabetes obviously is not a local problem, it's not a country problem-it's a worldwide problem.

Figure 1

Large population studies reveal that diabetes prevalence increases with advancing age ().³ In contrast, in clinical practice, the incidence of a new diagnosis of diabetes is highest in middle age, with slightly more than 50% of new cases diagnosed among people age 40 to 59.⁴ Although most cases of type 2 diabetes are diagnosed in adults, the prevalence of childhood type 2 diabetes is on the rise, with an estimated 3700 children and adolescents newly diagnosed with the disease each year.⁴ National survey data indicate that prevalence varies by ethnicity, with diagnosed diabetes in 6.6% of non-Hispanic white adults, 7.5% of Asian Americans, 10.4% of Hispanics, and 11.8% of non-Hispanic blacks.⁴ According to the Indian Health Service, 16.5% of American Indian/Alaskan Native adults also have diagnosed diabetes.⁴

Obesity, especially abdominal obesity, is an important causal factor in type 2 diabetes (see section on Natural History and Pathophysiology). CDC data demonstrate that geographic trends in diabetes prevalence correlate closely with those of obesity across US states and regions.⁵ As obesity has increased greatly from 1994 to 2007, type 2 diabetes has also increased.⁵ In 1994, no state exceeded an obesity prevalence of 22%, but in 2008, 28 states exceeded that level. In 1994, nearly all states had diagnosed diabetes prevalence less than 6%, but in 2008, 47 states exceeded that prevalence.⁵

The Burden of Diabetes

Morbidity and Mortality

In 2006, diabetes was the seventh leading cause of death on US death certificates.⁴ However, it is well known that diabetes is underreported as an underlying cause of death, and persons with diabetes have approximately twice the risk of death at any age compared with persons without the disease.⁴ Mortality in diabetes relates to glucose control. The United Kingdom Prospective Diabetes Study (UKPDS) showed that for every 1% rise in A1C, all-cause and diabetes-related mortality increase 14% and 21%, respectively.⁶ Even within the prediabetic range, elevated glucose levels-especially 2-hour postprandial glucose-are associated with higher mortality.⁷

Morbidity and mortality are directly related to the chronic complications of diabetes, which include both macrovascular disease (coronary, cerebrovascular, and peripheral arterial disease) and microvascular disease (retinopathy, neuropathy, nephropathy), as shown in Table 1.⁴ Heart disease and stroke kill 65% of people with diabetes.⁸ The death rate from heart disease and the risk of stroke are 2 to 4 times higher in patients with diabetes than in those without diabetes.⁴ Up to 75% of adults with diabetes have hypertension,⁴ and the combination of hypertension and diabetes doubles the risk of cardiovascular disease.⁹ Furthermore, diabetic dyslipidemia, associated with insulin resistance and characterized by high levels of triglycerides and small low-density lipoprotein (LDL)-cholesterol particles and low levels of high-density lipoprotein (HDL) cholesterol, contributes to atherosclerosis.⁹

The toll of microvascular disease on the health of patients with diabetes is staggering. Each year, more than 12,000 new cases of blindness result from diabetic retinopathy, making this complication the leading cause of new-onset blindness in persons 20 to 74 years of age.⁴ In more than 175,000 people with diabetes, nephropathy has resulted in end-stage renal disease requiring kidney transplantation or chronic dialysis.⁴ Up to 70% of diabetes patients have mild-to-severe neuropathy, with such symptoms as pain or impaired sensation in the hands or feet, carpal tunnel syndrome, impaired digestion, and/or erectile dysfunction.⁴ Especially when combined with peripheral artery disease, severe neuropathy results in lower-extremity amputations, of which more than 70,000 are performed annually.⁴ Other medical problems encountered by persons with diabetes include severe periodontal disease, miscarriages, major birth defects, and poorer prognosis in other illnesses (eg, pneumonia, influenza).⁴

Not surprisingly, patients with diabetic complications often demonstrate seriously impaired quality of life (QOL).

Quality of Life

Evidence has not demonstrated severe QOL impairment with well-controlled diabetes. In general, studies using generic health-related QOL measures have found moderate reduction in QOL among patients with diabetes compared with nondiabetic controls.¹⁰

However, diabetes that is not effectively controlled can have a substantial negative impact on QOL. Chronic diabetic complications, especially macrovascular disease, are strongly and consistently associated with reduced QOL.^10,11 In type 2 diabetes, symptoms of hyperglycemia or hypoglycemia have been associated with small but significant reductions in health-utility scores.¹² Even relatively mild hyperglycemia or hypoglycemia can be associated with physical, mood, and cognitive symptoms.¹³ Cognitive efficiency may decline by one third, with serious implications for driving and other hazardous tasks.¹³

QOL in diabetes appears to be strongly influenced by psychosocial factors (eg, health beliefs, social support, coping strategies, personality traits).¹¹ For example, depression, a common comorbidity in patients with diabetes, can severely impact QOL.¹⁴

Depression may result in a negative feedback loop of poor self-management and poor medical outcomes, leading to worsening depression and sense of failure.

¹¹ In contrast, an active coping style may result in a positive feedback loop of good self-management, improved functional status, and sense of well-being.¹¹

Economic Burden

Diabetes imposes huge medical costs on individual patients, payers, and the US healthcare system, and costs continue to increase. For the year 2007, the American Diabetes Association (ADA) estimated direct medical expenditures attributable to diabetes at $116 billion (compared with $91.8 billion in 2002¹⁵)-including $27 billion for diabetes care, $58 billion for chronic complications, and $31 billion for excess general medical costs.¹⁶ Indirect costs, which include those from disability, work loss, and premature mortality, were estimated at $58 billion, for total costs of $174 billion (from $132 billion in 2002¹⁵).¹⁶ Hospital inpatient care, diabetes medications and supplies, and physician office visits accounted for 50.2%, 12.1%, and 8.5%, respectively, of total costs.¹⁶

Don Balfour:

Diabetes is very prevalent; our health plan population with diabetes is now over 14,000 patients and growing at 6% a year, which is pretty frightening.

Adjusting for inflation, the 2002 total cost of $132 billion would be equivalent to $153 billion in 2007 dollars.¹⁶ Thus, in terms of 2007 dollars, there was a $21-billion increase in total diabetes costs between 2002 and 2007. This increase reflects several factors: increasing diabetes prevalence, medical costs rising faster than general inflation, and improved data and cost estimation methods.¹⁶

The rising cost of diabetes care is not inevitable, nor is it irreversible. If the lifestyle trends that contribute to diabetes onset and exacerbation (eg, obesity, lack of physical activity, poor diet) could be reversed, the trend of increasing prevalence could be reversed with resulting cost savings. Also, improved treatments and better glycemic control with a concomitant reduction in many diabetic complications can decrease costs significantly.¹⁷ Without doubt, however, the most effective strategy would require diagnosis and intervention early in the course of disease, before complications develop.

Natural History and Pathophysiology

Insulin Resistance and Beta-Cell Dysfunction

Type 2 diabetes results from the interaction of 2 defects: impaired insulin secretion (pancreatic beta-cell dysfunction) and impaired insulin sensitivity (insulin resistance).^18,19

Insulin has 3 main target tissues: liver, skeletal muscle, and fat. In the liver, insulin suppresses gluconeogenesis²⁰ and promotes glucose storage as glycogen.¹⁸ In skeletal muscle, insulin promotes glucose uptake, oxidation, and storage as glycogen.¹⁸ In fat, insulin suppresses lipolysis. Insulin resistance in liver and skeletal muscle is quite common. The NHANES survey suggested that approximately 40% of adults over the age of 60 show some degree of insulin resistance.² The majority of these subjects maintain normal glucose levels because their beta cells compensate by increasing their insulin secretion. However, in subjects at greater risk of becoming diabetic (eg, those who are obese or have a family history of diabetes), pancreatic insulin secretion cannot keep pace with the insulin resistance over time and blood sugar begins to rise. Subtle elevations are seen at first, but eventually, frank diabetes occurs.

Don Balfour:

It's paramount for us to treat these patients to goal and treat them as tight to control as we can because the complications are so expensive.

When the pancreas is no longer able to secrete enough insulin to compensate for insulin resistance, hyperglycemia develops due to a combination of increased hepatic glucose output and decreased skeletal muscle glucose uptake and disposal.²⁰ In addition, increased lipolysis releases free fatty acids (FFAs) into circulation, which further increases hepatic glucose output and impairs skeletal muscle glucose disposal.^19,20 Furthermore, both hyperglycemia and excess circulating FFAs may be toxic to beta cells (glucotoxicity and lipotoxicity), exacerbating betacell dysfunction and apoptosis (ie, cell death).¹⁸

The UKPDS demonstrated that by the time type 2 diabetes is diagnosed, approximately 50% of beta-cell function has already been lost. Another 15% loss occurs over the first 6 years after diagnosis.²¹ Backward extrapolation of that curve suggests that loss of beta-cell function begins as many as 10 years before diabetes is diagnosed.¹⁹

The natural history of type 2 diabetes, and the relationship between insulin resistance and beta-cell dysfunction, is illustrated in Figure 2.²²

The Role of Obesity

Obesity, particularly abdominal obesity, is correlated with the insulin resistance that is characteristic of type 2 diabetes.^20,23 Insulin resistance, in turn, may be the mechanism by which obesity leads to cardiovascular disease.⁹ Adipose tissue, once believed to be merely a storage depot for fat, is now known to secrete multiple biologically active molecules (adipocytokines).²⁰ In obesity, oversecretion of certain adipocytokines (such as tumor necrosis factor-alpha) that promote insulin resistance, and undersecretion of others (such as adiponectin) that enhance insulin action, may occur.¹⁹ However, the actions and contributions of various adipocytokines have not been fully elucidated.

Excess intra-abdominal (visceral) fat is particularly hazardous because it is less sensitive to insulin than subcutaneous fat-ie, its lipolysis is less easily suppressed by insulin.²⁰ Furthermore, lipolysis of visceral fat releases FFAs directly into the portal circulation, resulting in a more pronounced increase in gluconeogenesis.²⁰ Thus, abdominal obesity can contribute to the development of diabetes by processes involving both adipose tissues and the liver.

Genetics Versus Environment

Twin and familial studies suggest that individuals with type 2 diabetes have a genetic susceptibility to insulin resistance and/or beta-cell dysfunction.¹⁸ Monozygotic twins have approximately 70% concordance for type 2 diabetes, while other siblings have only about 35% concordance.²⁴ Offspring of one parent with diabetes have up to a 40% lifetime risk of type 2 diabetes; offspring of 2 parents with diabetes have an 80% lifetime risk.²⁴

Because there is less than 100% concordance for monozygotic twins, environmental (eg, lifestyle) factors must also play a role. The role of lifestyle is supported by a longitudinal observational study of more than 42,500 healthy men, comparing the effects of 2 carefully defined dietary patterns labeled as "Western" (characterized by higher consumption of red meat, processed meats, french fries, high-fat dairy products, refined grains, sweets, and desserts) versus "prudent" (characterized by higher consumption of vegetables, fruit, fish, poultry, and whole grains).²⁵ Higher Western dietary pattern scores (WDPS) were associated with an increased risk for diabetes.²⁵ A combination of high WDPS plus low physical activity increased the risk still further.²⁵ Diet also was shown to interact with family history.²⁵ The presence of both environmental and genetic factors in the development of diabetes suggests that periodic evaluation of asymptomatic adults should include discussions about diet, physical activity habits, as well as family history of diabetes and other metabolic conditions.

In addition to poor diet and physical inactivity, additional risk factors for diabetes include smoking, hypertension, and high blood cholesterol.²⁶

Current Standards for Screening and Diagnosis

As noted previously, type 2 diabetes is widely underdiagnosed, and with the rise in obesity and sedentary lifestyles, timely screening is increasing in importance. Early intervention in prediabetes has been shown to reduce the incidence of overt diabetes.²⁷

Furthermore, early intensive management of diabetes can reduce hospitalizations and delay or minimize both microvascular and macrovascular complications.

^28-31 Yet, 5% of the adult population has undiagnosed, and therefore untreated, diabetes.² Clearly, attempts to reduce morbidity and mortality from diabetes and its complications must begin with large-scale efforts to increase screening and diagnosis.

Screening

The ADA recommends that screening be considered in asymptomatic adults of any age who are overweight or obese (body mass index >25 kg/m2) and have 1 or more additional risk factors for type 2 diabetes.³² In asymptomatic adults without these risk factors, screening should begin at age 45. If the tests are normal, they should be repeated at 3-year intervals (or more frequently if indicated). At present, a fasting plasma glucose (FPG) test, a 2-hour oral glucose tolerance test (OGTT), or an A1C measurement can be used to screen for diabetes.

Andrew Ahmann:

Diabetes is such a pervasive disease with monumental ramifications and it affects such a large number of individuals. As an endocrinologist, I'm trying to find some balance between the need for a systematic and specialty care approach for diabetes because I see a real need for both, they need to be better coordinated. Likewise, there must be balance between the more costly and less costly therapies, depending on specific attributes of individual agents. For example, new therapies do provide some real options that I think are beneficial to individual patients.

For asymptomatic children who are overweight or obese and who have more than 2 additional risk factors for type 2 diabetes, the ADA recommends screening (preferably with FPG) starting at age 10 or onset of puberty (whichever comes first) and repeated at 3-year intervals. Screening is not recommended for children without these risk factors.³²

Diagnosis

Diagnosis of diabetes traditionally relied on FPG or a 2-hour OGTT. By ADA criteria, FPG >126 mg/dL or an OGTT 2-hour value of >200 mg/dL indicates diabetes.³³ The 2010 Clinical Practice Recommendations, however, now include A1C level as a diagnostic criterion for diabetes.³² An A1C value of >6.5% has been established as the cut point. Current ADA criteria for the diagnosis of diabetes and prediabetes are shown in Table 2.

Diagnostic problems, especially in primary care, include the difficulty of incorporating OGTT into routine examinations and false-negative results with FPG. It is possible that false-negative FPGs could contribute to late diagnosis or underdiagnosis of diabetes in the United States. When FPG results are in the normal range for patients who are at risk for diabetes because of coexisting conditions (eg, obesity, older age, hypertension, dyslipidemia), it is prudent not to rule out diabetes without further investigation. This investigation might include an A1C measurement or OGTT.

Glenda Owens:

Diabetes is one of the hardest diseases for me as a pharmacist of a health plan to manage. Diabetes management is directly linked to patient responsibility and it is very difficult to control behavior. Several of our plans are in southern states, where diabetes is very prevalent; Texas is an especially difficult area to manage due to multicultural issues.

The Role of A1C in Diagnosis

A1C has traditionally been used only for monitoring glycemia in people with diabetes, not for diagnosing the disease. However, in 2009, an International Expert Committee-appointed by the ADA, European Association for the Study of Diabetes, and International Diabetes Federation-issued a consensus statement recommending use of A1C to diagnose diabetes.³⁴

The committee cited several advantages of A1C over

FPG or OGTT³⁴:

• A1C is now better standardized than glucose measurement.
• A1C is a better index of glycemic exposure and risk for chronic complications.
• A1C has less biologic variability and more preanalytic stability than glucose.
• A1C does not require fasting or timed samples.
• A1C is relatively unaffected by acute changes in glucose levels (eg, due to stress or illness).

Because retinopathy risk increases substantially between A1C levels of 6.0% and 7.0%, an A1C of 6.5% was recommended as the cut point for diagnosis of diabetes.³⁴

The use of A1C to define prediabetes is problematic, because no A1C threshold has been identified below which there is no diabetes risk.³⁴ The committee recommended that A1C >6.0% should prompt preventive measures (ie, lifestyle changes).³⁴ More recently, the ADA established that an A1C level between 5.7% and 6.4% indicates prediabetes.³²

It should be noted that A1C cannot be interpreted accurately in people with certain hemoglobinopathies (eg, sickle cell), or any condition that alters red cell turnover (eg, hemolytic anemia, blood loss or transfusion, pregnancy). In such cases, traditional diagnostic tests should be used.³²

The Status of Diabetes Care: How Well Are We Doing?

Figure 3

NHANES data from 1994-2004 were analyzed to determine the proportion of people with diagnosed diabetes who had achieved the ADA goal of A1C <7%. Overall, goal achievement increased significantly-from 37.0% in 1999-2000 to 56.8% in 2003-2004. However, there were substantial disparities among ethnic groups, with African Americans and Mexican Americans less often achieving their goals compared with whites. Furthermore, although goal achievement among those minority populations improved between 1999-2000 and 2001-2002, no improvement occurred between 2001-2002 and 2003-2004 ().³⁵

Although the overall improvement is encouraging, more than 43% of US adults with diagnosed diabetes were still not achieving their A1C goals. From a population perspective, this cannot be considered adequate control of diabetes. The disparity between whites and ethnic minorities suggests that efforts targeting those minority populations are especially needed.

In addition to glycemic control, proper patient centered treatment considers other factors. Control of blood pressure in persons with diabetes can decrease the risks of microvascular and macrovascular complications by at least 33%; control of LDL cholesterol can decrease cardiovascular complications by 20% to 50%.⁴ Multiphasic treatment can be very successful in reducing complications, even if all the metabolic goals are not met.^36,37 Nonetheless, more aggressive metabolic control can only lead to greater benefits.

Unfortunately, a study in primary care patients with diabetes revealed discouraging results for control of blood pressure, LDL levels, and A1C.³⁴ Of the patients studied, only 40.5% had reached A1C <7%, 35.3% had blood pressure <130/85 mm Hg, and 43.7% had LDL <100 mg/dL. Only 7%, a distressingly low percentage, achieved all 3 goals.³⁸ With the high risk of vascular complications and resulting mortality, early and ongoing treatment of other major risk factors is essential for optimal care of persons who have diabetes.

Diagnosis of type 2 diabetes in all who meet the criteria remains a challenge. A diagnosis of prediabetes should ensure that healthcare professionals will provide patient education about lifestyle changes and careful monitoring. A diagnosis of overt diabetes should ensure regular monitoring and prescription medications. The ADA recommends that all newly diagnosed patients with type 2 diabetes be started on metformin therapy along with lifestyle changes, self-care training and follow-up, and increased attention to all other medical conditions and cardiovascular risk factors. Until all Americans with glycemic abnormalities receive this level of attention and care, the prevalence of diabetes is likely to increase along with diabetic progression, complications, and related mortality.

Conclusion

Type 2 diabetes is a highly prevalent and underdiagnosed disease, and its prevalence is increasing both in the United States and worldwide. A major cause of morbidity and mortality, diabetes is also a very costly disease in terms of both economic costs and QOL. Despite the development of new treatment options, control of diabetes remains suboptimal.

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